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The lack of a randomized trial comparing carfilzomib (K) versus elotuzumab (Elo) associated with lenalidomide and dexamethasone (Rd) prompted us to assess the relative usefulness of one triplet over the other. Five independent retrospective cohorts of 883 relapsed/refractory multiple myeloma (RRMM) patients, including 300 EloRd and 583 KRd cases, outside clinical trials, entered this non-randomized comparison. KRd cohort accounted for a higher incidence of younger patients, cases with ≥3 lines of therapy, already exposed to lenalidomide, International Staging System (ISS) stage III, and abnormal lactic dehydrogenase (LDH) level compared with EloRd cohort. Moreover, cytogenetic risk categories, detected in roughly one-third of cases, were equally distributed between the two therapy arms. The probability of CR+VGPR response was significantly higher in KRd (n = 314, 53.9%) than in EloRd patients (n = 111, 37.0%). Likewise, the cumulative incidence function of CR+VGPR, taking into account the competitive risk of death, was significantly higher in KRd arm patients than those in the EloRd arm (p = .003). Moreover, KRd treatment significantly reduced the progression or death risk by 46% in an adjusted multivariate analysis (HR: 0.54, 95% CI 0.42-0.69, p .0001). Finally, in an adjusted illness-progression/death model, the effect of KRd versus EloRd was of higher magnitude among those who achieved CR+VGPR (-39% hazard ratio reduction, p = .02) than among those who achieved VGPR (-29% hazard ratio reduction, p = .007). With limitations characteristic to any retrospective analysis, this current clinical practice study's overall results demonstrated potential benefits of KRd therapy compared with EloRd. This observation may help the daily clinical practice.

Vaccination is one of the most successful medical interventions that has saved the life of millions of people. Vaccination is particularly important in patients with multiple myeloma, who have an increased risk of infections due to the disease-inherent immune suppression, and because of the immune suppressive effects of therapy. Hence, all appropriate measures should be exploited, to elicit an effective immune response to common pathogens like influenza, pneumococci, varicella zoster virus, and to those bacteria and viruses (haemophilus influenzae, meningococci, and hepatitis) that frequently may pose a significant risk to patients with multiple myeloma. Patients after autologous, and specifically after allogeneic transplantation have severely reduced antibody titers, and therefore require a broader spectrum of vaccinations. Response to vaccination in myeloma often is less vigorous than in the general population, mandating either measurement of the postvaccination antibody titers and/or repeating the vaccination. Here, we compile the existing data on vaccination in multiple myeloma and provide recommendations for clinical practice. ispartof: LEUKEMIA vol:35 issue:1 pages:31-44 ispartof: location:England status: published

Minimal residual disease (MRD) monitoring by PCR methods is a strong and standardized predictor of clinical outcome in mantle cell lymphoma (MCL) and follicular lymphoma (FL). However, about 20% of MCL and 40% of FL patients lack a reliable molecular marker, being thus not eligible for MRD studies. Recently, Targeted Locus Amplification (TLA), a next generation sequencing (NGS) method based on the physical proximity of DNA sequences for target selection, identified novel gene rearrangements in leukemia. The aim of this study was to test TLA in MCL and FL diagnostic samples lacking a classical, PCR-detectable, t(11;14) MTC (BCL1/IGH) or t(14;18) MBR and MCR (BCL2/IGH) rearrangements. Overall, TLA was performed on 20 MCL bone marrow (BM) or peripheral blood (PB) primary samples and on 20 FL BM, identifying a novel BCL1 or BCL2/IGH breakpoint in 16 MCL and 8 FL patients (80% and 40%, respectively). These new breakpoints (named BCL1-TLA and BCL2-TLA) were validated by ASO primers design and compared as MRD markers to classical IGH rearrangements in 8 MCL: overall, MRD results by BCL1-TLA were superimposable (R Pearson=0,76) to the standardized IGH-based approach. Moreover, MRD by BCL2-TLA reached good sensitivity levels also in FL and was predictive of a primary refractory case. In conclusion, this study offers the proof of principle that TLA is a promising and reliable NGS-based technology for the identification of novel molecular markers, suitable for further MRD analysis in previously not traceable MCL and FL patients. This article is protected by copyright. All rights reserved.

Two hundred twenty-eight patients were observed for a median of 62.9 months. By study design, PET/CT scans were performed at baseline and before starting maintenance (premaintenance [PM]). The five-point Deauville scale (DS) was applied to describe BM (BM score [BMS]) and focal lesion (FL; FL score [FS]) uptake and tested a posteriori in uni- and multivariable analyses for their impact on clinical outcomes.At baseline, 78% of patients had FLs (11% extramedullary), 80% with an FS ≥ 4. All patients had BM diffuse uptake (35.5% with BMS ≥ 4). At PM, 31% of patients had visually detectable FLs (2% extramedullary), 24% and 67.7% of them with an FS of 3 and ≥ 4, respectively. At PM, 98% of patients retained residual BM diffuse uptake, which was significantly lower than at baseline (mainly between BMS 2 and 3, BMS was ≥ 4 in only 8.7% of patients). By both uni- and multivariable analysis, FS and BMS4 were associated with prolonged progression-free survival (PFS) and overall survival (OS) at PM (OS: hazard ratio [HR], 0.6 and 0.47, respectively; PFS: HR, 0.36 and 0.24, respectively).FL and BM FDG uptake lower than the liver background after therapy was an independent predictor for improved PFS and OS and can be proposed as the standardized criterion of PET complete metabolic response, confirming the value of the DS for patients with MM.

Minimal residual disease (MRD) detection represents a sensitive tool to appropriately measure the response obtained with therapies for multiple myeloma (MM). The achievement of MRD negativity has superseded the conventional complete response (CR) and has been proposed as a surrogate endpoint for progression-free survival and overall survival. Several techniques are available for the detection of MRD inside (next-generation sequencing, flow cytometry) and outside (PET/CT, magnetic resonance) the bone marrow, and their complementary use allows a precise definition of the efficacy of anti-myeloma treatments. This review summarizes MRD data and results from previous clinical trials, highlights open issues related to the role of MRD in MM and discusses how MRD could be implemented in clinical practice to inform on patient prognosis and drive therapeutic decisions.

We analyzed variations in terms of chromosomal abnormalities (CA) by fluorescence in situ hybridization (FISH) analysis on purified bone marrow plasma cells throughout the progression from monoclonal gammopathy of undetermined significance/smoldering multiple myeloma (MGUS/SMM) to newly diagnosed MM/plasma cell leukemia (NDMM/PCL) at diagnosis and from diagnostic samples to progressive disease. High risk was defined by the presence of at least del(17p), t(4;14), and/or t(14;16). 1p/1q detection (in the standard FISH panel from 2012 onward) was not available for all patients. We analyzed 139 MM/PCL diagnostic samples from 144 patients, with a median follow-up of 71 months: high-risk CA at diagnosis (MGUS/SMM or NDMM) was present in 28% of samples, whereas 37–39% showed high-risk CA at relapse. In 115 patients with NDMM who evolved to relapsed/refractory MM, we identified 3 different populations: (1) 31/115 patients (27%) with gain of new CA (del13, del17p, t(4;14), t(14;16) or 1q CA when available); (2) 10/115 (9%) patients with loss of a previously identified CA; and (3) 74 patients with no changes. The CA gain group showed a median overall survival of 66 months vs. 84 months in the third group (HR 0.56, 95% CI 0.34–0.92, p = 0.023). Clonal evolution occurs as disease progresses after different chemotherapy lines. Patients who acquired high-risk CA had the poorest prognosis. Our findings highlight the importance of performing FISH analysis both at diagnosis and at relapse.

Patients with multiple myeloma (MM) seem to be at increased risk for more severe COVID-19 infection and associated complications due to their immunocompromised state, the older age and comorbidities. The European Myeloma Network has provided an expert consensus statement in order to guide therapeutic decisions in the era of the COVID-19 pandemic. Patient education for personal hygiene and social distancing measures, along with treatment individualization, telemedicine and continuous surveillance for early diagnosis of COVID-19 are essential. In countries or local communities where COVID-19 infection is widely spread, MM patients should have a PCR test of nasopharyngeal swab for SARS-CoV-2 before hospital admission, starting a new treatment line, cell apheresis or ASCT in order to avoid ward or community spread and infections. Oral agent-based regimens should be considered, especially for the elderly and frail patients with standard risk disease, whereas de-intensified regimens for dexamethasone, bortezomib, carfilzomib and daratumumab should be used based on patient risk and response. Treatment initiation should not be postponed for patients with end organ damage, myeloma emergencies and aggressive relapses. Autologous (and especially allogeneic) transplantation should be delayed and extended induction should be administered, especially in standard risk patients and those with adequate MM response to induction. Watchful waiting should be considered for standard risk relapsed patients with low tumor burden, and slow biochemical relapses. The conduction of clinical trials should continue with appropriate adaptations to the current circumstances. Patients with MM and symptomatic COVID-19 disease should interrupt anti-myeloma treatment until recovery. For patients with positive PCR test for SARS-CoV-2, but with no symptoms for COVID-19, a 14-day quarantine should be considered if myeloma-related events allow the delay of treatment. The need for surveillance for drug interactions due to polypharmacy is highlighted. The participation in international COVID-19 cancer registries is greatly encouraged.

Autoimmune phenomena are frequently observed in patients with chronic lymphocytic leukemia (CLL) and are mainly attributable to underlying dysfunctions of the immune system. Autoimmune cytopenias (AIC) affect 4–7% of patients with CLL and mainly consist of autoimmune hemolytic anemia and immune thrombocytopenia. Although less common, non-hematological autoimmune manifestations have also been reported. Treatment of CLL associated AIC should be primarily directed against the autoimmune phenomenon, and CLL specific therapy should be reserved to refractory cases or patients with additional signs of disease progression. New targeted drugs (ibrutinib, idelalisib and venetoclax) recently entered the therapeutic armamentarium of CLL, showing excellent results in terms of efficacy and became an alternative option to standard chemo-immunotherapy for the management of CLL associated AIC. However, the possible role of these drugs in inducing or exacerbating autoimmune phenomena still needs to be elucidated. In this article, we review currently available data concerning autoimmune phenomena in patients with CLL, particularly focusing on patients treated with ibrutinib, idelalisib, or venetoclax, and we discuss the possible role of these agents in the management of AIC.

Background: Novel agents have recently questioned the role of both autotransplantation and consolidation therapy after intensification in newly diagnosed multiple myeloma. We prospectively compared intensification with transplantation versus bortezomib-melphalan-prednisone (VMP), and bortezomib-lenalidomide-dexamethasone (VRD) consolidation versus no consolidation. Methods: In this randomized, open-label, phase 3 study we recruited previously untreated myeloma patients aged up to 65 years at 172 sites of the European Myeloma Network. Patients were first randomized (1:1) to VMP (4 cycles) or transplantation, and afterwards to VRD consolidation (2 cycles) or no consolidation, followed by lenalidomide-maintenance. Progression-free survival from first and second randomization were primary endpoints. Comparison of single versus double transplantation was a secondary endpoint. Findings: Between February, 2011 and April, 2014, 1503 patients were enrolled. Overall, 1197 patients were eligible for the first randomization: 702 received transplantation and 495 VMP; 877 patients underwent the second randomization: 449 received VRD consolidation and 428 no consolidation. Progression-free survival from first randomization was significantly better with transplantation than with VMP (median, 56·7 versus 41·9 months; hazard ratio [HR] 0·73, 95% CI 0·62-0·85, p=0·0001). VRD consolidation prolonged median progression-free survival from second randomization compared with no consolidation (58·9 versus 45.5 months; HR 0·77, 95% CI 0·63-0·95, p=0·014). Overall survival estimates at 5 years were 75% with transplantation and 71·6% with VMP (HR 0·90, 95% CI 0·71-1.13, p=0·35). Double transplantation significantly prolonged progression-free survival (HR 0·74, 95% CI 0·56-0·98, p=0·036) and overall survival (HR 0·62, 95% CI 0·41-0·93, p=0·022) compared to a single transplantation. The rate of at least one grade ≥3 adverse event was 88% with transplantation versus 52% with VMP. Transplant-related mortality was 1%. Interpretation: In newly diagnosed myeloma patients, intensification therapy with transplantation significantly prolonged progression-free survival compared with VMP, although overall survival was similar. After intensification, VRD consolidation significantly improved progression-free survival compared with no consolidation. Trial Registration: This trial is registered with ClinicalTrials.gov, number NCT01208766. Funding Statement: The Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) sponsored and designed this study. Janssen and Celgene provided bortezomib and lenalidomide free of charge, respectively, and provided funding, but had no role in the analysis or interpretation of the data. Declaration of Interests: Michele Cavo: receives honoraria from Janssen, Celgene, Amgen, Bristol-Myers Squibb, Takeda, AbbVie, Sanofi, Adaptive Biotechnologies, and is a member of Janssen’s and Celgene’s Speaker’s Bureau. Francesca Gay: receives honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, Roche, AbbVie. Meral Beksac: receives honoraria from Celgene, Janssen, Sanofi, Takeda, Amgen, and is a member of Celgene’s, Janssen’s, Takeda’s, Amgen’s Speaker Bureau Lucia Pantani: receives honoraria from Celgene, Janssen, Takeda, Amgen Maria Teresa Petrucci: receives honoraria from Celgene, Janssen-Cilag, Bristol-Myers Squibb, Amgen, Takeda, Sanofi. Meletios A Dimopoulos: receives honoraria from Amgen, Takeda, Celgene, Bristol-Myers Squibb, Janssen. Luca Dozza: NO COI. Bronno van der Holt: NO COI Stefania Oliva: receives honoraria from Amgen, Celgene, Janssen, Adaptive Biotechnologies, Takeda. Vincent H.J. van der Velden: NO COI. Elena Zamagni: receives honoraria from Janssen, Bristol-Myers Squibb, Amgen, Takeda. Giuseppe A. Palumbo: receives honoraria from Amgen, Celgene, Jannsen, Novartis Francesca Patriarca: receives honoraria from Celgene, Janssen. Vittorio Montefusco: receives honoraria, travel support and research funding from Celgene, Janssen. Monica Galli: receives honoraria from Bristol-Meyers-Squibb, Celgene, Janssen, Leadiant, Takeda. Vladimir Maisnar : receives honoraria from Janssen, Amgen, Celgene, Takeda, and is a member of the Board of Directors or advisory committees for Janssen, Amgen, Celgene, Bristol-Myers Squibb, Takeda. Barbara Gamberi: receives honoraria from Amgen, Celgene, Sanofi, Janssen Stig Lenhoff: NO COI Angelo Belotti : receives honoraria from Jannsen, Celgene, Amgen. Ludek Pour: NO COI. Paula Ypma: NO COI. Mariella Grasso: NO COI. Sandra Croockewit: NO COI. Stelvio Ballanti: receives honoraria from Celgene, Janssen. Massimo Offidani: receives honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda. Donata Vincelli: NO COI. Renato Zambello: receives honoraria from Jannsen, Celgene. Anna Marina Liberati: receives research funding from Novartis, Janssen, Abbvie, Roche, Amgen, Celgene; receives honoraria from Abbvie, Amgen, Takeda, Servier; is a consultant for Incyte Niels Frost Andersen: NO COI. Sonja Zweegman: receives honoraria from Celgene, Sanofi, Takeda, Janssen, and research funding from Celgene, Takeda, Janssen. Rossella Troia: NO COI. Anna Pascarella: NO COI. Giulia Benevolo: receives honoraria from Novartis, Celgene, Amgen. Mark-David Levin: receives honoraria and travel support from Takeda, Janssen, Celgene, AmgenGerard Bos: NO COI. Heinz Ludwig: receives honoraria from Janssen, Celgene, Amgen, Sanofi, Bristol-Meyers Squibb, Seattle Genetics, is a member of Janssen’s, Celgene’s, Amgen’s, Sanofi’s, Bristol-Meyers Squibb’s, Seattle Genetics’s speakers bureau, and receives research funding from Amgen, Takeda Sara Aquino: receives honoraria from Amgen, Celgene, Janssen. Anna Maria Morelli: NO COI. Ka Lung Wu: NO COI. Rinske Boersma: NO COI. Roman Hajek: receives honoraria, and research funding from Amgen, Takeda, Celgene, Janssen, Abbvie, Novartis, PharmaMar, Bristol-Myers Squibb. Marc Durian: NO COI. Peter A von dem Borne: NO COI. Tommaso Caravita di Toritto: receives honoraria from Celgene, Janssen, Amgen. Christoph Driessen: NO COI. Giorgina Specchia: NO COI. Anders Waage: receives honoraria from Janssen, Takeda. Peter Gimsing: NO COI. Ulf-Henrik Mellqvist: receives honoraria from Amgen, Sanofi, Oncopeptides, Janssen, Takeda, Celgene. Marinus van Marwijk Kooy: NO COI. Monique Minnema: receives honoraria from Celgene, Amgen, Novartis, Servier, Jansen Cilag, Gilead, and receives research funding from Celgene. Caroline Mandigers: NO COI. Anna Mario Cafro: NO COI. Angelo Palmas: receives honoraria from Amgen, Janssen, Celgene, Takeda. Susanna Carvalho: NO COI. Andrew Spencer: is a Consultant for Celgene, Janssen, Secura Bio, Specialised Therapeutics Australia, AbbVie, Servier, Haemalogix, Sanofi; is a member of Celgene’s, Jannsen’s, Takeda’s Speaker’s Bureau; receives research funding from Celgene, Janssen, Amgen, Takeda, Servier, Haemalogi; receives honoraria from Celgene, Janssen, Amgen, Takeda, Secura Bio, Specialised Therapeutics Australia, AbbVie, Servier, Haemalogix, Sanofi Mario Boccadoro: receives honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, BristolMyers Squibb, AbbVie; receives research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, Mundipharma. Pieter Sonneveld: receives honoraria from Amgen, BMS, Celgene, Janssen, Karyopharm, Takeda, and receives research funding from Amgen, Celgene, Janssen, Karyopharm, SkylineDx, Takeda. Ethics Approval Statement: All patients provided written informed consent. The study was approved by the independent ethics committee or institutional review board at all participating sites and was done in accordance with International Conference on Harmonisation guidelines on Good Clinical Practice and the principles of the Declaration of Helsinki.

Immunotherapy is increasingly used in the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) are safe and effective ways to elicit immunotherapeutic responses. In 2015, daratumumab has become the first mAb approved by the Food and Drug Administration for clinical use in MM and, in the last 5 years, a lot of clinical and preclinical research has been done to optimize the use of this drug class. Currently, mAbs have already become part of standard-of-care combinations for the treatment of relapsed/refractory MM and very soon they will also be used in the frontline setting. The success of simple mAbs (‘naked mAbs’) prompted the development of new types of molecules. Antibody–drug conjugates (ADCs) are tumor-targeting mAbs that release a cytotoxic payload into the tumor cells upon antigen binding in order to destroy them. Bispecific antibodies (BiAbs) are mAbs simultaneously targeting a tumor-associated antigen and an immune cell-associated antigen in order to redirect the immune cell cytotoxicity against the tumor cell. These different constructs produced solid preclinical data and promising clinical data in phase I/II trials. The aim of this review article is to summarize all the recent developments in the field, including data on naked mAbs, ADCs and BiAbs.

Purpose: Duration of first remission is important for the survival of patients with multiple myeloma. Experimental Design: From the CoMMpass study (NCT01454297), 926 patients with newly diagnosed multiple myeloma, characterized by next-generation sequencing, were analyzed to evaluate those who experienced early progressive disease (PD; time to progression, TTP ≤18 months). Results: After a median follow-up of 39 months, early PD was detected in 191/926 (20.6%) patients, 228/926 (24.6%) patients had late PD (TTP >18 months), while 507/926 (54.8%) did not have PD at the current follow-up. Compared with patients with late PD, patients with early PD had a lower at least very good partial response rate (47% vs. 82%, P < 0.001) and more frequently acquired double refractoriness to immunomodulatory drugs (IMiD) and proteasome inhibitors (PI; 21% vs. 8%, P < 0.001). Patients with early PD were at higher risk of death compared with patients with late PD and no PD (HR, 3.65; 95% CI, 2.7–4.93; P < 0.001), showing a dismal median overall survival (32.8 months). In a multivariate logistic regression model, independent factors increasing the early PD risk were TP53 mutation (OR, 3.78, P < 0.001), high lactate dehydrogenase levels (OR, 3.15, P = 0.006), λ-chain translocation (OR, 2.25, P = 0.033), and IGLL5 mutation (OR, 2.15, P = 0.007). Carfilzomib-based induction (OR, 0.15, P = 0.014), autologous stem-cell transplantation (OR, 0.27, P < 0.001), and continuous therapy with PIs and IMiDs (OR, 0.34, P = 0.024) mitigated the risk of early PD. Conclusions: Early PD identifies a high-risk multiple myeloma population. Further research is needed to better identify baseline features predicting early PD and the optimal treatment approaches for patients at risk.

BACKGROUND: Multiple Myeloma (MM) maintenance therapy is a low intensive, prolonged treatment, commonly administered to newly diagnosed patients (pts) at the end of front-line regimens. Lenalidomide (LEN) is considered the best available maintenance option for MM, the actual benefits or disadvantages of a LEN-based maintenance and its potential role as “selective pressure” on MM sublcones are still unclear. AIM: In this study we estimated the role of LEN maintenance therapy in eliciting genomic changes in a cohort of MM pts homogeneously up-front treated. PATIENTS-METHODS: Whole genome Copy Number Alterations (CNA) was obtained by SNPs array in 54 pts samples collected both at diagnosis(D) and at first relapse(R). Pts had an high-risk (HR) disease, defined by a median TTP of 29m. A custom gene-level CN calling algorithm was set up, to compute the evolution of every gene CN value and the genomic evolutive trajectories associated to changes of these values. High-risk genomic loci were defined using GISTIC to derive target genomic relevant for MM biology. After PIs induction therapy, 31/54 pts were treated with HD chemotherapy followed by either single or double ASCT; LEN maintenance therapy was then offered both to 20/31 auto-transplanted and to 6/23 not auto-transplanted pts. RESULTS: Three main evolutive trajectories (linear L, drift D, and branching B) were defined according to the CN changes' direction, reflecting a putative positive, negative, or both positive and negative selective pressure, respectively. A fourth, stable (S) trajectory was also observed, characterized by the absence of CN changes. Overall, 29, 15 and 10 pts relapsed with B/D, L and S pattern, respectively; at R, all LEN-treated pts changed their sub-clonal architecture: a B/D evolutive pattern characterized 70% of pts. By contrast, genome remained mostly stable in 61% of not-treated pts. We then focused on CN changes of specific chromosomal regions and/or genomic loci identified as high-risk, whose prognostic role has been already established in MM (i.e. TP53, CDKN2C, CKS1B). When present at D, these CNA tended to persist throughout the disease course, regardless of whether pts received or not maintenance. The emersion of any of these CNAs at R was widely observed both in pts receiving or not maintenance, whereas a negative selective pressure over them was more likely to occur in pts receiving maintenance, as compared to the others (50% vs 11% of B/D trajectories in LEN-treated vs not-treated pts, respectively). Strikingly, in LEN-treated pts, the extension of both TTP and OS was favored by the extinction and/or negative selection (B/D patterns) of the HR CNAs, and shortened by their stability or positive selection (L/S patterns) (median TTP 46 vs 32m HR=3.6, p=0.01; median OS 111 vs 63m HR 5.7, p=0.04 in B/D vs L/S pts, respectively). On the contrary, the absence of maintenance selective pressure seemed to affect neither the evolution trajectory, nor the clinical course of not-treated pts. CONCLUSION: The extinction of sub-clones carrying HR lesions in pts receiving maintenance therapy is likely to be associated to the negative selection exerted by the therapy. This might explain the extended survival of these pts. On the contrary, the subclones of pts not receiving maintenance might randomly evolve, due to the absence of a specific selective pressure. Citation Format: Andrea Poletti, Vincenza Solli, Marina Martello, Enrica Borsi, Lucia Pantani, Agboyi Lakpo, Silvia Armuzzi, Luca Nunzio Cifarelli, Elena Zamagni, Paola Tacchetti, Serena Rocchi, Katia Mancuso, Ilaria Rizzello, Giulia Marzocchi, Nicoletta Testoni, Luca Dozza, Maria Teresa Petrucci, Anna Marina Liberati, Giuseppe Rossi, Mario Boccadoro, Michele Cavo, Carolina Terragna. Negative selective pressure exerted by maintenance therapy promotes the extinction of sub-clones carrying high-risk lesions in multiple myeloma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2700.

Simple Summary Choosing the optimal therapy for elderly patients with multiple myeloma (MM) poses a difficult challenge for clinicians. Older patients are an extremely heterogeneous population, they are underrepresented in clinical trials, and data on octogenarians have been mainly limited to real-life settings. Treatment options for intermediate and frail patients might include dose-adapted combinations and less toxic combinations based on novel agents. Moreover, the discriminative power of the International Myeloma Working Group (IMWG) frailty score in detecting frailty and vulnerability could be improved by combining together aging-related factors (performance status, comorbidities, functional status) with disease-related factors (International Staging System stage, cytogenetic risk). Objective parameters could improve the reproducibility of this score and limit the subjectivity determined by patient-reported questionnaires on functional evaluations. Efforts are ongoing to simplify the IMWG frailty score and expand its use in real-life clinical practice. Abstract Multiple myeloma (MM) mostly affects elderly patients, which represent a highly heterogeneous population. Indeed, comorbidities, frailty status and functional reserve may vary considerably among patients with similar chronological age. For this reason, the choice of treatment goals and intensity is particularly challenging in elderly patients, and it requires a multidimensional evaluation of the patients and the disease. In recent years, different tools to detect patient frailty have been developed, and the International Myeloma Working Group frailty score currently represents the gold standard. It identifies intermediate-fit and frail patients requiring gentler treatment approaches compared to fit patients, aiming to preserve quality of life and prevent toxicities. This subset of patients is underrepresented in clinical trials, and studies exploring frailty-adapted approaches are scarce, making the choice of therapy extremely challenging. Treatment options for intermediate-fit and frail patients might include dose-adapted combinations, doublets, and less toxic combinations based on novel agents. This review analyzes the available tools for the assessment of frailty and possible strategies to improve the discriminative power of the scores and expand their use in real-life and clinical trial settings. Moreover, it addresses the main therapeutic challenges in the management of intermediate-fit and frail MM patients at diagnosis and at relapse.

Immunotherapy is the latest innovation for the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) entered the clinical practice and are under evaluation in clinical trials. MAbs can target highly selective and specific antigens on the cell surface of MM cells causing cell death (CD38 and CS1), convey specific cytotoxic drugs (antibody-drug conjugates), remove the breaks of the immune system (programmed death 1 (PD-1) and PD-ligand 1/2 (L1/L2) axis), or boost it against myeloma cells (bi-specific mAbs and T cell engagers). Two mAbs have been approved for the treatment of MM: the anti-CD38 daratumumab for newly-diagnosed and relapsed/refractory patients and the anti-CS1 elotuzumab in the relapse setting. These compounds are under investigation in clinical trials to explore their synergy with other anti-MM regimens, both in the front-line and relapse settings. Other antibodies targeting various antigens are under evaluation. B cell maturation antigens (BCMAs), selectively expressed on plasma cells, emerged as a promising target and several compounds targeting it have been developed. Encouraging results have been reported with antibody drug conjugates (e.g., GSK2857916) and bispecific T cell engagers (BiTEs®), including AMG420, which re-directs T cell-mediated cytotoxicity against MM cells. Here, we present an overview on mAbs currently approved for the treatment of MM and promising compounds under investigation.

Therapeutic re-challenge is currently a debated issue in the field of multiple myeloma (MM), given the recent availability of several new drugs and combinations. However, very few specific evidences are available about bortezomib re-use at first relapse. This multicenter, observational, retrospective study enrolled 134 MM patients with significant response after bortezomib-based frontline regimens and who had received a first salvage treatment containing bortezomib at relapse. The overall response rate was 71%, including 40% partial responses, 24% very good partial responses, and 7% complete responses. Re-treatment was well-tolerated, with no significant new or unexpected toxicities observed. The median duration of second progression-free survival (PFS) was 15 months, while median PFS2 was 55 months. With a median follow-up of 56 months, overall survival was 94 months for the entire series, without significant differences between patients undergoing or not undergoing transplant procedures. This real-life survey indicates that re-treatment including bortezomib as a first salvage therapy could be still considered in MM patients achieving durable response after initial exposure to bortezomib.

Early toxic death (≤60 days of diagnosis) in elderly multiple myeloma (MM) patients is attributable to active disease, age and co-morbidities. Rate of early toxic deaths is 10% with conventional chemotherapy mainly due to infection and renal failure. Novel agents have improved MM outcome at the expense of newer toxicity.We analyzed 1146 individual patient data to assess toxic deaths during induction treatment with first-generation novel agents thalidomide, lenalidomide, bortezomib.During first-line therapy, 119/1146 patients (10%) died for any cause, and 47/1146 (4%) due to toxicity, including 12/1146 (1%) early deaths. The 24-month cumulative incidence was 4.1% without any difference between bortezomib (18/503 patients, 4%) and lenalidomide (29/643patients, 5%; p = 0.31). Toxic deaths occurred in 34/1039 (3%) patients80 years and 13/107 (12%) patients ≥80 years. Causes were cardiac events (28%), infections (26%) and vascular complications (15%). In a multivariate analysis, older age and unfavorable ISS stage increased the risk of death.First-generation novel agents significantly reduced toxic deaths compared to conventional chemotherapy. One third of deaths during first-line therapy were due to cumulative drug-related toxicities, thus supportive approaches and prevention strategies should be optimized. The higher mortality rate for toxicity in octogenarians confirms the need for a careful frailty assessment.

We here describe a novel method for MYD88L265P mutation detection and minimal residual disease monitoring in Waldenstrom macroglobulinemia, by droplet digital polymerase chain reaction, in bone marrow and peripheral blood cells, as well as in circulating cell-free DNA. Our method shows a sensitivity of 5.00×10−5, which is far superior to the widely used allele-specific polymerase chain reaction (1.00×10−3). Overall, 291 unsorted samples from 148 patients (133 with Waldenstrom macroglobulinemia, 11 with IgG lymphoplasmacytic lymphoma and 4 with IgM monoclonal gammopathy of undetermined significance) were analyzed: 194 were baseline samples and 97 were followup samples. One hundred and twenty-two of 128 (95.3%) bone marrow and 47/66 (71.2%) baseline peripheral blood samples scored positive for MYD88L265P. To investigate whether MYD88L265P detection by droplet digital polymerase chain reaction could be used for minimal residual disease monitoring, mutation levels were compared with IGH-based minimal residual disease analysis in 10 patients, and was found to be as informative as the classical, standardized, but not yet validated in Waldenstrom macroglobulinemia, IGH-based minimal residual disease assay (r2=0.64). Finally, MYD88L265P detection by droplet digital polymerase chain reaction on plasma circulating tumor DNA from 60 patients showed a good correlation with bone marrow findings (bone marrow median mutational value 1.92×10−2, plasma circulating tumor DNA value: 1.4×10−2, peripheral blood value: 1.03×10−3). This study indicates that droplet digital polymerase chain reaction assay of MYD88L265P is a feasible and sensitive tool for mutation screening and minimal residual disease monitoring in Waldenstrom macroglobulinemia. Both unsorted bone marrow and peripheral blood samples can be reliably tested, as can circulating tumor DNA, which represents an attractive, less invasive alternative to bone marrow for MYD88L265P detection.

Before the introduction of "new drugs," we designed a trial in which 162 newly diagnosed myeloma patients were biologically randomized to receive either an autologous stem cell transplant (auto-SCT) followed by a nonmyeloablative allogeneic stem cell transplant (allo-SCT) or a double auto-SCT. Fifty-eight patients in the allo-SCT arm and 46 in the double auto-SCT arm completed the assigned treatment. At a median follow-up of 12.3 years from allo-SCT and 12.1 years from second auto-SCT, median overall survival (OS) was 11.4 in the allo-SCT arm and 3.9 years in the auto-SCT -arm (P = .007), whereas event-free survival was 3.6 and 1.5 years (P .001), respectively. A subset of allo-SCT patients showed persistent molecular remission. Two-year cumulative incidence of chronic graft-versus-host disease was 67.2%. At 5 years, 39% of these patients were alive, disease-free, and off immunosuppression; 36.6% had relapsed and 12.2% were still on immunosuppression. Thirty-three of 58 patients (allo-SCT arm) and 39 of 46 (auto-SCT arm) relapsed at least once and were rescued with new drugs. In the allo-SCT arm, 2 patients in biochemical relapse did not reach clinical criteria for treatment. Overall 28 (90%) were treated with new drugs and 14 (45%) received donor lymphocyte infusions (DLIs). In 28 of 31 patients (90%) DLIs were given with new drugs. Median OS from first relapse was 7.5 years in the allo-SCT arm and 2 years in the auto-SCT arm (P = .01). Patients who received DLI showed significantly longer OS (hazard ratio, .38; P = .042) as compared with auto-SCT patients. This difference was slightly lower when only allo-SCT patients who did not receive DLIs were considered (hazard ratio, .56; P = .154). In summary, long-term disease-free survival and survival outcomes after treating relapse with new drugs with or without DLIs were better in allo-SCT patients.

Adoptive cellular therapy using chimeric antigen receptor T-cell (CART) therapy is currently being evaluated in patients with relapsed / refractory multiple myeloma (MM). The majority of CAR-T cell programs now being tested in clinical trials are targeting B-cell maturation antigen. Several recent phase I / II trials show promising preliminary results in patients with MM progressing on proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies targeting CD38. CAR-T cell therapy is a potentially life-threatening strategy that can only be administered in experienced centers. For the moment, CAR-T cell therapy for MM is still experimental, but once this strategy has been approved in relapsed/refractory MM, it will become one of the most important indications for this therapy in Europe and world-wide. This manuscript proposes practical considerations for the use of CAR-T cell therapy in MM, and discusses several important issues for its future development. ispartof: HAEMATOLOGICA vol:104 issue:12 pages:2358-2360 ispartof: location:Italy status: published

Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. DARA is approved as monotherapy or in combination with standard-of-care regimens for the treatment of relapsed or refractory multiple myeloma (RRMM). In the primary analysis (median follow-up, 16.9 months) of the phase 3 APOLLO study (NCT03180736), the addition of DARA to pomalidomide and dexamethasone (D-Pd) showed a significant progression-free survival (PFS) improvement over pomalidomide and dexamethasone (Pd) alone in patients (pts) with RRMM (Dimopoulos MA, et al. Lancet Oncol. 2021;22[6]:801-812). Here, we report results from the APOLLO study, including outcomes of pts refractory to lenalidomide based on the last dose of lenalidomide received. Methods: Eligible pts were ≥18 years of age, had RRMM, had received ≥1 prior line of therapy (including both a proteosome inhibitor and lenalidomide), and had responded to prior treatment; pts with only 1 prior line of therapy were required to be refractory to lenalidomide. Pts were randomized 1:1 to Pd ± DARA, stratified via International Staging System disease stage (I vs II vs III) and number of lines of prior therapy (1 vs 2-3 vs ≥4). All pts received 28-day cycles of pomalidomide (4 mg PO daily on Days 1-21) and dexamethasone (40 mg [20 mg for pts ≥75 years of age], PO daily on Days 1, 8, 15, and 22). Pts in the D-Pd group received DARA subcutaneously (DARA SC; 1,800 mg; co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; ENHANZE ® drug delivery technology, Halozyme, Inc.]) or, prior to a protocol amendment, intravenously (DARA IV; 16 mg/kg; n=7) weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter. Pts receiving DARA IV were allowed to switch to DARA SC starting on Day 1 of Cycle 3 or later. All pts were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS. Results: In total, 304 pts were randomized (D-Pd, n=151; Pd, n=153). At the time of randomization, 120 (79.5%) pts in the D-Pd group and 122 (79.7%) pts in the Pd group were refractory to lenalidomide. Among pts refractory to lenalidomide, the last dose of lenalidomide received was 5-10 mg in 30 (25.0%) pts in the D-Pd group and 31 (25.4%) pts in the Pd group and was 15-25 mg in 86 (71.7%) pts in the D-Pd group and 89 (73.0%) pts in the Pd group. With a median follow-up of 16.9 months, the median PFS in the overall population was 12.4 months in the D-Pd group versus 6.9 months in the Pd group (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.47-0.85; P=0.0018); the estimated 18-month PFS rate was 42.1% for the D-Pd group and 25.5% for the Pd group. Among pts refractory to lenalidomide, the median PFS was 9.9 months in the D-Pd group and 6.5 months in the Pd group (HR, 0.66; 95% CI, 0.49-0.90). For lenalidomide-refractory pts who last received a dose of 5-10 mg lenalidomide, the median PFS was 10.3 months for the D-Pd group and 8.5 months for the Pd group (HR, 0.75; 95% CI, 0.41-1.36); for lenalidomide-refractory pts who last received a dose of 15-25 mg lenalidomide, the median PFS was 10.7 months for the D-Pd group and 6.1 months for the Pd group (HR, 0.61; 95% CI, 0.42-0.88) (Figure). Grade 3/4 treatment-emergent adverse events occurred in 130 (87.3%) pts in the D-Pd group and 123 (82.0%) pts in the Pd group; the most frequently reported (≥15% in both groups) were neutropenia (67.8% vs 50.7%), thrombocytopenia (17.5% vs 18.0%), and anemia (16.8% vs 21.3%). Grade 3/4 pneumonia occurred in 20 (13.4%) pts in the D-Pd group and 10 (6.7%) of pts in the Pd group. Serious adverse events occurred in 75 (50.3%) pts in the D-Pd group and 59 (39.3%) pts in the Pd group. Conclusion: The addition of DARA to Pd provided a PFS benefit in the overall pt population and among pts refractory to lenalidomide. The safety profile observed in the APOLLO trial was consistent with previous reports for DARA SC and Pd. Additional analyses for lenalidomide-refractory pts, as well as efficacy and safety data for the overall population at longer follow up, will be presented. Figure 1 Figure 1. Disclosures Sonneveld: Celgene/BMS: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Terpos: Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Boccadoro: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie: Honoraria; Janssen and GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma: Research Funding. Delimpasi: Takeda: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Beksac: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Katodritou: GSK, Amgen, Karyopharm, Abbvie, Janssen-Cilag, Genesis Pharma, Sanofi: Honoraria, Research Funding. Moreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Oncopeptides: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Abbvie: Honoraria. Symeonidis: Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi/Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Demo: Research Funding; WinMedica: Research Funding; GenesisPharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bila: Janssen, Takeda, AMGEN: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Oriol: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mateos: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Oncopeptides: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees. Einsele: Janssen, Celgene/BMS, Amgen, GSK, Sanofi: Consultancy, Honoraria, Research Funding. Orfanidis: Health Data Specialists: Current holder of individual stocks in a privately-held company. Kampfenkel: Janssen: Current Employment. Qiu: Janssen: Current Employment. Amin: Janssen: Current Employment, Current equity holder in publicly-traded company. Kosh: Janssen: Current Employment. Tran: Janssen: Current Employment, Current equity holder in publicly-traded company. Carson: Janssen: Current Employment. Dimopoulos: Beigene: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria; BMS: Honoraria. OffLabel Disclosure: The regimen is approved for patients who have received at least two prior therapies, whereas the APOLLO study included patients who have received at least 1 prior therapy.

Background: During the past decade, prognostic tools and outcomes of patients with newly-diagnosed multiple myeloma (NDMM) markedly improved. Data from clinical trials evaluating early morbidity and mortality including patients with transplant-eligible NDMM treated with novel agents are scarce. Thus, we aimed to analyze early morbidity and mortality in this patient cohort, devise and validate a predictive score to identify patients at risk. Patients and methods: Between July 2005 and January 2018, 1333 patients with transplant-eligible NDMM from three subsequent phase III trials, HD4, MM5 and HD6 from the German-speaking Myeloma Multicenter Group (GMMG), received a novel agent-based induction therapy with either bortezomib (BTZ) / doxorubicine / dexamethasone (DEX; PAD: n=192, HD4; PAd: n=296, MM5), BTZ / cyclophosphamide / DEX (VCD: n=300, MM5), BTZ / lenalidomide / DEX (VRD: n=272, HD6) or elotuzumab / VRD (ELO-VRD: n=273, HD6). Severe infections (SI) were defined as any infection grade ≥ 3 according to the Common Terminology Criteria for Adverse Events (CTCAE). SI and early deaths were counted on and up to 30 days post induction therapy. Uni-/multivariable logistic regression models were used to assess predictive factors for SI and early death and to account for trial effects. Data from the European Myeloma Network (EMN) 02 / Dutch-Belgian Cooperative Trial Group for Hematology Oncology Foundation (HOVON) 95 phase III trial including 1497 patients with transplant-eligible NDMM receiving induction therapy with VCD were used to validate a predictive score for SI and early mortality. Results: Overall, early mortality during induction therapy was low (n=24, 1.8%) in the GMMG cohort. SI were the most common cause for early deaths (n=15, 62.5%) as compared to MM progression-related death (n=5, 20.8%) and other causes (n=4, 16.7%). Rates of SI during induction therapy were 11.9% (n=159) and decreased in subsequent trial generations: HD4-PAD: 27.1%, MM5-PAd: 10.8%, MM5-VCD: 9.3%, HD6-VRD: 7.3% and HD6-ELO-VRD: 9.9% of patients. In the EMN02/HO95 trial, early mortality was 1.7% (n=25) and rates of SI were 6.8% (n=101). A multivariate model including patient and disease baseline characteristics identified four major risk factors for SI and/or early death on induction therapy in the GMMG cohort: age (>60 years; odds ratio [OR]=1.70, 95% confidence interval [95% CI]: 1.21-2.40, p=0.002), International Staging System (stage III; OR=1.92, 95% CI: 1.22-2.94, p=0.005), platelet count (1; OR=1.82, 95% CI: 1.10-3.06, p=0.022). A sum score based on these four risk factors (one risk factor = one point) was built and included 519 (39.5%), 550 (41.9%) and 245 (18.6%) patients with a score of 0, 1 and ≥2 points. A higher score gradually predicted an increasing risk for SI and/or death during induction therapy: 0 points=7.9%, 1 point=11.5% and ≥2 points=23.2% (p In the EMN02/HO95 cohort, 673 (45.6%), 587 (39.7%) and 217 (14.7%) patients had a score of 0, 1 and ≥2 points. The score was successfully validated in the EMN02/HO95 cohort: SI and/or death during induction therapy: 0 points=5.0%, 1 point=8.3% and ≥2 points=11.9% (p Conclusions: To date, this is the largest pooled analysis of individual patient data on early morbidity and mortality in patients with transplant-eligible NDMM treated with novel agent-based induction therapy. Our analysis highlights a decreasing incidence of SI and early mortality and proposes a validated, easy-to-use score to identify patients at excessive risk for SI and/or early death during induction therapy. This allows the implementation of intensive monitoring, preventive and supportive strategies for this subgroup of patients in further clinical trials and also routine care. Figure 1 Figure 1. Disclosures Mai: Celgene / BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Glaxo Smith Kline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding. Salwender: AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Takeda: Honoraria; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; GlaxoSmithKline: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen-Cilag: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Oncopeptides: Honoraria; Chugai: Honoraria; Pfizer: Honoraria. Zweegman: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munder: GSK: Consultancy; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Takeda: Consultancy, Honoraria; Amgen: Honoraria; Sanofi: Consultancy; Janssen: Consultancy, Honoraria; Incyte: Research Funding. Pantani: Janssen: Honoraria; Amgen: Honoraria. Brossart: BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; MSD: Honoraria. Beksac: Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Oncopeptides: Consultancy. Raab: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Abbvie: Consultancy, Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Dürig: Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Besemer: Takeda: Honoraria; Janssen: Honoraria; GSK: Honoraria. Fenk: GSK: Honoraria; Amgen: Honoraria; Janssen: Honoraria; BMS/Celgene: Honoraria; Takeda: Honoraria. Haenel: Bayer Vital: Honoraria; Jazz: Consultancy, Honoraria; GSK: Consultancy; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Metzler: Takeda: Consultancy; BMS: Consultancy; GSK: Consultancy; Amgen: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy. Graeven: Amgen: Honoraria; Sanofi Aventis: Honoraria; Celgene: Honoraria, Research Funding; Johnson and Johnson: Honoraria; Astra Zeneca: Honoraria; MSD: Consultancy; Boehringer Ingelheim: Honoraria; BMS: Honoraria; Fujifilm: Honoraria; Roche: Research Funding; Gilead: Research Funding; Ipsen Bioscience: Research Funding; MacroGenics: Research Funding. Boccadoro: Janssen and GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie: Honoraria; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma: Research Funding. Scheid: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Abbvie: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dimopoulos: Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Beigene: Honoraria. Weisel: Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Cavo: Adaptive Biotechnologies: Consultancy, Honoraria; Novartis: Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sonneveld: SkylineDx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Goldschmidt: Mundipharma: Research Funding; Incyte: Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grant; Molecular Partners: Research Funding; MSD: Research Funding; GSK: Honoraria; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding.

Background: IRd has been approved for the treatment of RRMM based on the results of the TOURMALINE-MM1 study, (median progression-free survival [PFS] with IRd vs placebo-Rd: 20.6 vs 14.7 months). Several retrospective and prospective observational studies have shown comparable effectiveness of IRd in ≥2 nd line of therapy (LoT) in the real-world setting to that observed in the MM1 trial, with median PFS ranging from 15.6 to 27.6 months. Here we report an analysis of a large, globally representative dataset pooled from 3 observational studies to investigate the effectiveness of IRd in the overall RRMM population, by LoT, and in subpopulations of pts defined by frailty status. Methods: INSIGHT MM is a large, prospective study which has enrolled >4200 MM pts from Europe, Asia, the US, and Latin America, with a planned follow-up of ≥2 years. UVEA-IXA is a multicenter, longitudinal cohort study of ~300 RRMM pts receiving ixazomib-based treatment via an early access program in Europe. It comprises a retrospective phase (chart review of the period from ixazomib initiation to enrolment in UVEA-IXA) followed by a 1-year prospective follow-up period. REMIX is a retrospective/prospective study of ~200 pts receiving IRd via a compassionate use program in France. The INSURE pooled analysis included adult pts with ≥2 prior MM therapy lines, and who had received IRd in ≥2 nd LoT. PFS was a primary outcome measure; secondary outcome measures included duration of treatment (DoT), overall response rate (ORR), time-to-next therapy (TTNT), overall survival (OS), and safety. Using the Kaplan-Meier method, time-to-event endpoints were analyzed in the overall analysis population, by LoT, and in subpopulations of pts defined by a simplified frailty score (0-1 [non-frail] vs ≥2 [frail]). Adverse events (AEs) and discontinuations/dose reductions due to AEs, were reported separately for each study. Results: In total, 566 pts were identified in this pooled analysis (INSIGHT MM, n=181; UVEA-IXA, n=195; REMIX, n=190), with a median follow-up of 18.5 months overall. Median age at the start of IRd therapy was 68 years (range 36-92), with 21% of pts aged >75 years; 17.6% of pts had an Eastern Cooperative Oncology Group performance status ≥2; pts had received a median of 2 LoT prior to IRd; 41%, 38%, and 21% of pts received IRd as 2 nd, 3 rd, and ≥4 th LoT, respectively. Of 408 pts with frailty scores recorded, 166 (41%) were defined as frail, with similar percentages (39-42%) across all LoTs. Median DoT was 14.0 months overall and decreased with increasing LoT (Table). Median PFS was 20.8 months overall, ranging from 22.1 to 11.6 months with IRd as 2 nd and ≥4 th LoT, respectively (Figure/Table). OS data are not yet mature. Among 406 response-evaluable pts, the ORR was 64.5%, being highest in pts receiving IRd as 2 nd (70.7%) vs 3 rd (63.1%) or ≥4 th LoT (52.1%). In frail vs non-frail pts, median PFS was 11.9 vs 24.0 months, while median DoT was 9.7 vs 16.1 months, respectively; consistent trends for longer DoT/PFS with earlier vs later LoTs were seen in both frail and non-frail pts (Table). Analyses of REMIX AEs are ongoing. In INSIGHT, 30%, 23%, and 18% of pts discontinued ixazomib, lenalidomide, and dexamethasone, respectively, due to AEs; 14%, 19%, and 12% reduced their respective treatment dosage to manage AEs. In UVEA-IXA, discontinuation rates were 17%, 15%, and 10%, respectively; 9%, 9%, and 1%, had dose reductions. The most common AEs leading to ixazomib discontinuation in INSIGHT and UVEA-IXA were thrombocytopenia (19 and 24%, respectively), diarrhea (9 and 18%), infections and infestations/infection (15% and 6%), peripheral neuropathy (7 and 12%), and fatigue in INSIGHT only (11%). Analyses of TTNT, OS, AEs associated with treatment discontinuations in REMIX, and additional analyses of the frail cohort are ongoing and will be presented. Conclusions: The findings from this analysis of a large, global, pooled dataset of 566 pts show that the effectiveness of IRd in routine clinical practice is consistent with the efficacy of IRd observed in TOURMALINE-MM1 (median PFS 20.8 vs 20.6 months), with no new safety concerns. Our results suggest a benefit of treatment with IRd in earlier vs later lines, consistent with reports from previous, smaller real-world studies of IRd in RRMM pts. In addition, this analysis provides important insights on the effectiveness of IRd in frail pts, helping to increase the understanding of the achievable outcomes in this subpopulation. Figure 1 Figure 1. Disclosures Leleu: Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Gilead Sciences: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; AbbVie: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support. Boccadoro: Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Research Funding; AbbVie: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees. Lee: Sanofi: Consultancy; Karyopharm: Consultancy; Oncopetides: Consultancy; Takeda Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Regeneron: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Legend Biotech: Consultancy; Bristol Myers Squibb: Consultancy. Zonder: Intellia: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; Caelum Biosciences: Consultancy; Amgen: Consultancy; BMS: Consultancy, Research Funding; Janssen: Consultancy; Alnylam: Consultancy. Macro: Takeda: Honoraria, Other: Travel accomodation, Research Funding; Janssen: Honoraria, Other: Travel accomodation, Research Funding; GSK: Honoraria; Sanofi: Honoraria; Celgen/BMS: Honoraria. Ramasamy: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; Celgene (BMS): Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Conference registration, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hulin: abbvie: Honoraria; Janssen: Honoraria; Celgene/BMS: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Ren: Takeda: Current Employment. Bent-Ennakhil: Takeda: Current Employment. Bouillie: TAKEDA ONCOLOGIE FRANCE: Current Employment. Cherepanov: Takeda: Current Employment, Current equity holder in publicly-traded company. Stull: Takeda Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Terpos: Amgen: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding.

Introduction and background Treatment of newly diagnosed Multiple Myeloma (MM) with Bortezomib, Imid and Dexamethasone followed by high-dose therapy and Lenalidomide maintenance has become standard with an estimated progression-free survival (PFS) of 5 years. In the EMN02 collaborative trial VCD induction (Bortezomib, Cyclophosphamide, Dexamethasone) followed by HDM/ASCT or VMP (Bortezomib, Melphalan, Prednisone), followed by VRD consolidation and Lenalidomide maintenance until progression resulted in a median PFS of 57.5 months from start of maintenance at a median follow-up of 73 months (Cavo et al, Lancet Haematol 2020; Sonneveld et al, J Clin Oncol 2021). Patients with progressive disease during Lenalidomide maintenance are defined as double refractory and have limited options for treatment. The present Phase 2 trial was designed to evaluate a salvage treatment of next generation proteasome inhibition and IMId, i.e., Carfilzomib, continuous Pomalidomide and Dexamethasone (KPd) for patients who developed a first progression after treatment in EMN02 The primary endpoint was progression-free survival (PFS). This trial is registered as NTR5349 and EudraCT 2013-003265-34. Methods Patients were eligible if they had PD according to IMWG criteria during treatment in EMN02. Treatment consisted of 8 cycles of KPd, i.e. Carfilzomib (20/36mg/m 2, days 1,2,8,9,15,16) with Pomalidomide (4 mg days 1-21) and Dexamethasone (20mg days 1,2,8,9,15,16). In patients who had not previously received HDM/ASCT, HDM(200 mg/m 2) was administered followed by autologous transplantation with stem cells previously harvested.. Patients who achieved stable disease or better were randomized to receive Pomalidomide 4mg (21/28 days) with or without Dexamethasone 40mg (days 1, 8, 15, 22) in 28 days cycles until progression. Results At the time of the final analysis 112 patients were registered of whom 1 was ineligible. 59% had received prior HDM/ASCT and 41% VMP. Prior best responses in the EMN02 trial were 39% ³CR , 81% ≥VGPR, 96% ≥PR. The median duration of maintenance in EMN02 had been 33 months and median PFS from start of maintenance 59 months. At inclusion adverse risk factors were available in 92/111 patients, ie R-ISS II or III 62%, del17p 14%, t(14;16) 1%, t(4;14) 20%, amp1q 40%. One hundred (90%) of patients had progressed during or within 6 months after discontinuation of Lenalidomide maintenance. 86 (77%) patients completed 8 cycles of KPd, of whom 69(62%) without dose reduction and received continuous Pomalidomide with Dexamethasone (38%) or without (40%). The median time to discontinuation of Pomalidomide w/o Dexamethasone was 17 months (18 vs 15 months, n.s.). In addition, thirty-three of 42 (79%) eligible patients received their first HDM plus ASCT. Time to first response was 2 months. Best response on protocol was 37% ≥CR, 75% ≥VGPR, 92% ≥PR, respectively. At a median follow-up of 40 months (range 9-66 months) median PFS from registration was 26 months. PFS from randomization was 27 months (Pom/Dex) and 18 months (Pom) respectively (HR 0.68, 95%CI 0.41-1.13, p=0.14). 70 (63%) of patients are alive and in follow-up. With Cox regression analysis predefined risk factors including high-risk cytogenetics (HR 1.36, 95%CI 0.80-2.41), prior HDM/ASCT (HR 1.25, 95%CI 0.78-2.01) and duration of prior maintenance >36 months (HR 3.56, 95%CI 1.42-8.96) were not significant. Median overall survival (OS) was 67 months. KPd-emerging grade 3 and 4 adverse events included hematologic (41%), cardiovascular (6%), respiratory (3%), infections (17%) and neuropathy (2%). There were 6 fatal SAEs not related to progression (1 patient cardiovascular). Discussion This Phase 2 trial demonstrates that KPd followed by Pomalidomide until progression is an effective and safe triple drug regimen in second-line for patients who are refractory to Lenalidomide. The benefit is observed across subgroups of risk factors. A 92% overall response and 26 months PFS is clinically relevant in this population and compares favourably to Pom/Vd. Using this regimen HDM/ASCT could be performed in the majority of patients. Acknowledgements This trial was conducted as an investigator sponsored trial by HOVON and the European Myeloma Network EMN and supported by a grant from the Dutch Cancer Foundation and by independent grants and drug supply from Amgen and BMS/Celgene. Disclosures Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Zweegman: Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo: Novartis: Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Broyl: Sanofi: Honoraria; Janssen Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Meyer Squibb: Honoraria; Amgen: Honoraria. Corradini: Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; BMS: Other: Travel and accommodation; Sanofi: Consultancy, Honoraria; Incyte: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations. Minnema: BMS: Consultancy; Janssen: Consultancy; Cilag: Consultancy; Celgene: Other: Travel expenses; Alnylam: Consultancy; Kite/Gilead: Consultancy. Boccadoro: Janssen and GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie: Honoraria; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma: Research Funding.

multiple myeloma (MM) is a plasma cell disorder that represents the second most frequent hematologic cancer. Although MM is still an incurable disease, prognosis has improved in the last decades thanks to the introduction of novel agents such as proteasome inhibitors (PIs), immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors. Areas covered: ixazomib is the first oral PI recently approved by Food and Drug Administration (FDA) and European Medicine Agency (EMA) in combination with lenalidomide and dexamethasone as salvage therapy in MM patients. In this paper, we focus on its pharmacokinetics features, as well as its safety and efficacy in clinical studies. Expert opinion: ixazomib can be considered an oral analogue of bortezomib, with 9.5-day half-life, 58% of oral bioavailability, and a large distribution volume of 543L. These features make it a versatile molecule, potentially useful both in combination and as single agent. Oral route of administration and good efficacy/safety profile are its winning characteristics, providing the rationale for a future role also in the maintenance setting.

Background Gain and/or amplification of chromosome 1q are frequently associated with multiple myeloma (MM). The number of 1q copies correlates with a poor prognosis. Our aim was to evaluate the impact on clinical outcome and the transcriptome changes induced by Gain1q (3 copies of 1q) and 1q amplification (Amp1q, ≥4 copies of 1q) in patients (pts) enrolled in the randomized FORTE trial (NCT02203643). Methods Fluorescence in situ hybridization (FISH) on CD138+ purified bone marrow plasma cells was centralized and performed at baseline. The cut-off level of Gain1q was 10% of nuclei with ≥3 copies of 1q, while Amp1q was defined as ≥20% of nuclei with ≥4 copies of 1q. Transcriptome data from pts enrolled in the MMRF CoMMpass study (NCT01454297) were used to find differentially expressed genes (DEGs) in Gain/Amp1q pts. An independent cohort enrolled in the FORTE trial was subjected to RNAseq and used as validation. Results A total of 474 pts were enrolled in the FORTE trial. 1q copy number was missing in 74 pts; thus, 400 pts were evaluable. The median follow-up was 51 months; 219 (55%) pts belonged to the Normal 1q, 129 (32%) to the Gain1q, and 52 (13%) to the Amp1q group. In a multivariate analysis, progression-free survival (PFS) was shorter in the presence of Gain1q (HR 1.65 vs Normal 1q, p=0.005) and Amp1q (HR 3.13 vs Normal 1q, p Conclusion Amp1q universally predicts poor PFS and OS, despite the use of new drug combinations. A gene network centered on Myc may contribute to the high-risk behavior of these pts. The study of DEGs associated with Gain and Amp1q can identify new ‘druggable’ targets to be further tested in this high-risk patient population.

Introduction Multiple myeloma (MM) patients (pts) with high-risk cytogenetic abnormalities (CA) have a shorter survival as compared to the standard-risk ones. In the FORTE study, carfilzomib-lenalidomide-dexamethasone induction/consolidation with ASCT (KRd-ASCT) significantly improved progression-free survival (PFS) vs KRd without ASCT (KRd12) or carfilzomib-cyclophosphamide-dexamethasone (KCd) plus ASCT (KCd-ASCT). KR maintenance also prolonged PFS vs R. The primary aim of this analysis was to evaluate the impact of treatment on PFS and 1-year sustained MRD negativity (1y-MRD neg) rates according to pt cytogenetic risk. Methods Pts were randomized to KRd-ASCT vs KCd-ASCT vs KRd12 and, thereafter, to KR vs R maintenance. High risk (HiR) was defined as the presence of ≥1 HiR CA [del17p, t(4;14), t(14;16), del1p and 1q gain (3 copies) or amp1q (≥4 copies)], double hit (DH) as the presence of ≥2 HiR CA, standard risk (SR) as the absence of all evaluated HiR CA. Results 396 out of 474 enrolled pts with complete fluorescence in situ hybridization (FISH) data were included in the analysis: 243 HiR, 105 DH and 153 SR pts. Among HiR pts, 60 had del17p, 65 t(4;14), 20 t(14;16), 44 del1p, 126 1q gain and 49 amp1q. SR pts benefited from intensification with KRd-ASCT vs KRd12 (HR 0.47, p=0.05) and KCd-ASCT (HR 0.38, p=0.01), with a 4-year PFS of 80%, 67% and 57%, respectively. In HiR pts, KRd-ASCT improved PFS vs KRd12 (HR 0.6, p=0.04) and KCd-ASCT (HR 0.57, p=0.01), with a 4-year PFS of 62%, 45% and 45%, respectively. The advantage with KRd-ASCT vs KRd12 (HR 0.53, p=0.07) and KCd-ASCT (HR 0.49; p=0.03) was also observed in DH pts (4-year PFS 55%, 31% and 33%, respectively). Despite the limited number of patients in each subgroup, a trend towards a PFS benefit from KRd-ASCT vs KRd12 was observed in pts with del17p (HR 0.61, p=0.3), t(4;14) (HR 0.59, p=0.2) and 1q gain (HR 0.45, p=0.02). In pts with del1p, KRd-ASCT (HR 0.24, p=0.06) and KRd12 (HR 0.33, p=0.09) showed superiority over KCd-ASCT, while amp1q pts had the worst outcome regardless of treatment (KRd-ASCT vs KCd-ASCT, HR 1.16, p=0.73; KRd12 vs KCd-ASCT, HR 1.34, p=0.45). KR improved PFS vs R in SR (3-year PFS 90% vs 73%, HR 0.42, p=0.06), HiR (3-year PFS 69% vs 56%, HR 0.6, p=0.04) and DH pts (3-year PFS 67% vs 42%, HR 0.53, p=0.1). Despite the small subgroups, a beneficial trend with KR vs R was observed in pts with del17p (HR 0.59, p=0.37), t(4;14) (HR 0.59, p=0.3), 1q gain (HR 0.54, p=0.07) and del1p (HR 0.23, p=0.08), while amp1q pts showed the worst outcome and no benefit from KR vs R (HR 0.83, p=0.7). Conclusion KRd-ASCT and KR maintenance are highly effective in SR and also in HiR and DH pts, with impressive 4-year PFS from diagnosis (KRd-ASCT: HiR 62%, DH 55%) and 3-year PFS from maintenance (KR: HiR 69%, DH 67%), thus providing an effective option in HiR pts, who still represent an unmet medical need.

Background Despite an improvement in treatment response, high-risk multiple myeloma (MM) patients (pts) experience early relapse and short disease-free survival. Together with more validated high-risk features, high levels of circulating plasma cells (high CPC) have been considered a marker of aggressive disease and poor outcome (F. Gay et al, ASH 2019; W.I. Gonsalves et al, Am J Hematol 2020). To date, there are no uniform data on the optimal cut-off predictive of clinical outcome. No prospective data on CPC are available in the setting of novel-drug clinical trials with comprehensive baseline evaluation and minimal residual disease (MRD) assessment. Aims 1) To identify the best cut-off for CPC to predict progression-free survival (PFS); 2) to assess the impact of high CPC levels on the clinical outcome of newly diagnosed (ND)MM pts in the context of concomitant risk features and MRD evaluation. Methods In the multicenter randomized FORTE clinical trial, 474 NDMM pts ≤65 years were randomized (R1) to receive either: carfilzomib-lenalidomide-dexamethasone (KRd) induction-autologous stem-cell transplant-KRd consolidation (KRd_ASCT); KRd for 12 cycles (KRd12); or carfilzomib-cyclophosphamide-dexamethasone (KCd) induction-ASCT-KCd consolidation (KCd_ASCT). Thereafter, pts were randomized (R2) to maintenance treatment with lenalidomide alone (R) or plus carfilzomib (KR). MRD was assessed by 2nd-generation multiparameter flow cytometry (MFC, sensitivity 10-5) in pts who achieved ≥very good partial response before maintenance and then every 6 months. At diagnosis, single-platform FC was used to sort and count CPC. Receiver Operating Characteristic (ROC) analysis was used to define a cut-off based on PFS at 36 months as outcome. Correlations between high CPC and the most important baseline prognostic features (age, International Staging System (ISS), lactate dehydrogenase (LDH), chromosomal abnormalities (CA) by FISH [(del17p, t(4;14), t(14;16), t(11;14), amp1q, del1p, del13], Revised-ISS (R-ISS)) were explored. Hence, we performed a multivariate (MV) analysis to assess the impact of high CPC on the achievement of MRD negativity, on PFS and OS. Finally, we evaluated the impact of baseline CPC and MRD achievement. Results CPC analysis was performed in 401/474 pts at diagnosis; median follow-up was 44.2 months (39.6-47.9) and baseline features were similar to those reported in the overall FORTE population. Median CPC were 0.02% (IQR 0-0.14). The optimal CPC cut-off to predict PFS (ROC analysis) was 0.07% (5 cells/ul, 0.005 x109/l) and was consistent with a cut-off previously identified as a predictor of sustained MRD negativity (MRDsus12; L. Bertamini et al, EHA 2020). High-CPC pts (>0.07%) were 130/401 (32%), while 271/401 (68%) had low CPC (≤0.07%). The proportion of high-CPC pts was comparable among treatment arms. Baseline features significantly associated with high CPC in a MV analysis were: ISS II/III, high LDH, amp1q, t(4;14), t(14;16) and bone marrow plasma cells (>60%). Regarding PFS, in a MV analysis adjusted for R-ISS and R1 treatment, including all the baseline features, high CPC were associated with a lower PFS (HR 2.49, 95% CI 1.76-3.51, P The impact of baseline CPC levels on PFS was consistent in all high-risk subgroups (Fig. 1C), except in those patients who achieved pre-maintenance MRD negativity [(neg); interaction P=0.03]. Low-CPC and MRD-neg pts showed the best outcome with a 3-year PFS of 84%. Low-CPC MRD-positive (pos) and high-CPC MRD-neg pts had similar 3-year PFS (70% vs 68%). High-CPC MRD-pos pts had a dismal outcome (3-year PFS 32%; Fig. 1D). Conclusion High CPC with a cut-off of 0.07% (5 cells/ul, 0.005 x109/l) is a strong and independent high-risk factor, predicting a shorter PFS and OS even in the context of other high-risk features. The achievement of MRD neg independently improved the poor prognosis of high-CPC patients. Figure 1 Disclosures D'Agostino: GSK: Membership on an entity's Board of Directors or advisory committees. Galieni:Janssen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Molica:Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tacchetti:Oncopeptides: Honoraria; AbbVie: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Gay:GSK: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding. Oliva:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including carfilzomib, cyclophosphamide, lenalidomide and dexamethasone).

Background: 18F-FDG-PET/CT is currently the standard technique to define imaging-minimal residual disease (MRD) in multiple myeloma (MM) patients. A joint analysis of 2 prospective randomized trials in newly diagnosed transplant-eligible MM (NDTEMM) patients applied for the first time the Deauville Scores (DS) to focal lesions (FS) and bone marrow uptake (BMS) showing the liver background (DS < 4) as the best cut-off to define PET/CT negativity after therapy and complete metabolic response (CMR) (Zamagni et al, ASH 2018). Validation of this new standardized criteria in an independent prospective series of NDTEMM patients is highly required. Imaging-PET/CT MRD also showed to be complementary to Multiparameter Flow Cytometry (MFC) in predicting patient's outcomes (Moreau P, JCO 2017). In this analysis, we aimed at confirming the applicability and validity of DS criteria to define PET/CT CMR and showing their impact on patient's outcomes in the multicenter phase II randomized FORTE trial for NDTEMM patients. We also looked at the complementarity with BM techniques, especially MFC. Methods: NDTEMM patients ≤ 65 years were randomized to receive carfilzomib, lenalidomide, dexamethasone (KRD) induction - autologous stem cell transplantation (ASCT) intensification-KRd consolidation (arm A); KRd12 (arm B) and carfilzomib, cyclophosphamide, dexamethasone (KCd) induction-ASCT intensification-KCd consolidation (arm C). Thereafter, patients were randomized to maintenance with lenalidomide alone or plus carfilzomib. PET/CT scans were performed locally at baseline (B) and prior to the start of maintenance (PM). DS were applied both in the BM and FLs, as previously described (Zamagni E, EHA 2020). CMR was defined as DS < 4 both in the FLs and BM. MRD evaluation was performed by 8-color second-generation flow cytometry (sensitivity 10-5) in patients who achieved at least VGPR before maintenance (Gay F, ASCO 2019). The impact of each parameter on outcomes was evaluated by landmark analyses at PM. A multivariable Cox regression analysis was adopted to identify independent predictors for PFS and OS. Results: 182 out of the 474 global patients enrolled in the trial had a pre- and post-treatment PET/CT evaluation available and were included in this analysis. Patients' baseline characteristics were: median age 57 years, ISS and R-ISS stage III 18% and 10%, respectively, high-risk cytogenetics (t(4;14) ± del(17p) ± t(14;16), detected by FISH) 26%, reflecting baseline clinical features of the entire FORTE population. At B, 93% of patients had FLs, with a median maximum standardized uptake value (SUVmax) of 5.7 [IQR: 4.1-8.1], 7% presented extra-medullary lesions and nearly all patients had increased BM uptake, with a median SUVmax of 3.4 [IQR: 2.8-4.3]. FS and BMS ≥ 4 were present in 87% and 57% of patients, respectively. At PM, PET/CT negativity according to DS < 4, was present in 80% in the FLs and 85% in the BM, respectively. 63% showed CMR. 92% and 61% of patients achieved ≥ VGPR and CR as best response, respectively, while 73% of them achieved MFC MRD negativity. The achievement of a best CR significantly correlated with BMS < 4 at PM (P= 0.003). In univariate analysis, at Landmark time PM, FS Conclusion: In conclusion, the present analysis confirms the applicability and validity of DS criteria to define PET/CT CMR in an independent prospective series of NDTEMM patients. CMR significantly and independently correlated in uni- and multivariable analysis with patient's outcomes in terms of PFS and OS and was complementary to the MFC MRD negativity. Figure Disclosures Zamagni: Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau. Gay:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. D'Agostino:GSK: Membership on an entity's Board of Directors or advisory committees. Galli:Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria; BMS: Honoraria. Zambello:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Rivolti:Celgene: Membership on an entity's Board of Directors or advisory committees. Tacchetti:Bristol-Myers Squibb: Honoraria; AbbVie: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Oncopeptides: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Fanti:Bayer, Astellas, GE Healthcare, ANMI, Janssen: Membership on an entity's Board of Directors or advisory committees; Bayer, Astellas, GE Healthcare, Sanofi, AAA: Honoraria. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Cavo:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Oliva:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria.

Background. Infections represent a major cause of toxicity in newly diagnosed multiple myeloma (NDMM) patients, and their incidence is higher during the first 4 months of therapy (Dumontet, Leukemia 2018). The use of prophylactic levofloxacin for the first 3 months of therapy demonstrated to reduce rates of infections (Dryson, Lancet Hematol 2019). However, factors predicting the risk of infections in patients treated with novel agents and the need for antimicrobial prophylaxis for all vs selected patients remain under debate. We investigated the incidence of severe infections and associated baseline risk-factors in NDMM patients. Methods. Data from Italian patients enrolled in clinical trials and receiving carfilzomib-based (IST-CAR-506, IST-CAR-561), bortezomib-based (EMN02) and lenalidomide-based (EMN01, RV-MM-PI-0752, RV-MM-EMN-441) treatment were pooled together and analyzed. The primary aim of the analysis was to evaluate the incidence of severe infections, defined as any grade (G) 3-5 event or G2 if involving the lung/lower respiratory tract (CTCAE version 4.0). The rate of early severe infections (i.e. infections occurring during the first 4 months of treatment) was also analyzed. Secondary goals were to identify baseline factors associated with an increased risk of early severe infections and to evaluate the impact of early severe infections on treatment outcome. Results. A total of 1892 patients were included in the analysis. Median age was 65 years, 970 (51%) patients were transplant eligible (TE) and 922 (49%) transplant ineligible (NTE). Overall, 1059 (56%) patients received IMiD-based induction therapy and 833 (44%) a PI-based induction therapy. Median follow-up was 68 months. We recorded 898 infections of any grade, of which 436 (49%) were considered severe. Most frequent severe infections included lung/lower respiratory tract infection (50%), febrile neutropenia (23%) and sepsis/septic shock (10%). Overall, severe infections occurred when myeloma response to treatment was ≤PR in 62% of cases, VGPR in 29% and sCR/CR in 9%. 654 (35%) patients reported at least 1 infection of any grade and 377 (20%) patients at least one severe infection. Early infections (first 4 months) occurred in 243 patients (13%) and early severe infections in 129 patients (6.8%). Overall, 21 patients (1.1%) died due to infection, of whom 6 during the first 4 months. In a multivariate analysis (Table), main factors associated with increased risk of early severe infections were ISS stage 3 (OR 2.14, 95% CI 1.32-3.48), presence of del17p by FISH (OR 1.80, 95% CI 1.1-2.96), intermediate fit status (OR 1.88 95% CI 1.1-3.21) and frail status (OR 2.12, 95% CI 1.08-4.18) according to IMWG frailty score (Palumbo, Blood 2015). No difference in risk of early severe infections was observed according to induction treatment with PI vs IMiD (OR 1.10, 95%CI 0.68-1.78). In a time-dependent Cox regression analysis adjusted for potential confounders (age, RISS stage and performance status), the risk of disease progression/death was significantly higher in patients who had an early severe infection compared to patients without early severe infection (median PFS 21.3 months vs 31.3 months, HR 1.32, 95% CI 1.07-1.63, p Conclusions. We found that 34% of patients experiencing severe infections had the event during the first 4 months of therapy. Patients with aggressive disease and elderly frail patients are at higher risk of early severe infections, hampering treatment adherence and efficacy, and eventually affecting PFS and OS. Identifying patients more susceptible to severe infections through easily available parameters could pave the way for the evaluation of risk-adapted antimicrobial prophylaxis in clinical trials. Table 1 Disclosures D'Agostino: GSK: Membership on an entity's Board of Directors or advisory committees. Offidani:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Petrucci:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Liberati:JANSSEN: Honoraria; AMGEN: Honoraria; CELGENE: Honoraria; ROCHE: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; ONCOPEPTIDES AB: Honoraria, Research Funding; TAKEDA: Honoraria, Research Funding; MORPHOSYS: Honoraria, Research Funding; ONCONOVA: Honoraria, Research Funding; ABBVIE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; KARYOPHARM: Honoraria, Research Funding; BMS: Honoraria; BEIGENE: Honoraria; ARCHIGEN: Honoraria; BIOPHARMA: Honoraria; FIBROGEN: Honoraria; INCYTE: Honoraria; VERASTEM: Honoraria, Research Funding. Benevolo:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Gaidano:Sunesys: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galli:Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria; BMS: Honoraria. Corradini:Janssen: Consultancy, Honoraria; Incyte: Consultancy; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; KiowaKirin: Consultancy, Honoraria; Kite: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Conticello:Amgen, Takeda, Janssen: Honoraria. Cavo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau. Sonneveld:Skyline Dx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Boccadoro:Mundipharma: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria. Bringhen:Bristol-Myers Squibb: Honoraria; Takeda: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including carfilzomib, cyclophosphamide, dexamethasone, bortezomib, melphalan, prednisone and lenalidomide).

INTRODUCTION. Elderly patients (pts) with newly diagnosed multiple myeloma (NDMM) are a heterogeneous population. The IMWG frailty score stratifies pts ≥65 years into 3 categories (fit, intermediate-fit and frail), according to chronological age, comorbidities and functional abilities, with different prognosis. We previously reported results from the phase II EMN10-Unito study investigating 4 Ixazomib-based induction regimens followed by Ixazomib maintenance in elderly NDMM pts. Here we present a post-hoc analysis of safety and efficacy of ixazomib-based induction regimens and maintenance according to IMWG frailty score. METHODS. NDMM, transplant-ineligible pts ≥65 years were enrolled. Treatment consisted of 9 induction cycles of Ixazomib combined with dexamethasone (Id), Cyclophosphamide-dexamethasone (ICd), Thalidomide-dexamethasone (ITd) or Bendamustine-dexamethasone (IBd), followed by single-agent Ixazomib maintenance for up to 2 years. Pts were stratified into 3 groups (fit, intermediate-fit and frail) according to IMWG frailty score. The aim of this analysis was to evaluate the efficacy (TTP, PFS, PFS2 and OS) and safety of ixazomib-based induction regimens and single-agent ixazomib maintenance in the 3 patient subgroups. RESULTS. 171 pts were enrolled in the study and started treatment; of these, 75 (44%) were classified as fit, 53 (31%) as intermediate-fit and 43 (25%) as frail. As expected, the median age was higher in frail (79 years) as compared with fit (71 years) and intermediate-fit (76 years) pts, and a worse ECOG score (1-2) was reported in frail (67%) as compared with fit (46%) and intermediate-fit pts (46%). Frail pts were also more likely to have ISS 2-3 myeloma (82%) compared with fit (59%) and intermediate-fit (77%) ones. The median follow-up for the entire population was 27 months. The ORR and VGPR rates after the induction were similar in fit (71%; 42%), intermediate-fit (74%; 38%) and frail pts (76%; 40%), although fit (8%) and intermediate-fit (13%) pts were more likely to achieve a CR than frail ones (2%). No significant differences in median PFS were observed among fit (14.1 months; HR: 0.75, p=0.27), intermediate-fit (14.8, HR: 0.68, p=0.12) as compared to frail pts (12.2 months). The median PFS2 was significantly longer in fit (41.1, HR: 0.48; p=0.04) and intermediate-fit (35.6, HR: 0.47, p=0.03) in comparison with frail pts (28.6 months). OS was longer in fit pts (NR; HR: 0.36, p=0.02) and intermediate-fit (NR; HR: 0.58, p=0.15) as compared to frail ones (36.7 months). The rates of grade 3-4 adverse events (AEs) and grade 3-4 non-hematological AEs during the induction phase were higher in frail pts (47% / 37%) as compared to fit (28% / 24%) and intermediate-fit (32% / 26%) ones. Similarly, the risk of treatment discontinuation was higher in frail (21%) as compared to fit (11%) and intermediate-fit pts (9%). When comparing PFS with three- vs two-drug ixazomib-based induction, both fit (HR: 0.75) and intermediate-fit (HR: 0.69) pts benefited from the use a triplet over a doublet; whereas, no difference between three- and two-drug combinations was observed in frail pts (HR: 1.01). Overall, 102 pts (60%) completed the induction phase and proceeded to ixazomib maintenance: of these, 46 (45%) were fit, 35 (34%) intermediate-fit and 21 (21%) frail. The median PFS from start of maintenance in the overall population was 15 months, without significant differences in intermediate-fit (HR: 0.92) and frail (HR: 1.14) pts as compared to fit ones. Concerning the safety of ixazomib maintenance, grade 3-4 non-hematological AEs were infrequent, occurring in 15% of fit pts (15%), 3% of intermediate-fit and 5% of frail (5%) ones. Ixazomib dose reductions were more frequent in frail (24%) as compared to fit (13%) and intermediate-fit (11%) pts, although a similar percentage of pts discontinued ixazomib due to AEs in the three groups (fit: 11%; intermediate-fit: 15%; frail: 10%). CONCLUSIONS. Ixazomib-based regimens had similar efficacy in terms of ORR and PFS, irrespective of frailty status, although AEs, dose modifications and treatment discontinuation were more frequent in frail pts. Importantly, frail pts did not seem to benefit from the addition of a third drug over the use of a doublet induction therapy. Single-agent ixazomib maintenance was effective and well tolerated in fit, as well as in intermediate-fit and frail pts, thus representing an appealing maintenance option in elderly MM. Disclosures Mina: Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. Larocca:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Offidani:Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Galli:BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. De Sabbata:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boccadoro:Mundipharma: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Bringhen:Bristol-Myers Squibb: Honoraria; Takeda: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including ixazomib, dexamethasone, cyclophosphamide, thalidomide and bendamustine).

INTRODUCTION. The proteasome inhibitor (PI) Ixazomib, approved for the treatment of relapsed/refractory multiple myeloma (MM), represents an appealing option for the management of elderly patients, due to its oral administration and the lack of peripheral neuropathy. We previously presented preliminary results of the phase II EMN10-Unito study investigating Ixazomib in combination with dexamethasone (Id), Cyclophosphamide-dexamethasone (ICd), Thalidomide-dexamethasone (ITd) or Bendamustine-dexamethasone (IBd) as induction therapy followed by single-agent Ixazomib maintenance in transplant-ineligible newly diagnosed (ND) MM patients. Here we present updated results of the study with a longer follow-up. METHODS. Transplant-ineligible NDMM patients ≥65 years were enrolled. Treatment consisted of 9 28-day induction cycles of Ixazomib 4 mg on days 1,8,15 and dexamethasone 40 mg on days 1,8,15,22 or Id plus either Cyclophosphamide 300 mg/m2 orally on days 1,8,15 or Thalidomide 100 mg/day or Bendamustine 75 mg/m2 iv on days 1,8; followed by Ixazomib maintenance (4 mg on days 1,8,15) for up to 2 years. The primary endpoint was the selection of the most effective induction regimen considering a 2-year progression-free survival (PFS) ≥65% as satisfactory; secondary endpoints were very good partial response (VGPR), PFS2, overall survival (OS) and adverse events (AEs) during induction and maintenance. RESULTS. 171 patients (Id 41, ICd 59, ITd 60 and IBd 11) with a median age of 74 years were enrolled and started treatment. Two of the four investigational arms were prematurely closed due to low-enrollment (IBd arm, 11 patients enrolled) and high risk of inefficacy (Id, 41 patients enrolled). Median follow-up was 27 months. After the induction phase, ICd and ITd resulted in higher ≥ PR (75%-84% vs. 57%; p Overall, 102 patients (60%) completed the induction phase and proceeded to ixazomib maintenance (median follow-up from start of maintenance: 18 months). The best response during maintenance was PR in 26%, VGPR in 29%, and complete response (CR) in 26% of patients; 18% of patients improved the response obtained during induction by at least one IMWG category. The median PFS from start of maintenance was 15 months. The median duration of maintenance was 12 months. All grades AEs occurred in 39% of patients during maintenance, while grade 3-4 AEs occurred in 10% of patients. Grade 1-2 peripheral neuropathy (PN) was reported in 15% of patients, without grade 3-4 events. Overall, 15% required at least one dose reduction of ixazomib and 12% discontinued ixazomib maintenance due to AEs. CONCLUSIONS. Safety and efficacy data suggest that Id combined with cyclophosphamide was the most promising induction strategy compared to the other investigated combinations. Continuous treatment with single-agent Ixazomib confirmed its efficacy and tolerability in elderly NDMM patients. Disclosures Mina: Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:GSK: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Corradini:KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria. Liberati:CELGENE: Honoraria; BIOPHARMA: Honoraria; ARCHIGEN: Honoraria; BEIGENE: Honoraria; BMS: Honoraria; AMGEN: Honoraria; FIBROGEN: Honoraria; INCYTE: Honoraria; VERASTEM: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; ONCOPEPTIDES AB: Honoraria, Research Funding; TAKEDA: Honoraria, Research Funding; MORPHOSYS: Honoraria, Research Funding; ONCONOVA: Honoraria, Research Funding; ABBVIE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; KARYOPHARM: Honoraria, Research Funding; JANSSEN: Honoraria. Zambello:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Bringhen:Takeda: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including ixazomib, dexamethasone, cyclophosphamide, thalidomide and bendamustine).

Introduction: DARA is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. In the phase 3 ALCYONE study (median follow-up of 40.1 months), DARA in combination with VMP (D-VMP) reduced the risk of disease progression or death by 58% versus VMP alone (median 36.4 vs 19.3 months; HR, 0.42; 95% CI, 0.34-0.51; P Methods: Pts with TIE NDMM were randomized 1:1 to receive up to nine 6-week cycles of VMP (V 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, and 32 of Cycle 1 and Days 1, 8, 22, and 29 of Cycles 2-9; M 9 mg/m2 PO on Days 1-4 of Cycles 1-9; and P 60 mg/m2 PO on Days 1-4 of Cycles 1-9) ± DARA (16 mg/kg intravenously once weekly (QW) for Cycle 1 and Q3W for Cycles 2-9). Pts in the D-VMP group received DARA as maintenance therapy Q4W for Cycles 10+ until disease progression or unacceptable toxicity. The primary endpoint was PFS. Secondary endpoints included overall response rate (ORR), rate of ≥CR, rate of ≥very good partial response (VGPR), MRD-negativity rate (10-5), OS, and HRQoL. Outcomes were also examined at the time of best response at the beginning of DARA monotherapy (Cycle 10+) and 1 and 2 years after beginning DARA monotherapy. Results: A total of 706 (D-VMP, n=350; VMP, n=356) pts were randomized. Baseline characteristics were well balanced between groups. After a median follow-up of 40.1 months, D-VMP increased the ORR (90.9% vs 73.9%) and the rates of ≥CR (46% vs 25%), ≥VGPR (73% vs 50%), MRD-negativity (28% vs 7%; all P For patients in the D-VMP group who received DARA monotherapy in Cycle 10+, responses continued to deepen: rates of ≥CR improved from 44% at the beginning of maintenance to 64% and 68% at 1 and 2 years, respectively, after the start of DARA maintenance therapy. As in the full study population, improved PFS and OS were observed with deepening responses. Conclusions: D-VMP induced deep responses in TIE NDMM pts and improved PFS, regardless of response status. Depth of response improved PFS, OS, and time to subsequent therapy and responses continued to deepen for patients receiving DARA maintenance therapy. HRQoL was improved in both treatment groups over the course of the study as clinical response deepened. These findings suggest that the addition of DARA to VMP achieves and maintains deep responses for TIE NDMM pts, leading to better outcomes and HRQoL. Disclosures Rodriguez-Otero: Janssen, BMS: Other: Travel, accommodations, expenses; Janssen, BMS, AbbVie, Sanofi, GSK, Oncopeptides, Kite, Amgen: Consultancy, Honoraria; BMS, Janssen, Amgen: Honoraria; Celgene-BMS: Consultancy, Honoraria; Mundipharma: Research Funding. Boccadoro:Mundipharma: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Martinez-Lopez:Novartis: Consultancy; Incyte: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding. Lucio:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Nagy:MorphoSys AG: Patents & Royalties. Liberati:Onconova: Research Funding; Takeda: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Pfizer: Research Funding; Abbvie: Honoraria, Research Funding; Morphosys: Research Funding; Novartis: Research Funding; Incyte: Honoraria; Oncopeptides: Research Funding; Karyopharm: Research Funding; Verastem: Research Funding; Janssen: Honoraria, Research Funding. Takamatsu:Adaptive Biotechnologies: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Ono pharmaceutical: Honoraria, Research Funding; Janssen Pharmaceutical: Consultancy, Honoraria, Research Funding; SRL: Consultancy, Research Funding. Romejko-Jarosinska:Janssen: Honoraria; Celgene: Honoraria; Gilead: Honoraria, Other: travel expences ; Servier: Honoraria; Sanofi: Honoraria; Roche: Honoraria, Other: travel expences ; Macopharma: Other: travel expences ; Servier: Other: travel expences . Knop:Celgene; Bristol Myers Squibb; Sanofi; Janssen: Honoraria. Forsyth:Amgen: Consultancy; Janssen Pharmaceuticals Australia: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gries:Janssen: Current Employment, Current equity holder in publicly-traded company. Pei:Janssen: Current Employment, Current equity holder in publicly-traded company. Kudva:Memorial Sloan Kettering Cancer Center: Other: non-paid consultancy; Janssen: Current Employment, Current equity holder in publicly-traded company. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Wroblewski:Susan Wrobleski: Current Employment, Current equity holder in publicly-traded company. Carson:Janssen: Current Employment. Dimopoulos:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau.

Introduction: The multicentre, randomized, open-label, phase 3 EMN02/HO95 study for patients with newly diagnosed multiple myeloma (NDMM) included two randomization stages (1:1) to (R1) intensification therapy with either upfront ASCT or bortezomib-melphalan-prednisone (VMP), and thereafter to (R2) consolidation therapy or no consolidation, followed by lenalidomide maintenance in both arms. Results of the final analysis from R1 (M. Cavo et al. Lancet Haematol. 2020, 7, e456-68) showed that at a median follow-up of 60.5 months progression-free survival (PFS), the primary study endpoint, was significantly improved with ASCT compared with VMP (median, 57 versus 42 months; HR 0.73, 95% CI 0.62-0.85, adjusted p=0.0001). However, no difference between these groups was found in terms of overall survival (OS), a secondary endpoint (HR 0·90, 0·71-1·13, adjusted p=0·35). Methods: We performed an updated analysis of the study with longer-term follow-up. Efficacy endpoints included OS, PFS on next-line therapy (PFS2), and time to next treatment (TTnT). Analyses were restricted to patients randomized to either ASCT (n=702) or VMP (n=495). Clinical outcomes of patients randomized to upfront ASCT or receiving ASCT at the time of progression after primary randomization to VMP (delayed ASCT) were also explored. Results: At an extended median follow-up of 75 months (IQR 67-84), patients randomized to ASCT had a significantly longer OS than those randomized to VMP (Figure). Median OS was not reached in both arms, and the 75-month survival estimate was 69% (95% CI 65-73) in the ASCT group versus 63% (95% CI 59-68) in the VMP group (HR 0.81, 95% CI 0.66-0-98, adjusted p=0.034). Patients who benefited the most from randomization to ASCT were those with unfavourable prognostic characteristics at baseline, including ISS disease stage 2-3 (HR 0.78, 95% CI 0.61-0.99, p=0.047), R-ISS stage 2-3 (HR 0.79, 95% CI 0.62-0.99, p=0.042), and the presence of at least one of the following cytogenetic abnormalities on FISH analysis: t(4;14) and/or t(14;16) in ≥10% CD138-positive plasma cells, and/or del(17p) in ≥20% enriched plasma cells. Overall, the 75-month OS estimate for patients with a high-risk cytogenetic profile was 54% with ASCT versus 39% with VMP (HR 0.61, 95% CI 0.42-0.89, p=0.010). The magnitude of OS benefit with ASCT, as measured by the HR value, was the highest for patients with del(17p) positivity (HR 0.49, 95% CI 0.28-0.86, p=0.013). PFS2 from R1 was significantly longer for patients in the ASCT arm than for those in the VMP arm. The 75-month PFS2 estimate was 57% in the ASCT group and it was 49% in the VMP group (HR 0.76, 95% CI 0.64-0.90, adjusted p=0.002) (Figure). Patients randomized to ASCT had a significantly longer TTnT in comparison with those who were randomly assigned to VMP. Median TTnT values for these groups were 66 versus 47 months, respectively (HR 0.71, 95% CI 0.60-0.82, adjusted p Conclusions: Upfront ASCT significantly prolonged OS, PFS2 and TTnT in comparison with VMP in NDMM patients. Figure Disclosures Cavo: Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Gay:AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Beksac:Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Petrucci:GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zweegman:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zamagni:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau. Palumbo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galli:BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Maisnar:Janssen, Takeda, Amgen, BMS/Celgene, The Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hansson:Amgen, Celgene, Takeda, Janssen Cilag: Consultancy. Belotti:Celgene: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Offidani:Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Zambello:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Liberati:Verastem: Research Funding; Janssen: Honoraria, Research Funding; Takeda: Research Funding; Morphosys: Research Funding; Novartis: Research Funding; GSK: Research Funding; Incyte: Honoraria; Oncopeptides: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Research Funding; Onconova: Research Funding; Pfizer: Research Funding; Karyopharm: Research Funding. Broyl:Janssen, Celgene, Takeda, Amgen: Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Ludwig:Seattle Genetics: Other: Advisory Boards; Takeda: Research Funding; Sanofi: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Janssen: Other: Advisory Boards, Speakers Bureau; Celgene: Speakers Bureau. Hajek:Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Waage:Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Shire: Honoraria. Mellqvist:Janssen. Celgene, Amgen: Honoraria. Boccadoro:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

Introduction Immunomodulatory drug (IMiD)-based regimens are a standard of care (SOC) for RRMM. Daratumumab (DARA) is a CD38-targeted mAb approved for treatment of pts with RRMM. The subcutaneous (SC) formulation of DARA has a similar safety profile as intravenous DARA, with a statistically significant reduction in infusion-related reaction (IRR) rates and a considerably shorter administration duration of 5 mins. DARA SC is approved for use in the US, EU, Canada, and Korea. In the phase 1b study of DARA plus the IMiD pomalidomide, D-Pd induced deep responses and was well tolerated in pts with heavily pretreated RRMM, including those with prior lenalidomide (len) treatment. D-Pd is approved in the US for RRMM pts with ≥2 prior lines of therapy, including len and a proteasome inhibitor (PI). APOLLO (NCT03180736) is a phase 3 study conducted in collaboration between European Myeloma Network investigators and Janssen to evaluate DARA SC plus Pd vs Pd alone in RRMM pts who had received ≥1 prior line of therapy including len and a PI. We report the primary analysis of APOLLO. Methods In this open-label, multicenter study, eligible pts had RRMM and received ≥1 prior line of therapy including len and a PI, had responded to prior treatment and progressed on or after their last regimen; pts with only 1 prior line of therapy (1PL) were required to be refractory to len. Prior anti-CD38 or pomalidomide was not permitted. Pts were randomized 1:1 to Pd ± DARA SC. Stratification was based on International Staging System (ISS) disease stage (I, II, III) and number of lines of prior therapy (1, 2-3, ≥4). All pts received 28-day treatment cycles (C). P: 4 mg (PO) QD on Days 1-21; d: 40 mg (PO) on Days 1, 8, 15 and 22 (20 mg for pts ≥75 years of age). For D-Pd pts, DARA was given QW for C 1-2, Q2W for C 3-6, and Q4W thereafter. Prior to protocol amendment, pts received DARA IV 16 mg/kg (n=7); after protocol amendment, all pts received DARA SC 1,800 mg co-formulated with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.). All pts were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS. Major secondary endpoints included overall response rate, rates of very good partial response or better and complete response or better, MRD-negativity rate, overall survival (OS), and safety. Results A total of 304 pts from 12 European countries were randomized (151 D-Pd; 153 Pd). The median (range) age was 67 (35-90) years, and 45%/33%/22% pts were ISS stage I/II/III. 35% had high cytogenetic risk (presence of del17p, t[14;16], or t[4;14]). 11% of pts had received 1PL (median [range] prior lines of therapy = 2 [1-5]). 82% of pts were refractory to len, 68% of pts were refractory to a PI, and 63% of pts were refractory to both. Median duration of treatment was 11.5 months with D-Pd vs 6.6 months with Pd. The primary analysis was performed after 190 PFS events. The study met its primary endpoint of improved PFS; the hazard ratio (HR) was 0.63 (95% CI, 0.47-0.85; P=0.0018), representing a 37% reduction in the risk of progression or death in pts treated with D-Pd. The median PFS for the D-Pd vs Pd arms was 12.4 vs 6.9 months, respectively. With a median follow-up of 16.9 months, 99 pts (33%) have died; the HR for OS was 0.91 (95% CI, 0.61-1.35); survival data are immature and follow-up is ongoing. ≥CR rates for D-Pd vs Pd were 24.5% vs 3.9%; ≥VGPR rates were 51.0% vs 19.6%. The most common grade 3/4 adverse events with a >5% difference between D-Pd vs Pd were neutropenia (68% vs 51%), leukopenia (17% vs 5%), lymphopenia (12% vs 3%), febrile neutropenia (9% vs 3%), and pneumonia (13% vs 7%). The rate of IRRs with DARA SC was low (6%, all grade 1/2), and 2% of pts had local injection-site reactions (all grade 1). Median duration of injection was 5 mins. Rates of study treatment discontinuation due to TEAEs were similar for D-Pd vs Pd (2% vs 3%). The safety profile of D-Pd is consistent with known profiles of DARA SC and Pd. Conclusion In this phase 3 study evaluating DARA SC plus Pd, D-Pd significantly reduced the risk of progression or death by 37% in pts with RRMM who had received ≥1 prior line of therapy vs Pd alone. No new safety concerns were observed. The IRR rate was very low and administration duration short, thus increasing convenience for pts and decreasing treatment burden. Collectively, these data show that D-Pd is an effective and convenient treatment for pts with RRMM who received ≥1 prior therapy, including len and a PI. Disclosures Dimopoulos: Beigene: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Terpos:Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Beksac:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Katodritou:Theagenion Cancer Hospital: Current Employment; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Other: Expenses, Research Funding; Genesis Pharma: Honoraria, Other: Expenses, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau:Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Sanofi: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy. Symeonidis:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; WinMedica: Research Funding; GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding. Oriol:Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Celgene/Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Mateos:Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Einsele:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Orfanidis:Health Data Specialists: Current Employment, Current equity holder in private company. Ahmadi:Genmab: Current Employment, Current equity holder in publicly-traded company. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Kampfenkel:Janssen: Current Employment. Schecter:Janssen: Current Employment, Current equity holder in publicly-traded company. Qiu:Janssen: Current Employment. Amin:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Carson:Janssen: Current Employment. Sonneveld:Skyline Dx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding.

Background. The World Health Organization defines Waldenström Macroglobulinemia (WM) as a lymphoplasmacytic lymphoma associated with a serum immunoglobulin M (IgM) monoclonal protein. Since bone marrow (BM) infiltration is always present, while extramedullary involvement is infrequent, trephine BM biopsy is mandatory based on currently used diagnostic criteria, while multiparameter flow cytometry (MFC) studies are recommended to support the diagnosis (Owen et al, 2003). Next generation flow cytometry using panels with 8 to 17 monoclonal antibodies (MoAb), high number of cell acquisitions and appropriate software have shown an increased sensitivity, being able to detect one tumor cell among 10.000 normal cells (10-4) or even more. Aims of the study. Here we report an extensive phenotypic characterization by eight color MFC of a large prospective cohort of newly diagnosed WM patients, enrolled in the multicenter, observational trial BIO-WM (NCT03521596). In this study we evaluated the potential role of MFC on BM and peripheral blood (PB) samples as an alternative to BM biopsy in the diagnostic work-up of WM, with the final goal to assess the feasibility of a non-invasive or at least less invasive diagnostics. Methods. The diagnosis of WM was made using the criteria of the Second International Workshop on WM. Patients without bone marrow biopsy were excluded from the analysis. Whole BM and PB samples were processed following the bulk lysis protocol and stained using 8-color combination of the following fluorochrome-conjugated monoclonal antibodies: cIgM, CD56, CD5, CD19, CyK, CyL, CD38, CD45 (screening panel). CD5- lymphoproliferative disorders with two populations in different maturation stage showing identical cytoplasmatic light chain restriction underwent further characterization with six 8 color-panels (characterization panel). A minimum of 1x106/L cells per tube was acquired. The full list of monoclonal antibodies is reported in Table 1. Results. We analyzed 173 prospective patients with a histologic diagnosis of WM, either asymptomatic (n=46, 27%) or symptomatic (n=127, 73%). Their baseline characteristics are reported in Table 2. MFC results on BM samples collected at diagnosis were available in 165 patients. The median white blood cell (WBC) count was 13.5 x 109/L (IQR: 4.9-94) and the median number of cell acquisitions was 1.16 x 106 (IQR: 0.91-1.58). Clonal CD19+ B-cells were detected by MFC in 155/165 cases (94%) and showed k light chain restriction in 76% of cases. The median percentage of clonal CD19+ B-cells out of total BM WBC was 5.9% (IQR: 2.9-12.4). Twelve cases out of 165 (7%) were CD5+. The complete phenotype of clonal B CD19+ lymphocytes is shown in Figure 1. Clonal CD38+ plasma cells were detected in BM samples in 86% of cases and were CD20+ in 51% of cases. The median percentage of clonal CD38+ plasma cells out of total BM WBC was 0.18% (IQR: 0.05-0.47). The complete antigenic expression of clonal plasma cells is shown in Figure 2. The MYD88 (L265P) mutation was found with droplet digital polymerase chain reaction (dd-PCR) in 95% of patients with detectable clonal CD19+ B-cells in BM samples, without significant difference between CD5- and CD5+ cases (95% versus 93%, P=0.698). Paired BM and PB samples were available in 157 patients. Clonal CD19+ B-cells were detected in BM samples in 149/157 cases (95%) and in PB samples in 98/157 cases (58%). Overall, there was a slight agreement between BM and PB MFC results according to Landis and Koch scale (63%, k = 0.138). Conclusions. The comparison of MFC results on BM samples with BM histology in this large prospective cohort of WM patients suggests that eight-color MFC is highly sensitive and is able to identify the majority of patients with WM. Conversely, the comparison of MFC results on paired BM and PB samples indicates that MFC on PB samples has a low sensitivity, missing approximately 40% of cases. The integration of MFC results on BM samples with MYD88 mutation status assessed with a highly sensitive method such as dd-PCR may be considered as an alternative, less invasive method for the diagnosis of WM. Further analyses within this trial will assess the role of MFC combined with molecular profile of patients for the differential diagnosis between WM and other mature B-cell lymphoproliferative disorders as well as for the discrimination between WM and IgM monoclonal gammopathy of undetermined significance. Figure 1 Disclosures Varettoni: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Travel/accommodations/expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses. Ferrero:Servier: Speakers Bureau; Gilead: Research Funding, Speakers Bureau; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Puig:JANSSEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; TAKEDA: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; AMGEN: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; THE BINDING SITE: Consultancy, Honoraria; BRISTOL-MYERS SQUIBB: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau; CELGENE: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau. Ferrari:Abbvie: Honoraria. Laurenti:Janssen: Honoraria; Gilead: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Marchetti:Takeda: Other: Sponsored meetings; Pfeizer: Other: Sponsored meetings; AbbVie: Other: Sponsored meetings; Gilead: Consultancy; Novartis: Speakers Bureau; Amgen: Speakers Bureau. Re:BerGenBio ASA: Research Funding. Boccadoro:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding; AbbVie: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Garcia-Sanz:Novartis: Honoraria; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Gilead: Honoraria, Research Funding; BMS: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding.

Background. In multiple myeloma (MM), the role of minimal residual disease (MRD) by multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) is well established (H. Avet-Loiseau et al. IMW 2019, S. Oliva et al. EHA 2020). Aims. The aims of this analysis were the evaluation of (1) the rate of conversion from MRD-positivity (MRD-pos) to MRD-negativity (MRD-neg) with MFC and NGS during maintenance and (2) the impact on progression-free survival (PFS) and overall survival (OS) of MRD-neg with both techniques in different subgroups including different treatment arms. Methods. Newly diagnosed (ND)MM patients (pts) aged ≤65 years were randomized (R1) to receive carfilzomib (K)-lenalidomide (R)-dexamethasone (d) induction followed by autologous stem-cell transplantation (ASCT) and KRd consolidation (KRd_ASCT), 12 KRd cycles (KRd12), or K-cyclophosphamide(C)-d induction followed by ASCT and KCd consolidation (KCd_ASCT). After consolidation, pts were further randomized (R2) to KR vs R maintenance. MRD was assessed every 6 months (m) by 8-color second-generation flow cytometry (sensitivity 10-5) in pts with ≥very good partial response (VGPR). In pts achieving at least a complete response (≥CR), MRD was also assessed by NGS at the same time points (Adaptive Biotechnologies, Seattle, US-WA; sensitivity 10-5-10-6). Logistic regression analysis adjusted for International Staging System (ISS) stage (I vs II/III) and R1 was performed to evaluate the conversion rate from MRD-pos to MRD-neg during maintenance (KR vs R). PFS and OS of MRD-neg vs MRD-pos in the intention-to-treat (ITT) population were evaluated. For these analyses, MFC-pos pts included those who were positive by MRD plus those Results. Rates of MRD-neg by MFC and NGS before maintenance in the 3 induction/consolidation arms have been previously presented (S. Oliva et al. EHA 2020). At R2, 65% of randomized pts were MRD-neg by MFC (equally distributed in the 2 arms); 39% (48/123) of MRD-pos pts turned MRD-neg after a median of 7.6 m (IQR 6.5-12): 46% (29/63) in KR vs 32% (19/60) in R (OR 2.27; P=0.04) arms. At R2, 72% of pts evaluable for CR were MRD-neg by NGS (equally distributed in the 2 arms); 33% of MRD-pos pts (15/45) became MRD-neg at 10-5: 39% (9/23) in KR vs 27% (6/22) in R arms (=NS). In the ITT analysis, after a median follow-up of 45 m from R1, pts who were MRD-neg before maintenance by both techniques showed a superimposable prolonged PFS and OS vs pts who were MRD-pos: 3-year PFS was 80% vs 52% (HR 0.36, 95% CI 0.26-0.49 P The impact of pre-maintenance MRD negativity by MFC on PFS was explored in different treatment arms: 3-year PFS was longer in KRd_ASCT vs KRd12 and in KRd_ASCT vs KCd_ASCT arms; MRD-pos pts showed a similar PFS in the 3 arms. The same trend was shown by NGS MRD negativity: 3-year PFS was longer in KRd_ASCT vs KRd12 and in KRd_ASCT vs KCd_ASCT arms. A longer PFS was observed in pre-maintenance MRD-neg pts who were randomized to KR vs R both by MFC (HR 0.51, P=0.02) and NGS (HR 0.38, P=0.03); similar features were observed in MRD-pos pts (Fig. 1B). Conclusions. KR maintenance induced a high rate of conversion from MRD-pos to MRD-neg both by MFC and NGS. The outcomes of pts who were MRD-neg by MFC and NGS at 10-5 were similar, as well as those of pts with 1-year sustained MRD-neg both by MFC and NGS. These clinical findings confirmed a high degree of concordance between these two techniques. MRD-neg pts receiving KRD_ASCT showed a longer PFS (88% at 3 years) than pts receiving KRd12 and KCd_ASCT. KR vs R significantly prolonged PFS even in pts who were MRD-neg before maintenance. Figure 1 Disclosures Oliva: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Petrucci:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. D'Agostino:GSK: Membership on an entity's Board of Directors or advisory committees. Jacob:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Gozzetti:Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Research Funding. Kirsch:Adaptive Biotechnologies: Current Employment. Corradini:KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Musto:Amgen: Honoraria; Celgene: Honoraria. Boccadoro:Sanofi: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Zamagni:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gay:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including carfilzomib, cyclophosphamide, lenalidomide and dexamethasone).

Background. High-dose melphalan followed by autologous stem cell transplantation is a standard of care in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients and is also an option at relapse. Therefore, since the minimum number of CD34+ cells required to ensure adequate bone marrow recovery after myeloablative chemotherapy is 2x10^6/kg, an adequate upfront stem-cell collection is necessary in MM patients. Approximately 5-15% of MM patients mobilized with granulocyte colony-stimulating factor (G-CSF) or G-CSF+cyclophosphamide (G-CSF/CY) fail stem-cell collection ( Methods. NDMM patients undergoing stem-cell mobilization with cyclophosphamide (2-4 g/m2) and G-CSF (5-10 mcg/kg/day), with on-demand plerixafor according to clinical practice ( Results. At the data cut-off (09 June 2020), a total of 252 patients had been enrolled: of these, 192 patients (59, 29-72 years) were available for the analysis. The median number of induction cycles before mobilization was 4 (range 1-7); median time from diagnosis to mobilization was 6 months (IQR 5-8). Induction therapy consisted of a bortezomib-based regimen in 171 (90%), carfilzomib/lenalidomide-based regimen in 14 (7%), lenalidomide-based regimen in 3 patients (2%). 187/192 (97%) patients successfully collected ≥2 x 10^6/Kg CD34: of these, 153/192 (80%) collected with G-CSF/CY, 29/192 (15%) required the administration of plerixafor. The PM rate was 5/192 (2.5%): of these, 3/5 did not receive plerixafor in addition to G-CSF/CY, while 2/5 failed stem-cell collection despite the use of plerixafor. The median number of CD34 collected was 9.8x10^6/Kg (6.7-14.2). The median number of CD34/Kg collected with or without plerixafor was 5.1 (4.3-9.1) and 10.6 (8.1-14.4), respectively. The median number of apheresis days was 1 (IQR 1-2), with a stem-cell collection efficiency (CD34 number collected/ days of apheresis) equal to 7.7 x10^6 CD34/kg/day. The median number of apheresis days was 1 without plerixafor and 2 with plerixafor, with a stem-cell collection efficiency (CD34 number collected/ days of apheresis) equal to 8.8 without plerixafor and 3 with plerixafor. In patients who received plerixafor, the median number of CD34/ul pre-apheresis was 16 (10-19.5); after the administration of plerixafor, the median number of CD34/ul pre-apheresis increased to 46 (21-81). Non hematological AEs within 30 days after mobilization occurred in 8% of patients (grade 3-4: 2%); all grade and grade 3-4 infections occurred in 2% of patients each. In a multivariate analysis, main factors predicting the use of plerixafor were ISS 3 (vs. 1, OR 4.43; p=0.008), bone marrow plasma cells at diagnosis >60% (OR 3.85; p=0.006), white blood cell (WBC) count pre-mobilization (OR 6.66; p Conclusion. "On-demand" plerixafor combined with G-CSF/CY is a safe and effective rescue strategy for stem-cell collection in MM, reducing the PM rate to 2.5%. Extensive bone marrow plasmacytosis, ISS 3 disease at diagnosis, use of lenalidomide during induction and a low WBC count pre-mobilization predicted the use of plerixafor. Thus, pre-emptive administration of plerixafor in patients presenting one or more risk factors for poor mobilization might help in further reducing the PM rate. Disclosures Mina: Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Petrucci:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lemoli:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BerGenBio ASA: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Offidani:BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Corradini:F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Incyte: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; KiowaKirin: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Sanofi: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Kite: Consultancy, Honoraria. Cavo:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria. Boccadoro:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; AbbVie: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Larocca:Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of patients with multiple myeloma (including cyclophosphamide, G-CSF and plerixafor).

8046 Background: APOLLO (NCT03180736) is a phase 3 trial of pomalidomide and dexamethasone (Pd) ± subcutaneous daratumumab (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) in patients with RRMM and ≥1 prior line of therapy including lenalidomide and a proteasome inhibitor. After 16.9 months (mo) median follow-up, D-Pd significantly reduced the rate of progression or death by 37% relative to Pd. Patients with RRMM have reduced HRQoL compared with age- and sex-matched populations. Here, we present PROs from the APOLLO trial. Methods: Patients were randomized 1:1 to D-Pd or Pd and treated in 28-day cycles until disease progression/unacceptable toxicity. PROs were assessed on Day 1 of each cycle using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30), EORTC QLQ Multiple Myeloma Module 20-item (MY20), and EuroQol 5-dimensional descriptive system. PRO analyses were performed on patients from the intent-to-treat population with a baseline (BL) and ≥1 post-BL assessment. Treatment effect was assessed by a mixed effects model with repeated measures. Time to worsening was estimated using the Kaplan-Meier method. Results: A total of 304 patients were included (151 D-Pd, 153 Pd). Median treatment duration was 11.5 mo with D-Pd vs 6.6 mo with Pd. At Cycle 16 (Cyc 16), 63 and 40 patients remained on treatment in the D-Pd and Pd groups, respectively. Compliance rates for PRO instruments were high and comparable between groups. Patients treated with D-Pd had a reduction in pain (maximum improvement: 6.8 points at Cyc 12) measured with the EORTC QLQ-C30 and no mean change in disease symptoms or the treatment side effects subscales of the EORTC QLQ-MY20. Group mean physical and emotional functioning were unchanged from BL with D-Pd but worsened in the Pd group (maximum worsening: 6.4 at Cyc 4 and 9.1 points at Cyc 14). The proportion of patients with a meaningful improvement from BL was 55.0% vs 49.0% for disease symptoms, 43.0% vs 35.3% for physical functioning, and 41.7% vs 31.4% for emotional functioning with D-Pd vs Pd, respectively. Median time to worsening was ̃4 mo, except for the disease symptoms subscale (̃10 mo); there were no differences between groups. Conclusions: When daratumumab was added to Pd, patients did not experience any decrements in HRQoL while on treatment, but some patients experienced reductions in pain as well as clinically meaningful improvements in symptoms and emotional/physical function. These findings complement the clinical benefits of D-Pd in RRMM patients and further support its use in this RRMM population. Clinical trial information: NCT03180736.

8002 Background: Cytogenetic abnormalities (CA) are one of the most powerful prognostic factors in multiple myeloma (MM). In the FORTE study, carfilzomib-lenalidomide-dexamethasone induction/consolidation with ASCT (KRd_ASCT) significantly improved progression-free survival (PFS) vs KRd without ASCT (KRd12, HR 0.64) or carfilzomib-cyclophosphamide-dexamethasone (KCd) plus ASCT (KCd_ASCT, HR 0.53). KR maintenance significantly improved PFS vs R (HR 0.63). Methods: MM patients (pts) were randomized to KRd_ASCT vs KCd_ASCT vs KRd12 and, thereafter, to KR vs R maintenance. Subgroup analyses according to FISH evaluated the impact of each single high-risk (HiR) CA [del17p, t(4;14), t(14;16), del1p and 1q gain (3 copies) or amp1q (≥4 copies)] and that of combined CA, defining HiR by the presence of ≥1 HiR CA and double-hit (DH) by the presence of ≥2 HiR CA. Pts negative for all the HiR CA were considered at standard risk (SR). The primary objective was the impact of treatment on PFS according to pt risk. Results: 396 out of 474 enrolled pts were included in the analysis with complete FISH data: 243 HiR, 105 DH and 153 SR. Among HiR pts, 60 had del17p, 65 t(4;14), 20 t(14;16), 44 del1p, 126 1q gain and 49 amp1q. SR pts benefited from intensification with KRd_ASCT vs KRd12 (HR 0.47, p = 0.05) and KCd_ASCT (HR 0.38, p = 0.01), with a 4-year PFS of 80%, 67% and 57%, respectively. In HiR pts, KRd_ASCT improved PFS vs KRd12 (HR 0.6, p = 0.04) and KCd_ASCT (HR 0.57, p = 0.01), with a 4-year PFS of 62%, 45% and 45%, respectively. The advantage with KRd_ASCT vs KRd12 (HR 0.53, p = 0.07) and KCd_ASCT (HR 0.49; p = 0.03) was also observed in DH pts (4-year PFS 55%, 31% and 33%, respectively). Analyses by single CA were limited by the small number of pts in each subgroup, but a trend towards a PFS benefit from KRd_ASCT vs KRd12 was seen in pts with del17p (HR 0.61, p = 0.3), t(4;14) (HR 0.59, p = 0.2) and 1q gain (HR 0.45, p = 0.02). In pts with del1p, KRd_ASCT (HR 0.24, p = 0.06) and KRd12 (HR 0.33, p = 0.09) showed superiority over KCd_ASCT, while amp1q pts had the worst outcome regardless of treatment (KRd_ASCT vs KCd_ASCT, HR 1.16, p = 0.73; KRd12 vs KCd_ASCT, HR 1.34, p = 0.45). KR improved PFS vs R in SR (3-year PFS 90% vs 73%, HR 0.42, p = 0.06), HiR (3-year PFS 69% vs 56%, HR 0.6, p = 0.04) and DH pts (3-year PFS 67% vs 42%, HR 0.53, p = 0.1). Despite the small subgroups, a beneficial trend with KR vs R was observed in pts with del17p (HR 0.59, p = 0.37), t(4;14) (HR 0.59, p = 0.3), 1q gain (HR 0.54, p = 0.07) and del1p (HR 0.23, p = 0.08), while amp1q pts showed the worst outcome and no benefit from KR vs R (HR 0.83, p = 0.7). Conclusions: KRd_ASCT and KR maintenance are highly effective in SR and also in HiR and DH pts, with impressive 4-year PFS from diagnosis (KRd_ASCT: HiR 62%, DH 55%) and 3-year PFS from maintenance (KR: HiR 69%, DH 67%), thus supporting their use in HiR pts, who represent an unmet medical need. Clinical trial information: NCT02203643.

Introduction Flow cytometry is a useful tool for diagnosis and minimal residual disease (MRD) study of hematological diseases. Standard sample preparation protocols are characterized by stain-lyse-wash (SLW). To prevent nonspecific bindings and achieve high sensitivity in MRD studies, lyse-wash-stain-wash (LWSW) is required. To our knowledge, no comparison between the two methods has been performed. Methods We compared mean fluorescence intensity (MFI), stain index, signal-to-noise ratio, and percentage of positive cells of 104 antibodies and of 13 selected antibodies tested in 10 samples simultaneously prepared with the two methods. Results MFI and percentages of positive cells obtained by the two methods did not show significant differences and showed a very high correlation. Stain index and signal-to-noise ratio presented higher values for kappa and lambda surface chains in LWSW samples and a trend of higher values for the other antibodies in SLW samples. Conclusions We suggest to use LWSW method also at diagnosis to obtain more comparable antibody intensity expressions when samples from the same patient are processed for MRD evaluation after bulk lysis. Moreover, LWSW can prevent nonspecific bindings, shows no differences in the identification and quantitation of the populations of interest, and reduces acquisition of cell debris.

Advances in understanding myeloma biology have shown that disease progression is not only the consequence of intrinsic tumor changes but also of interactions between the tumor and the microenvironment in which the cancer grows. The immune system is an important component of the tumor microenvironment in myeloma, and acting on the immune system is an appealing new treatment strategy. There are 2 ways to act toward immune cells and boost antitumor immunity: (1) to increase antitumor activity (acting on T and NK cytotoxic cells), and (2) to reduce immunosuppression (acting on myeloid-derived stem cells and T regulatory cells). Checkpoint inhibitors and adoptive cell therapy (ACT) are 2 of the main actors, together with monoclonal antibodies and immunomodulatory agents, in the immune-oncologic approach. The aim of checkpoint inhibitors is to release the brakes that block the action of the immune system against the tumor. Anti-programmed death-1 (PD-1) and PD-1-Ligand, as well as anti-CTLA4 and KIR are currently under evaluation, as single agents or in combination, with the best results achieved so far with combination of anti-PD-1 and immunomodulatory agents. The aim of ACT is to create an immune effector specific against the tumor. Preliminary results on chimeric antigen receptor (CAR) T cells, first against CD19, and more recently against B-cell maturation antigen, have shown to induce durable responses in heavily pretreated patients. This review focuses on the most recent clinical results available on the use of checkpoint inhibitors and CAR-T cells in myeloma, in the context of the new immune-oncologic approach.

In the past few years, multiple targeted therapies and immunotherapies including second generation immunomodulatory drugs (pomalidomide) and proteasome inhibitors (carfilzomib, ixazomib), monoclonal antibodies and checkpoint inhibitors were approved for the treatment of myeloma or entered advanced phases of clinical testing. These agents showed significant activity in advanced myeloma and increased the available treatment strategies. Pomalidomide is well-tolerated and effective in patients with relapsed/refractory multiple myeloma who have exhausted any possible treatment with lenalidomide and bortezomib. Carfilzomib, a second-generation proteasome inhibitor, is active as a single agent and in combination with other anti-myeloma agents. Ixazomib is the first oral proteasome inhibitor to be evaluated in myeloma and is associated with a good safety profile and anti-myeloma activity in relapsed/refractory patients, even in those refractory to bortezomib. Monoclonal antibodies and immune checkpoint inhibitors are likely to play a major role in the treatment of myeloma over the next decade. In phase 3 studies, triplet regimens based on these agents combined with a backbone therapy (including lenalidomide, pomalidomide or bortezomib) were more efficacious than doublet regimens in patients with relapsed/refractory multiple myeloma, with limited additional toxic effects. This paper aims to provide an overview of the recent use of these agents for the treatment of myeloma, in particular focusing on the role of multi-agent combinations.