Search

AL amyloidosis is a systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. High dose intravenous melphalan and autologous stem cell transplantation was developed for the treatment of AL amyloidosis in the early 1990s and was prompted by its success in multiple myeloma. This application has evolved significantly over the past three decades. These guidelines provide a comprehensive assessment of eligibility criteria, stem cell collection and mobilisation strategies and regimens, risk-adapted melphalan dosing, role for induction and consolidation therapies, specific supportive care management, long-term outcome with respect to survival, haematologic response and relapse and organ responses following stem cell transplantation. These guidelines are developed by the experts in the field on behalf of the stem cell transplant working group of the International Society of Amyloidosis (ISA) and European Haematology Association (EHA).

Introduction: The objective of this study was to understand the potential use of single agents and drug combinations in multiple myeloma (MM) across treatment lines in the years 2021 and 2023. Methods: The method used was Delphi Panel Method survey, administered to European Myeloma Network (EMN) Italy Working Group centres. Future treatments were identified assessing all available web-based information sources, including therapies (single drugs or combinations) with strong evidence of efficacy, likely to be on the Italian market in 2021 and 2023. Participants were asked to report on the likelihood of prescription for MM therapies, across treatment lines. Results: Across the 15 centres taking part in the survey, about 890 patients per year are forecasted to receive a new diagnosis of MM. In 2021, the Panel forecasted 66% of 1L-TE (transplant eligible) patients will be treated with bortezomib-thalidomide-dexamethasone (VTD) and 32% of patients with daratumumab-bortezomib-thalidomide-dexamethasone (DVTd), with a substantial decrease of VTD (15%) and a marked increase of DVTd (81%) forecasted for 2023. The 2L and 3L R(lenalidomide)-based combination treatments are expected to drop and will likely be substituted by a steep increase in P(pomalidomide)-based regimes (from 7% to 23%). On the contrary, in 3L treatment, all combination therapies (with the exception of IsaPd – isatuximab-pomalidomide-dexamethasone) are expected to lose market share in favour of the most recent new therapies. Conclusions: Expert Panel agrees that many different new drugs and combinations will be used in MM, with different mechanisms of action, both at diagnosis and in subsequent phases of the disease, with a corresponding decline of the drugs currently used.

Autoimmune cytopenias (AICs) affect 5% to 9% of patients with chronic lymphocytic leukemia (CLL). Targeted drugs—ibrutinib, idelalisib, and venetoclax—have a prominent role in the treatment of CLL, but their impact on CLL-associated AICs is largely unknown. In this study, we evaluated the characteristics and outcome of preexisting AICs and described the incidence, quality, and management of treatment-emergent AICs during therapy with targeted drugs in patients with CLL. We collected data from 572 patients treated with ibrutinib (9% in combination with an anti-CD20 monoclonal antibody), 143 treated with idelalisib-rituximab, and 100 treated with venetoclax (12% in combination with an anti-CD20 monoclonal antibody). A history of preexisting AICs was reported in 104 (13%) of 815 patients. Interestingly, 80% of patients whose AICs had not resolved when treatment with a targeted drug was started experienced an improvement or a resolution during therapy. Treatment-emergent AICs occurred in 1% of patients during ibrutinib therapy, in 0.9% during idelalisib therapy, and in 7% during venetoclax therapy, with an estimated incidence rate of 5, 6, and 69 episodes per 1000 patients per year of exposure in the 3 treatment groups, respectively. The vast majority of patients who developed treatment-emergent AICs had unfavorable biological features such as an unmutated IGHV and a del(17p) and/or TP53 mutation. Notably, despite AICs, 83% of patients were able to continue the targeted drug, in some cases in combination with additional immunosuppressive agents. Overall, treatment with ibrutinib, idelalisib, or venetoclax seems to have a beneficial impact on CLL-associated AICs, inducing an improvement or even a resolution of preexisting AICs in most cases and eliciting treatment-emergent AICs in a negligible portion of patients.

Multiple available combinations of proteasome inhibitors, immunomodulators (IMIDs), and monoclonal antibodies are shifting the relapsed/refractory multiple myeloma (RRMM) treatment landscape. Lack of head-to-head trials of triplet regimens highlights the need for real-world (RW) evidence. We conducted an RW comparative effectiveness analysis of bortezomib (V), carfilzomib (K), ixazomib (I), and daratumumab (D) combined with either lenalidomide or pomalidomide plus dexamethasone (Rd or Pd) in RRMM. A retrospective cohort of patients initiating triplet regimens in line of therapy (LOT) ≥ 2 on/after 1/1/2014 was followed between 1/2007 and 3/2018 in Optum’s deidentified US electronic health records database. Time to next treatment (TTNT) was estimated using Kaplan-Meier methods; regimens were compared using covariate-adjusted Cox proportional hazard models. Seven hundred forty-one patients (820 patient LOTs) with an Rd backbone (VRd, n = 349; KRd, n = 218; DRd, n = 99; IRd, n = 154) and 348 patients (392 patient LOTs) with a Pd backbone (VPd, n = 52; KPd, n = 146; DPd, n = 149; IPd, n = 45) in LOTs ≥2 were identified. More patients ≥75 years received IRd (39.6%), IPd (37.8%), and VRd (36.7%) than other triplets. More patients receiving VRd/VPd were in LOT2 vs other triplets. Unadjusted median TTNT in LOT ≥ 2: VRd, 13.9; KRd, 8.7; IRd, 11.4; DRd, not estimable (NE); and VPd, 12.0; KPd, 6.7; IPd, 9.5 months; DPd, NE. In covariate-adjusted analysis, only KRd vs DRd was associated with a significantly higher risk of next LOT initiation/death (HR 1.72; P = 0.0142); no Pd triplet was significantly different vs DPd in LOT ≥ 2. Our data highlight important efficacy/effectiveness gaps between results observed in phase 3 clinical trials and those realized in the RW.

ispartof: HEMASPHERE vol:5 issue:2 ispartof: location:United States status: published

Introduction Daratumumab is a CD38-targeting monoclonal antibody that has demonstrated clinical benefit for multiple myeloma. Daratumumab inhibition of CD38, which is expressed on immune cell populations and cardiomyocytes, could potentially affect cardiac function. This QTc substudy of the phase 2 CENTAURUS study investigated the potential effect of intravenous daratumumab monotherapy on QTc prolongation and other electrocardiogram (ECG) parameters, including concentration-QTc effect modeling. Methods Patients had intermediate- or high-risk smoldering multiple myeloma. Patients with QT interval corrected by Fridericia’s formula (QTcF) > 470 ms, QRS interval ≥ 110 ms, or PR interval ≥ 200 ms were excluded. Triplicate ECGs were collected at screening, Dose 1, and Dose 8. Analyses of on-treatment ECGs were conducted with a time-matched baseline (primary analysis). By time-point, pharmacokinetic-pharmacodynamic (PK/PD), and outlier analyses were conducted. Results Of 123 patients in CENTAURUS, 31 were enrolled in the QTc substudy. Daratumumab produced a small increase in heart rate (5–12 beats per minute) of unclear significance. There was a small but clinically insignificant effect on QTc, as measured by both time-matched time-point and PK/PD analyses. The primary analysis demonstrated a maximum mean increase in QTcF of 9.1 ms (90% 2-sided upper confidence interval [CI], 14.1 ms). The primary PK/PD analysis predicted a maximum QTcF increase of 8.5 ms (90% 2-sided upper CI, 13.5 ms). No patient had an abnormal U wave, a new QTcF > 500 ms, or > 60 ms change from baseline for QTcF. Conclusion Analysis of ECG intervals and concentration-QTc relationships showed a small but clinically insignificant effect of daratumumab. Trial Registration ClinicalTrials.gov Identifier: NCT02316106. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-020-01601-w.

PURPOSE 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is currently the standard technique to define minimal residual disease (MRD) status outside the bone marrow (BM) in patients with multiple myeloma (MM). This study aimed to define criteria for PET complete metabolic response after therapy, jointly analyzing a subgroup of newly diagnosed transplantation-eligible patients with MM enrolled in two independent European randomized phase III trials (IFM/DFCI2009 and EMN02/HO95). PATIENTS AND METHODS 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. RESULTS 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 BMS < 4 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) CONCLUSION 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.

NA

Background: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study. Methods: In this randomised, open-label, phase 3 study, patients aged 18–65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1–2, 4–5, 8–9, and 11–12 in the VTD regimen, and 40 mg on days 1–4 and 9–12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484. Findings: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2–131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28–41) compared with 17% (13–23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50–0·77]; p

Background. The Revised International Staging system (R-ISS) is the standard risk stratification model used for newly diagnosed (ND) multiple myeloma (MM) (Palumbo et al. JCO 2015). R-ISS identifies 3 groups of patients (pts) with different PFS and OS. However, 60% of pts are considered as intermediate-risk (R-ISS II), possibly including pts with different risk of progression/death. Recently, 1q copy number alterations (CNAs), which were not included in the R-ISS, proved to be a poor prognostic factor in NDMM pts. The European Myeloma Network (EMN), under the umbrella of the HARMONY project, collected more than 7000 patient data from European clinical trials. The aim of this analysis is to revise the R-ISS risk stratification model, by analyzing the prognostic value of each single baseline risk feature, including 1q CNAs, to improve prognostication in NDMM pts. Methods. Data from 15 European clinical trials enrolling NDMM pts from 2005 to 2014 were collected through EMN and registered in HARMONY platform. HARMONY is a European public-private partnership focusing on hematologic malignancies with unmet medical needs, including MM. OMOP Common Data Model was used to harmonize data. All pts received an immunomodulatory agent (IMiD) and/or a proteasome inhibitor (PI) upfront. In a multivariate Cox regression analysis adjusted for age, sex and therapy, we evaluated the impact of each risk feature on overall survival (OS) and progression-free survival (PFS). The hazard of death conferred by the most significant variables was used to create an additive risk score. Results. 7077 NDMM pts were registered in the HARMONY platform and included in the analysis. Data were mature with a median follow-up of 75 months; median age was 62 years. The majority of pts were transplant-eligible (65%). 40% of the pts received IMiDs only, 15% PIs only, 46% both drug classes during their first-line treatment. In a multivariate Cox model, ISS (II vs I HR 1.55 p These prognostic variables were simultaneously present in 2227 pts and the most frequent reason of exclusion of the remaining pts was 1q CNAs that was missing in some of the trials. We exploited the OS impact of these risk features in pts with complete data to create an additive scoring system (Table 1). Pts were then stratified into 4 groups: Low [(n=429 (19.3%), score 0)], Low-Intermediate [(n=686 (30.8%), score 0.5-1], Intermediate-High [(n=917 (41.2%), score 1.5-2.5] and High [(n=195 (8.8%), score 3-5]. Each group showed significantly different OS (Figure 1A) and PFS (Figure 1B). Median OS was not reached vs 109.2 vs 68.5 vs 37.9 months and median PFS was 68 vs 45.5 vs 30.2 vs 19.9 months in the above 4 risk groups, respectively. With this new stratification model, R-ISS stage II pts (n=1372) were better distributed into Low-Intermediate (n=517), Intermediate-High (n=811) and High risk (n=44) groups, confirming that this wide group included heterogeneous pts with a different risk of progression and/or death. This new risk stratification maintained its prognostic value in subgroup analysis of transplant-eligible and transplant-ineligible pts and in pts receiving IMiDs, PIs or both. Conclusion. This analysis on a large number of patient data collected thanks to a well-established European collaboration demonstrated that the existing R-ISS stratification model may be improved. This additive scoring system based on the impact of single risk features could be the future risk stratification model for NDMM, so called "R2-ISS". About half of the pts can be classified as Low or Low-Intermediate risk and about half of the pts can be classified as Intermediate-High or High risk, representing an opportunity to design risk-adapted approaches in a meaningful number of pts. Moreover, such additive risk score easily allows the inclusion of new prognostic variables in the future as they continue to emerge. The inclusion of new patient data is ongoing, and validation in an independent cohort is planned. Disclosures D'Agostino: GSK: Membership on an entity's Board of Directors or advisory committees. Waage:Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Shire: Honoraria. Zamagni:Sanofi: 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; 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; 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. Mateos:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; PharmaMar-Zeltia: Consultancy; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; 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. Larocca:Takeda: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria. van de Donk:Takeda: Other: Ad Board; Genentech: Other: Ad Board; Bayer: Other: Ad Board; BMS: Other: Ad Board, Research Funding; Amgen: Other: Ad Board, Research Funding; Celgene: Other: Ad Board, Research Funding; Novartis: Other: Ad Board; Janssen: Other: Ad Board, Research Funding. Cairns:Celgene, Amgen, Merck: Research Funding; Celgene: Other: Travel Support. Salwender:Takeda: Honoraria; Bristol-Myers Squibb/Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria; Sanofi: Honoraria; GlaxoSmithKline: Honoraria; AbbVie: Honoraria. Blade Creixenti:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Dürig:Janssen: Consultancy; AbbVie: Consultancy; Celgene: Consultancy. Bringhen:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Celgene: 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. 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; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo:AbbVie: 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, Speakers Bureau; 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; 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; 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. Goldschmidt:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Molecular Partners: Research Funding; Merck Sharp and Dohme (MSD): Research Funding; Novartis: Honoraria, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Mundipharma GmbH: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding. Cook:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; IQVIA: Research Funding; Sanofi: Consultancy; Amgen: Consultancy; Roche: Consultancy; Karyopharm: Consultancy. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, 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. Sonneveld:Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma.

Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

The last twenty years have introduced new therapeutic agents for multiple myeloma (MM); these include proteasome inhibitors (PIs), immunomodulatory drugs (IMDs) and monoclonal antibodies (mAbs). However, MM remains incurable, hence there is an unmet need for new agents for the treatment of advanced refractory disease. New agents could also be used in early lines to achieve improved, more sustained remission.We review the most promising agents investigated in early-phase trials for the treatment of MM and provide an emphasis on new agents directed against well-known targets (new PIs, IMDs and anti-CD38 mAbs). Drugs that work through distinct and numerous mechanisms of action (e.g. pro-apoptotic agents and tyrosine kinase inhibitors) and innovative immunotherapeutic approaches are also described. The paper culminates with our perspective on therapeutic approaches on the horizon for this disease.IMD iberdomide and the export protein inhibitor selinexor demonstrated efficacy in heavily pretreated patients who had no other therapeutic options. We expect that immunotherapy with anti-BCMA BTEs and ADCs will revolutionize the approach to treating the early stages of the disease. Data on venetoclax in t(11;14)-positive patients may pave the way for personalized therapy. Not all new agents under early clinical evaluation will be investigated in regulatory phase III trials; one of the most important challenges is to identify those that could make a difference.

Background The emergence of highly active novel agents has led some to question the role of autologous haematopoietic stem-cell transplantation (HSCT) and subsequent consolidation therapy in newly diagnosed multiple myeloma. We therefore compared autologous HSCT with bortezomib-melphalan-prednisone (VMP) as intensification therapy, and bortezomib-lenalidomide-dexamethasone (VRD) consolidation therapy with no consolidation.Methods In this randomised, open-label, phase 3 study we recruited previously untreated patients with multiple myeloma at 172 academic and community practice centres of the European Myeloma Network. Eligible patients were aged 18-65 years, had symptomatic multiple myeloma stage 1-3 according to the International Staging System (I S S), measurable disease (serum M protein >10 g/L or urine M protein >200 mg in 24 h or abnormal free light chain [FLC] ratio with involved FLC >100 mg/L, or proven plasmacytoma by biopsy), and WHO performance status grade 0-2 (grade 3 was allowed if secondary to myeloma). Patients were first randomly assigned (1:1) to receive either four 42-day cycles of bortezomib (1.3 mg/m 2 administered intravenously or subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32) combined with melphalan (9 mg/m(2) administered orally on days 1-4) and prednisone (60 mg/m(2) administered orally on days 1-4) or autologous HSCT after high-dose melphalan (200 mg/m(2)), stratified by site and ISS disease stage. In centres with a double HS CT policy, the first randomisation (1:1:1) was to VMP or single or double HSCT. Afterwards, a second randomisation assigned patients to receive two 28-day cycles of consolidation therapy with bortezomib (1.3 mg/m(2)either intravenously or subcutaneously on days 1, 4, 8, and 11), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12) or no consolidation; both groups received lenalidomide maintenance therapy (10 mg orally on days 1-21 of a 28-day cycle). The primary outcomes were progression-free survival from the first and second randomisations, analysed in the intention-to-treat population, which included all patients who underwent each randomisation. All patients who received at least one dose of study drugs were included in the safety analyses. This study is registered with the EU Clinical Trials Register (EudraCT 2009-017903-28) and ClinicalTrials.gov (NCT01208766), and has completed recruitment.Findings Between Feb 25, 2011, and April 3, 2014, 1503 patients were enrolled. 1197 patients were eligible for the first randomisation, of whom 702 were assigned to autologous HSCT and 495 to VMP; 877 patients who were eligible for the first randomisation underwent the second randomisation to VRD consolidation (n=449) or no consolidation (n=428). The data cutoff date for the current analysis was Nov 26, 2018. At a median follow-up of 60.3 months (IQR 52. 2-67. 6), median progression-free survival was significantly improved with autologous HSCT compared with VMP (56.7 months [95% CI 49.3-64.5] vs 41.9 months [37.5-46.9]; hazard ratio [HR] 0.73, 0.62-0.85; p=0.0001). For the second randomisation, the number of events of progression or death at data cutoff was lower than that preplanned for the final analysis; therefore, the results from the second protocol-specified interim analysis, when 66% of events were reached, are reported (data cutoff Jan 18, 2018). At a median follow-up of 42.1 months (IQR 32.3-49.2), consolidation therapy with VRD significantly improved median progression-free survival compared with no consolidation (58.9 months [54.0-not estimable] vs 45.5 months [39.5-58.4]; HR 0.77, 0.63-0.95; p=0.014). The most common grade >= 3 adverse events in the autologous HSCT group compared to the VMP group included neutropenia (513 [79%] of 652 patients vs 137 [29%] of 472 patients), thrombocytopenia (541 [83%] vs 74 [16%]), gastrointestinal disorders (80 [12%] vs 25 [5%]), and infections (192 [30%] vs 18 [4%]). 239 (34%) of 702 patients in the autologous HSCT group and 135 (27%) of 495 in the VMP group had at least one serious adverse event. Infection was the most common serious adverse event in each of the treatment groups (206 [56%] of 368 and 70 [37%] of 189). 38 (12%) of 311 deaths from first randomisation were likely to be treatment related: 26 (68%) in the autologous HSCT group and 12 (32%) in the VMP group, most frequently due to infections (eight [21%]), cardiac events (six [16%]), and second primary malignancies (20 [53%]).Interpretation This study supports the use of autologous HSCT as intensification therapy and the use of consolidation therapy in patients with newly diagnosed multiple myeloma, even in the era of novel agents. The role of high-dose chemotherapy needs to be reassessed in future studies, in particular in patients with undetectable minimal residual disease after four-drug induction regimens including a monoclonal antiboby combined with an immunomodulatory agent and a proteasome inhibitor plus dexamethasone. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Practical, safe, and effective hemostatic approach to orthopedic surgery using Extended Half‐Life factor IX in hemophilia B. By intraindividual comparison, we found a lower FIX consumption, number of infusions, and cost compared to plasma‐derived FIX.

PURPOSE Data collection in clinical trials is becoming complex, with a huge number of variables that need to be recorded, verified, and analyzed to effectively measure clinical outcomes. In this study, we used data warehouse (DW) concepts to achieve this goal. A DW was developed to accommodate data from a large clinical trial, including all the characteristics collected. We present the results related to baseline variables with the following objectives: developing a data quality (DQ) control strategy and improving outcome analysis according to the clinical trial primary end points. METHODS Data were retrieved from the electronic case reporting forms (eCRFs) of the phase III, multicenter MCL0208 trial (ClinicalTrials.gov identifier: NCT02354313 ) of the Fondazione Italiana Linfomi for younger patients with untreated mantle cell lymphoma (MCL). The DW was created with a relational database management system. Recommended DQ dimensions were observed to monitor the activity of each site to handle DQ management during patient follow-up. The DQ management was applied to clinically relevant parameters that predicted progression-free survival to assess its impact. RESULTS The DW encompassed 16 tables, which included 226 variables for 300 patients and 199,500 items of data. The tool allowed cross-comparison analysis and detected some incongruities in eCRFs, prompting queries to clinical centers. This had an impact on clinical end points, as the DQ control strategy was able to improve the prognostic stratification according to single parameters, such as tumor infiltration by flow cytometry, and even using established prognosticators, such as the MCL International Prognostic Index. CONCLUSION The DW is a powerful tool to organize results from large phase III clinical trials and to effectively improve DQ through the application of effective engineered tools.

Background: Bortezomib-based induction followed by high-dose melphalan (200 mg/m2) and autologous stem-cell transplantation (MEL200-ASCT) and maintenance treatment with lenalidomide alone is the current standard of care for young and fit patients with newly diagnosed multiple myeloma. We aimed to evaluate the efficacy and safety of different carfilzomib-based induction and consolidation approaches with or without transplantation and of maintenance treatment with carfilzomib plus lenalidomide versus lenalidomide alone in newly diagnosed multiple myeloma. Methods: UNITO-MM-01/FORTE was a randomised, open-label, phase 2 trial done in 42 Italian academic and community practice centres. We enrolled transplant-eligible patients with newly diagnosed multiple myeloma aged 65 years or younger with a Karnofsky Performance Status of 60% or higher. Patients were stratified according to International Staging System stage (I vs II/III) and age (

Patients with multiple myeloma frequently present with substantial immune impairment and an increased risk for infections and infection-related mortality. The risk for infection with SARS-CoV-2 virus and resulting mortality is also increased, emphasising the importance of protecting patients by vaccination. Available data in patients with multiple myeloma suggest a suboptimal anti-SARS-CoV-2 immune response, meaning a proportion of patients are unprotected. Factors associated with poor response are uncontrolled disease, immunosuppression, concomitant therapy, more lines of therapy, and CD38 antibody-directed and B-cell maturation antigen-directed therapy. These facts suggest that monitoring the immune response to vaccination in patients with multiple myeloma might provide guidance for clinical management, such as administration of additional doses of the same or another vaccine, or even temporary treatment discontinuation, if possible. In those who do not exhibit a good response, prophylactic treatment with neutralising monoclonal antibody cocktails might be considered. In patients deficient of a SARS-CoV-2 immune response, adherence to measures for infection risk reduction is particularly recommended. This consensus was generated by members of the European Multiple Myeloma Network and some external experts. The panel members convened in virtual meetings and conducted an extensive literature research and evaluated recently published data and work presented at meetings, as well as findings from their own studies. The outcome of the discussions on establishing consensus recommendations for COVID-19, This study has been funded by the Austrian Forum against Cancer, which covered in part expenses for interaction between authors and for secretarial support.

Elderly transplant-ineligible (NTE) patients represent the majority of patients affected by multiple myeloma (MM). Elderly patients are a highly heterogeneous population, with large variability in health and functional status. Thus, choosing their optimal treatment is challenging. A wide range of first-line treatments is available, and novel-agent combinations, including monoclonal antibodies (mAbs), have recently entered clinical practice. The combination of the anti-CD38 mAb daratumumab with bortezomib, melphalan and prednisone (Dara-VMP) or lenalidomide and dexamethasone (Dara-Rd) demonstrated impressive advantages in terms of progression-free survival and minimal residual disease negativity, as compared to VMP and Rd, without safety concerns. Another anti-CD38 mAb, isatuximab, is showing encouraging results, and new isatuximab-based combinations might enter clinical practice in the future. Nevertheless, available data come from clinical trials with selected patient populations and, to date, the manageability of these regimens in real-life patients or in frail patients remains unknown. Frailty-tailored treatments, including mAbs, are under evaluation in preliminary studies. In this review, we analyze recently approved mAb-based treatments for NTE newly diagnosed MM patients and new combinations under evaluation, focusing on the efficacy and safety of these regimens and on open issues regarding the choice of therapy for elderly patients.

PURPOSE To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease–negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and

Background: In a phase 1b study, intravenous daratumumab plus pomalidomide and dexamethasone induced a very good partial response or better rate of 42% and was well tolerated in patients with heavily pretreated multiple myeloma. We aimed to evaluate whether daratumumab plus pomalidomide and dexamethasone would improve progression-free survival versus pomalidomide and dexamethasone alone in patients with previously treated multiple myeloma. Methods: In this ongoing, open-label, randomised, phase 3 trial (APOLLO) done at 48 academic centres and hospitals across 12 European countries, eligible patients were aged 18 years or older, had relapsed or refractory multiple myeloma with measurable disease, had an Eastern Cooperative Oncology Group performance status of 0–2, had at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if only one previous line of therapy was received. Patients were randomly assigned (1:1) by an interactive web-response system in a random block size of two or four to receive pomalidomide and dexamethasone alone or daratumumab plus pomalidomide and dexamethasone. Randomisation was stratified by number of previous lines of therapy and International Staging System disease stage. All patients received oral pomalidomide (4 mg, once daily on days 1–21) and oral dexamethasone (40 mg once daily on days 1, 8, 15, and 22; 20 mg for those aged 75 years or older) at each 28-day cycle. The daratumumab plus pomalidomide and dexamethasone group received daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) weekly during cycles 1 and 2, every 2 weeks during cycles 3–6, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT03180736. Findings: Between June 22, 2017, and June 13, 2019, 304 patients (median age 67 years [IQR 60–72]; 161 [53%] men and 143 [47%] women) were randomly assigned to the daratumumab plus pomalidomide and dexamethasone group (n=151) or the pomalidomide and dexamethasone group (n=153). At a median follow-up of 16·9 months (IQR 14·4–20·6), the daratumumab plus pomalidomide and dexamethasone group showed improved progression-free survival compared with the pomalidomide and dexamethasone group (median 12·4 months [95% CI 8·3–19·3] vs 6·9 months [5·5–9·3]; hazard ratio 0·63 [95% CI 0·47–0·85], two-sided p=0·0018). The most common grade 3 or 4 adverse events were neutropenia (101 [68%] of 149 patients in the daratumumab plus pomalidomide and dexamethasone group vs 76 [51%] of 150 patients in the pomalidomide and dexamethasone group), anaemia (25 [17%] vs 32 [21%]), and thrombocytopenia (26 [17%] vs 27 [18%]). Serious adverse events occurred in 75 (50%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group versus 59 (39%) of 150 patients in the pomalidomide and dexamethasone group; pneumonia (23 [15%] vs 12 [8%] patients) and lower respiratory tract infection (18 [12%] vs 14 [9%]) were most common. Treatment-emergent deaths were reported in 11 (7%) patients in the daratumumab plus pomalidomide and dexamethasone group versus 11 (7%) patients in the pomalidomide and dexamethasone group. Interpretation: Among patients with relapsed or refractory multiple myeloma, daratumumab plus pomalidomide and dexamethasone reduced the risk of disease progression or death versus pomalidomide and dexamethasone alone and could be considered a new treatment option in this setting. Funding: European Myeloma Network and Janssen Research and Development., European Myeloma Network and Janssen Research and Development.

Chimeric antigen receptor (CAR) T cells (CAR-T) have dramatically changed the treatment landscape of B-cell malignancies, providing a potential cure for relapsed/refractory patients. Long-term responses in patients with acute lymphoblastic leukemia and non Hodgkin lymphomas have encouraged further development in myeloma. In particular, B-cell maturation antigen (BCMA)-targeted CAR-T have established very promising results in heavily pre-treated patients. Moreover, CAR-T targeting other antigens (i.e., SLAMF7 and CD44v6) are currently under investigation. However, none of these current autologous therapies have been approved, and despite high overall response rates across studies, main issues such as long-term outcome, toxicities, treatment resistance, and management of complications limit as yet their widespread use. Here, we critically review the most important pre-clinical and clinical findings, recent advances in CAR-T against myeloma, as well as discoveries in the biology of a still incurable disease, that, all together, will further improve safety and efficacy in relapsed/refractory patients, urgently in need of novel treatment options.

Background. Proteasome inhibitor (PI)-based induction/consolidation proved to be effective in newly diagnosed multiple myeloma (NDMM) patients (pts) eligible for melphalan 200 mg/m2 plus autologous stem-cell transplantation (MEL200-ASCT). High response rates have been reported with carfilzomib (K) plus lenalidomide-dexamethasone (KRd) or cyclophosphamide-dexamethasone (KCd). Lenalidomide (R) alone is a standard of care for post-ASCT maintenance; K maintenance showed promising results in phase I/II studies, but no data on KR maintenance vs R are available. Aims. The aims of this analysis were to evaluate the progression-free survival (PFS) of KRd induction-ASCT-KRd consolidation (KRd_ASCT) vs 12 cycles of KRd (KRd12) vs KCd induction-ASCT-KCd consolidation (KCd_ASCT) and the PFS of KR vs R maintenance. Secondary aims were efficacy in different subgroups of pts and safety of the maintenance phase. Methods. NDMM pts ≤65 years were randomized [R1: 1:1:1, stratification International Staging System (ISS) and age] to: KRd_ASCT: 4 28-day cycles with KRd induction (K 20/36 mg/m2 IV days 1,2,8,9,15,16; R 25 mg days 1-21; dexamethasone [d] 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KRd consolidation cycles; KRd12: 12 KRd cycles; KCd_ASCT: 4 28-day induction cycles with KCd (K 20/36 mg/m2 IV days 1,2,8,9,15,16; cyclophosphamide 300 mg/m2 days 1,8,15; d 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KCd consolidation cycles. Thereafter, pts were randomized (R2) to maintenance with KR (K 36 mg/m2 days 1,2,15,16, subsequently amended to 70 mg/m2 days 1,15 for up to 2 years; plus R 10 mg days 1-21 every 28 days until progression) or R alone (10 mg days 1-21 every 28 days until progression). Centralized minimal residual disease (MRD) evaluation (8-color second-generation flow cytometry, sensitivity 10-5) was performed in pts achieving ≥very good partial response before maintenance and every 6 months (m) during maintenance. Data cut-off was June 30, 2020. Results. 474 NDMM pts were randomized (KRd_ASCT, n=158; KRd12, n=157; KCd_ASCT, n=159) and analyzed. Pt characteristics were well balanced. Intention-to-treat (ITT) data of pre-maintenance MRD (KRd_ASCT, 62%; KRd12 56%, KCd_ASCT 43%) and safety of the induction/consolidation phases in the 3 arms were already reported (F. Gay et al. ASH 2018; S. Oliva et al. ASH 2019). After a median follow-up from R1 of 45 m, median PFS was not reached with KRd_ASCT, 57 m with KRd12 and 53 m with KCd_ASCT (KRd_ASCT vs KCd_ASCT: HR 0.53, P During maintenance, a similar proportion of pts experienced ≥1 grade (G)3-4 hematologic adverse events (AEs)/serious AEs (SAEs) in the 2 arms (KR 22% vs R 23%); the most frequent were neutropenia (KR 18% vs R 21%) and thrombocytopenia (KR 3% vs R 3%). Rate of ≥1 G3-4 non-hematologic AEs/SAEs was higher with KR (27%) compared with R (15%), P=0.012; the most frequent were infections (KR 4% vs R 7%); all other events were reported in ≤5% of pts and included: gastrointestinal (KR 5% vs R 2%), cardiac (KR 4% vs R 1%), hypertension (KR 3% vs R 0%), and thrombotic microangiopathy (3% vs 0%). 4 pts developed a second primary malignancy in KR (breast 1 pt; thyroid 1 pt; myelodysplastic syndrome 1 pt; non-melanoma skin cancer 1pt) vs 1 pt in R (acute lymphoblastic leukemia). Dose reductions of R were reported in 23% of KR and 29% of R pts; dose reductions of K were reported in 20% of pts. The rate of discontinuation due to AEs was similar in the 2 arms (KR 10% vs R 9%). Conclusions. Treatment with KRd_ASCT significantly improved PFS compared with both KRd12 and KCd_ASCT. Maintenance with KR also improved PFS vs R. Figure Disclosures Gay: Amgen: 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; 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; GSK: 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; 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. Musto:Celgene: Honoraria; Amgen: Honoraria. Galli:BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Belotti:Jannsen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. 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; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, 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; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau. 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. 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. D'Agostino:GSK: Membership on an entity's Board of Directors or advisory committees. Liberati: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; INCYTE: Honoraria; JANSSEN: Honoraria; CELGENE: Honoraria; AMGEN: Honoraria; BMS: Honoraria; BEIGENE: Honoraria; ARCHIGEN: Honoraria; BIOPHARMA: Honoraria; FIBROGEN: Honoraria. Offidani:Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Cavo:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, 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; 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; Karyopharm: Honoraria; 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 accomodations, Speakers Bureau. Boccadoro: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; Celgene: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. 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 The role of consolidation treatment for newly diagnosed, transplant eligible MM (NDMM) patients has never been prospectively addressed in a randomised trial. Methods The EMN02/HOVON95 trial was designed to compare intensification therapy using 4 cycles of bortezomib-melphalan-prednisone (VMP) vs high-dose melphalan (HDM) plus single or double autologous stem cell transplantation (ASCT), after induction with VCD (R1) (M. Cavo et al. Lancet Haemat 2020, 7, e456-68). A second randomisation was performed after intensification for consolidation treatment with 2 cycles of bortezomib-lenalidomide-dexamethasone (VRD) vs no consolidation (R2), in both arms followed by lenalidomide (10 mg) maintenance until progression or unacceptable toxicity. Patients assigned to consolidation treatment received two 28-day cycles of VRD, each comprising bortezomib (1·3 mg/m2 either i.v. or s.c., on days 1, 4, 8, and 11) combined with lenalidomide (25 mg orally, on days 1 through 21), and dexamethasone (20 mg orally, on days 1, 2, 4, 5, 8, 9, 11, and 12). Primary study end points were progression-free survival (PFS) from R1 and PFS from R2. Secondary endpoints included response and survival. Here we report the final analysis for R2 which was performed in July 2020. Results From February 2011 to April 2014, 1503 pts aged ≤ 65 years with symptomatic MM were enrolled in 172 EMN centres, of whom 1500 were eligible. Of these, 1212 were randomised (stratification by ISS stage) to VMP (495 pts) or HDM (1 or 2 ASCT) (702 pts). For R2 894 patients were eligible, of whom 878 had also been included in R1. These 878 patients were randomised to consolidation (451 pts) or no consolidation (427 pts). Median follow-up from R2 was 71.3 months (IQR 63-80). Response status at time of R2 was equal in both arms, ie ≥ CR (20%), ≥ VGPR (67%), ≥ PR (92%). At the time of this final analysis, 512 events for PFS after R2 had been reported. 5-year PFS from R2 was 50% (95% confidence interval (CI) 45-55) with consolidation and 42% (95% CI 37-46) without, while median PFS from R2 was 59 vs 43 months, respectively. PFS from R2 with adjustment for R1 was prolonged in pts randomised to VRD consolidation (hazard ratio (HR)=0.80; 95% CI=0.67-0.95; P=0.013), which is consistent with the results of the first and second interim analyses (P. Sonneveld et al. ASH 2016, abstract #242; EHA 2018, abstract #1525). With Cox regression analysis revised ISS3 stage (HR 2.05, 95%CI 1.43-2.92) and ampl1q (HR 1.68, 95%CI 1.38-2.06) were adverse prognostic factors at diagnosis. The PFS benefit was observed across most predefined subgroups, including revised ISS stage I-III, standard-risk cytogenetics and both treatment arms of the first randomisation (VMP or HDM treatment). The median duration of maintenance treatment was 33 months (0-97+ months), with 32% of patients still on treatment at 5 years after start of lenalidomide. The secondary endpoint response >=CR after consolidation vs no consolidation before start of maintenance was 34% vs 18%, respectively (p=CR on protocol was 59% with consolidation and 45% without, respectively (p Conclusions Consolidation treatment with VRD followed by continuous lenalidomide maintenance improves PFS and quality of response in NDMM as compared to maintenance alone. The rate of toxicity and second primary malignancies is acceptable. This study is registered with EudraCT number 2009-017903-28 and ClinicalTrials.gov NCT01208766, and has completed recruitment. This independent trial was supported by the Dutch Cancer Society (grant 2010-4798), and unrestricted grants from Celgene and Janssen Figure Disclosures Sonneveld: Takeda: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Janssen: 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; 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. Ludwig:Takeda: Research Funding; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Janssen: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Sanofi: Other: Advisory Boards, Speakers Bureau; Seattle Genetics: Other: Advisory Boards. Zweegman: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; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Hajek:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria. Gay:GSK: 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; 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; 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mellqvist:Janssen. Celgene, Amgen: Honoraria. Schjesvold:Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy; Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria. Offidani:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. 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.

Background It is becoming increasingly important in the treatment of MM to improve our understanding of routine clinical practice and of the effectiveness of new agents and regimens outside the clinical trial setting. UVEA-IXA is a European, multicenter, observational, longitudinal cohort study of RRMM pts who received therapy with ixazomib, the first oral proteasome inhibitor (PI), at MM specialist centers via an Early Access Program (EAP) in 8 European countries (Czech Republic, Greece, Hungary, Italy, Slovakia, Slovenia, Spain, UK). Ixazomib was available in Europe via the EAP from Nov 2015, when it was initially approved in the US in combination with lenalidomide and dexamethasone for the treatment of MM pts who have received ≥1 prior therapy, until European approval in Nov 2016. Approvals were based on the results of the phase 3 TOURMALINE-MM1 study (Moreau NEJM 2016). We report data from the second interim analysis of pts enrolled in the UVEA-IXA study. Methods The UVEA-IXA observation period comprises two parts: a retrospective chart review, starting from ixazomib therapy initiation in the EAP, followed by a 1-yr prospective follow-up period from the date of chart abstraction, with data captured quarterly per local regulations. Pts eligible for the UVEA-IXA study were adult MM pts in biochemical and/or symptomatic relapse after 1-3 prior lines of therapy, who had not received any anti-MM therapy for >3 cycles (except steroids) at the time of ixazomib therapy initiation, and who had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2. Lenalidomide- or PI-refractory (disease progression on treatment or within 60 d after last dose) pts were excluded from UVEA-IXA. The primary endpoints of UVEA-IXA were response (per International Myeloma Working Group criteria) and progression-free survival (PFS; from ixazomib therapy initiation in the EAP to first documented disease progression/death during the observation period). Results A total of 359 pts were enrolled into UVEA-IXA. At data cutoff (May 22, 2020), 302 pts were evaluable for analysis; 55% were male; median age at enrollment was 68 yrs (range 36-92), with 39% aged ≥70 yrs. At the time of initiating ixazomib therapy, 36/117 (31%) pts had International Staging System (ISS) stage III disease, and 61/301 (20%) had an ECOG PS of 2; 60% of all evaluable pts had ≥1 comorbidity, including hypertension (26%), renal disease (23%), and diabetes (10%). Median time from MM diagnosis was 37.0 mos (range 4.9-231.7), and 39%, 43%, and 18% of pts had received 1, 2, and 3 prior lines of therapy. These included (in any line) bortezomib (89%), thalidomide (52%), transplant (47%), melphalan (22%), lenalidomide (17%), carfilzomib (5%), and pomalidomide (2%). The median follow-up period among 295 pts with available data was 24.9 mos (range 0.2-49.3); of all evaluable pts, 160 (53%) discontinued the study (of these, 88% discontinued due to death). Pts received ixazomib for a median of 10.8 mos (range 0.2-49.3), and most pts also received lenalidomide (97%) and dexamethasone (96%). Among 275 pts with data on best response, the overall response rate (ORR) was 60% (Table 1). Median PFS was 15.6 mos (95% CI 11.8-20.0; Figure). Ixazomib and lenalidomide dose reductions and discontinuations are summarized in Table 2. In 187 pts who received ≥4 cycles of ixazomib, rates of any-grade, grade ≥3, and serious adverse events (AEs) were 60%, 33%, and 23%; the most common AEs of any grade were diarrhea and thrombocytopenia (14% each), rash (7%), peripheral neuropathy (6%), and nausea/vomiting (5%); the most common grade ≥3 AE was thrombocytopenia (6%). Conclusions Data from the second interim analysis of UVEA-IXA demonstrate that ixazomib-based therapy is effective outside the clinical trial setting, with an ORR of 60% and a median PFS of 15.6 mos. Compared with TOURMALINE-MM1 pts (ixazomib arm; ORR 78%, median PFS 20.6 mos), UVEA-IXA pts have higher rates of ECOG PS 2 (20% vs 5%) and ISS stage III MM (31% vs 12%), and had received more prior therapies (61% vs 38% had ≥2 prior therapies). The most common AEs were gastrointestinal and hematologic AEs, in line with the well-characterized and manageable safety profile of ixazomib, although data are not directly comparable with clinical trial safety data due to the retrospective/infrequent prospective collection schedule. Ixazomib-based therapy is an effective and tolerable treatment option outside the clinical trial setting. Disclosures Ludwig: Celgene: Speakers Bureau; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Takeda: Research Funding; Seattle Genetics: Other: Advisory Boards; Janssen: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Sanofi: Other: Advisory Boards, Speakers Bureau. Terpos:Genesis: Research Funding; Sanofi: Honoraria; Genesis: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Janssen: Research Funding; Takeda: Research Funding; BMS: Honoraria; Amgen: Research Funding; Celgene: Honoraria. Mateos:Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: 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; AbbVie: 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; Sanofi: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Mundipharma: 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; 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. Kishore:Celgene: Other. Ramasamy:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Fernandez:MediNeos Observational Research: Current Employment. Ferri:MediNeos Observational Research: Current Employment. Bent-Ennakhil:Takeda Pharmaceuticals International AG: Current Employment. Zomas:Takeda Pharmaceuticals International AG: Current Employment. Gavini:Takeda Pharmaceuticals International AG: Current Employment. 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.

Background Copy-number alterations of chromosome 1q are frequently found in multiple myeloma (MM) and are associated with poor prognosis. Recently, it has been demonstrated that the number of 1q copies correlates with a high-risk behavior (BA Walker et al, Leukemia 2019, TM Schmidt et al, Blood Cancer J 2019), but no data are available in carfilzomib-treated patients (pts). Here we aim at dissecting the role of Gain1q (3 copies of 1q) vs amplification 1q (Amp1q, ≥4 copies of 1q) in carfilzomib-treated NDMM pts enrolled in the randomized FORTE trial (NCT02203643). Methods Fluorescence in situ hybridization (FISH) in CD138+ purified bone marrow plasma cells (BMPCs) was centralized and performed at baseline. Two hundred BMPC nuclei from each sample were scored. The cut-off level for Gain1q was 10% of nuclei with ≥3 copies of 1q (mean plus 3 standard deviations of 1q alterations in BMPC from 15 healthy donors). The cut-off for Amp1q was 20% of nuclei with ≥4 copies of 1q. In the FORTE trial, transplant-eligible NDMM pts were randomized 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 to receive KR vs R maintenance. Results A total of 474 pts were enrolled. Median follow-up from 1st randomization was 45 months (m). Evaluation of 1q by FISH was missing in 70 pts (15%), while in 4 pts (1%) FISH was present but the number of 1q copies was not evaluable. Among evaluable pts, chromosome 1q was normal in 219 (55%) pts, Gain1q was found in 129 (32%) pts, while Amp1q in 52 (13%). Gain1q- and Amp1q-positive pts were well distributed among treatment arms. Baseline characteristics associated with Amp1q, compared to Gain1q, were LDH >upper limit of normal (P=0.002) and low hemoglobin (P=0.029) and platelets (P=0.044). Best response to therapy was not significantly different in Normal 1q vs Gain1q vs Amp1q groups (≥very good partial response rates: 85% vs 84% vs 77%; stringent complete response rates: 52% vs 50% vs 38%). Best overall minimal residual disease negativity by flow cytometry (sensitivity 10-5) pre-maintenance was also not significantly different (55% vs 55% vs 44%, respectively). In a multivariate analysis adjusted for treatment and Revised International Staging System (R-ISS), the risk of progression/death was significantly higher in the presence of Gain1q vs Normal 1q (HR 1.65, 95% CI 1.14-2.37, P=0.007) and the highest in the presence of Amp1q as compared to both Normal 1q (HR 3.04, 95% CI 1.99-4.65, P Median progression-free-survival (PFS) was not reached in the Normal 1q group, while Gain1q (53 m) and especially Amp1q (21.8 m) groups performed very poorly. The presence of Amp1q vs Normal 1q (HR 5.88, 95% CI 3.10-11.17, P Subgroup analysis on the presence/absence of concomitant high-risk features was performed. Gain1q predicted a lower PFS compared to Normal 1q in the presence of concomitant standard-risk features (ISS 1, ISS 2, standard-risk cytogenetics) but not in the presence of high-risk disease (ISS 3, high-risk cytogenetics). On the other hand, the worse prognosis of Amp1q pts was confirmed across all subgroups. A subgroup analysis according to the upfront treatment received was performed. Interestingly, treatment with KRd_ASCT completely abrogated the risk conferred by Gain1q (HR 1.25 vs Normal 1q, 95% CI 0.58-2.7, P=0.565), while Amp1q-positive pts still showed a very poor outcome (median PFS 17 m, HR 6.03 vs Normal 1q, 95% CI 2.78-13.1, P In KCd_ASCT and KRd12-treated pts, the 3 groups performed similarly to the overall population. Conclusion This is a first report on the prognostic role of the number of 1q copies in carfilzomib-treated NDMM pts. Having ≥4 copies of 1q universally predicts a very poor PFS and OS despite the use of a 2nd generation proteasome inhibitor upfront. On the other hand, KRd_ASCT completely abrogated the PFS disadvantage conferred by 3 copies of 1q. RNA sequencing on representative samples of Normal 1q vs Gain1q vs Amp1q is in progress to explore differentially expressed genes in Amp1q pts that could be exploited in future treatment strategies. Figure 1 Disclosures D'Agostino: GSK: Membership on an entity's Board of Directors or advisory committees. Giuliani:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Participation in congresses, Research Funding; Janssen Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Other: Clinical study sponsorship; participation in congresses, Research Funding; Millennium Pharmaceutical: Other: Clinical study sponsorship, Research Funding; GSK: Other: Clinical study sponsorship, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Other: Participation in congresses. Tacchetti:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Oncopeptides: Honoraria; Bristol-Myers Squibb: Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Boccadoro:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Gay: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; 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; 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; Bristol-Myers Squibb: 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, lenalidomide and dexamethasone).

[Aim]: To evaluate the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma in routine clinical practice. Patients & methods: Patient-level data from the global, observational INSIGHT MM and the Czech Registry of Monoclonal Gammopathies were integrated and analyzed., [Results]: At data cut-off, 263 patients from 13 countries were included. Median time from diagnosis to start of IRd was 35.8 months; median duration of follow-up was 14.8 months. Overall response rate was 73%, median progression-free survival, 21.2 months and time-to-next therapy, 33.0 months. Ixazomib/lenalidomide dose reductions were required in 17%/36% of patients; 32%/30% of patients discontinued ixazomib/lenalidomide due to adverse events., [Conclusion]: The effectiveness and safety of IRd in routine clinical practice are comparable to those reported in TOURMALINE-MM1., This work was supported by Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Minimal residual disease (MRD) by multiparameter flow cytometry (MFC) is the most effective tool to define a deep response in multiple myeloma (MM). We conducted an MRD correlative study of the EMN02/HO95 MM phase III trial in newly diagnosed MM patients achieving a suspected complete response before maintenance and every 6 months during maintenance. Patients received high-dose melphalan (HDM) versus bortezomib-melphalan-prednisone (VMP) intensification, followed by bortezomib-lenalidomide-dexamethasone (VRd) versus no consolidation, and lenalidomide maintenance. Bone marrow (BM) samples were processed in three European laboratories, applying EuroFlow-based MFC protocols (eight colors, two tubes) with 10−4−10−5 sensitivity. At enrollment in the MRD correlative study, 76% (244/321) of patients were MRD-negative. In the intention-to-treat analysis, after a median follow-up of 75 months, 5-year progression-free survival was 66% in MRD-negative versus 31% in MRD-positive patients (HR 0.39; p p

Aim: This study aimed to report patterns of biosimilar filgrastim prophylaxis and outcomes of chemotherapy-induced neutropenia (CIN)/febrile neutropenia (FN) in patients with hematological malignancies or solid tumors. Patients & methods: MONITOR-GCSF is a real-world study of 1447 cancer patients receiving CIN/FN prophylaxis with biosimilar filgrastim (solid tumors: 77.2%; hematological malignancies: 22.8%). Results: Differences in prophylaxis intensity and day of initiation relative to guideline recommendations were observed. In hematology patients, higher rates of CIN and FN occurred at cycle level, and rate of FN was higher at patient level (9.1 vs 5.0% in solid tumor patients). Conclusion: Adequate GCSF support in hematology and solid tumor patients is important to prevent CIN/FN and related hospitalizations and chemotherapy disturbances.

With the introduction of new drugs with different mechanisms of action, multiple myeloma (MM) patients’ outcomes have improved. However, the efficacy seen in clinical trials is often not seen in real-world settings and data on the effectiveness of MM therapies are needed. INSIGHT MM is a prospective, global, non-interventional, observational study that is enrolling approximately 4200 patients with newly diagnosed or relapsed/refractory MM, making it the largest study of its kind to date. The study aims to describe contemporary, real-world patterns of patient characteristics, clinical disease presentation, therapies chosen, clinical outcomes (response, treatment duration, time-to-next-therapy, progression-free and overall survival), safety, healthcare resource utilization and quality of life. One interim analysis has been conducted to date; current accrual is approximately 3094 patients. Trial registration number: NCT02761187, Lay abstract Survival of patients with myeloma, a type of bone marrow cancer affecting the production of healthy blood cells, has improved due to the development and approval of new treatments. Treatments are approved based on clinical trials; however, limited data are available that confirm the effectiveness of these same treatments in real-world routine clinical practice. INSIGHT MM is a large, global study that will follow approximately 4200 myeloma patients from real-world settings for a minimum of 5 years, describing their clinical characteristics, type of therapy received and their response to treatment, including survival and toxicity. This review describes the study aims and methods.

Twice-weekly carfilzomib is approved at 27 and 56 mg/m(2) to treat relapsed multiple myeloma patients. In the phase III study ARROW, once-weekly 70 mg/m 2 carfilzomib prolonged the median progression-free survival of relapsed multiple myeloma patients in comparison with twice-weekly 27 mg/m(2) carfilzomib, without adding significant toxicity. Data were pooled from two phase I/II studies of newly diagnosed multiple myeloma patients who received nine induction cycles of carfilzomib (either 70 mg/m(2) once-weekly or 36 mg/m(2) twice-weekly), cyclophosphamide and dexamethasone, followed by carfilzomib maintenance. Overall, 121 transplant-ineligible patients with newly diagnosed multiple myeloma were analyzed (once-weekly, n=63; twice-weekly, n=58). We found no significant difference in median progression-free survival [35.7 months (95%CI: 23.7-not reached, NR) vs 35.5 months (95%CI: 24.3-NR); HR: 1.39; P=0.26] and 3-year overall survival [70% [95%CI: 59%-84%) vs 72% (95%CI: 60%-85%); HR: 1.27; P=0.5] between once-weekly and twice-weekly carfilzomib. From the start of maintenance, 3-year progression-free survival [47% (95%CI: 33%-68%) vs 51% (95%CI: 38%-70%); HR: 1.04; P=0.92] and overall survival [72% (95%CI: 58%-89%) vs 73% (95%CI: 59%-90%); HR: 0.82; P=0.71] were similar in the once- versus twice-weekly carfilzomib. The rate of grade 3-5 hematologic (24% vs 30%; P=0.82) and non-hematologic (38% vs 41%; P=0.83) adverse events was similar in the two groups. Once-weekly 70 mg/m(2) carfilzomib as induction and maintenance therapy for newly diagnosed multiple myeloma patients was as safe and effective as twice-weekly 36 mg/m(2) carfilzomib and provided a more convenient schedule. The trials are registered at clinicaltrials.gov identifiers: 01857115 (IST-CAR-561) and 01346787 (IST-CAR-506).

Background: Minimal residual disease (MRD) is one of the most relevant prognostic factors in patients with multiple myeloma (MM); however, the impact of maintenance therapy on MRD levels remains unclear. Among patients with newly diagnosed MM (NDMM) who received lenalidomide maintenance until they developed disease progression, the role of MRD status as a predictor of progression-free survival (PFS) was evaluated by multiparameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) analysis. Methods: Seventy-three patients with NDMM enrolled in the RV-MM-EMN-441 (clinical trials.gov identifier, NCT01091831) and RV-MM-COOP-0556 (clinicaltrials.gov identifier, NCT01208766; European Myeloma Network EMN02/HO95 MM Trial) phase 3 trials who achieved at least a very good partial response after intensification/consolidation were included. The median patient age was 57 years (interquartile range, 53-61 years), and all patients received lenalidomide maintenance until they developed progression. MRD was evaluated on bone marrow after intensification/consolidation, after 6 courses of maintenance, and every 6 months thereafter until clinical relapse using both ASO-RQ-PCR (sensitivity, 10 −5 ) and MFC (sensitivity, from 10 −4 to 10 −5 ). Results: After intensification/consolidation, 33 of 72 patients (46%) achieved a molecular complete response (m-CR), and 44 of 70 (63%) achieved a flow complete response (flow-CR). Almost 27% of patients who were MRD-positive after consolidation became MRD-negative during maintenance. After a median follow-up of 38 months, PFS was prolonged in patients who achieved negative MRD status during maintenance according to results from both ASO-RQ-PCR analysis (hazard ratio, 0.29; 95% confidence interval, 0.14-0.62; P =.0013) and MFC (hazard ratio, 0.19; 95% confidence interval, 0.09-0.41; P

Cellular therapies are a rapidly evolving approach to treat cancer in the light of their unique mechanism of action that potentially overcomes drug resistance and induces durable remissions. Modalities of adoptive cell therapy include gene-modified T cells expressing novel T cell receptors or chimeric antigen receptors (CAR) that modify the immune system to recognize tumor cells and carry out potent anti-tumor effector functions. CAR T cells have shown very promising clinical results and several trials are being conducted worldwide to establish their role in cancer treatment. Most successful results have been observed in lymphoproliferative disorders with the use of CD19-directed CAR T cells, which led to their commercial approval by FDA. In this review, we provide a comprehensive overview of the current role of CAR T cell therapies in hematological malignancies and solid tumors, their associated toxicities and potential future developments in the armamentarium for cancer treatment.

Background Immune therapies have had a major impact in multiple myeloma (MM). Responses induced in relapsed and/or refractory MM (RRMM) patients (pts) are unprecedented; however the key challenge is their durability. Most immunotherapeutic approaches rely on the fitness of pts’ T cells but exposure to multiple therapies may alter immune cell numbers and function. Here we analyzed and compared the transcriptome and phenotype of T cells from healthy donors (HD), newly diagnosed MM (NDMM) and RRMM pts. Methods Peripheral Blood Mononuclear Cells (PBMCs) from age-matched HD, NDMM and RRMM pts were collected before the start of a new line of treatment. Single cell RNA sequencing (scRNAseq) was performed and proportion of cell types were inferred using a reference PBMC dataset with Seurat. Cell type proportions were also estimated with CyTOF and conventional flow cytometry Results PBMCs from 10 HDs (median age 69, range 53-79), 20 NDMM pts (median age 71, range 54-88), 20 RRMM pts (median age 71, range 54-80) were analyzed. RRMM pts were exposed to 1 (n=8), 2 (n=6) or 3 (n=6) lines of treatment. All RRMM pts were exposed to a proteasome inhibitor, 75% were exposed to an immunomodulatory drug, and 65% received autologous stem cell transplantation. 48 out of 50 samples were processed by scRNAseq, 45 by CyTOF and 33 by flow cytometry. NDMM pts demonstrated a trend towards lower frequency of CD4 T cells compared to HD. This decreased number was accompanied by a decrease in the expression of genes involved in mitochondrial oxidative phosphorylation and an increase in expression of immediate early response genes (e.g. FOS, JUN, JUNB). In the CD8 compartment, CD8 naive cells were lower in NDMM compared to HD. No differences were found on CD8 central memory, effector memory and/or terminal effector populations In RRMM, the proportion of naive CD4 cells was significantly lower compared to NDMM (p Conclusion T cell phenotypes in MM pts are altered, especially after treatment. These findings may provide the rationale for the investigation of immunotherapy in NDMM and less heavily pretreated MM. Ongoing functional studies will demonstrate whether these phenotypic and transcriptomic changes lead to less fit T cells with consequent impact on effectiveness of T cell directed therapies.

Lenalidomide-dexamethasone (Rd) is standard treatment for elderly patients with multiple myeloma (MM). In this randomized phase 3 study, we investigated efficacy and feasibility of dose/schedule-adjusted Rd followed by maintenance at 10 mg per day without dexamethasone (Rd-R) vs continuous Rd in elderly, intermediate-fit newly diagnosed patients with MM. Primary end point was event-free survival (EFS), defined as progression/death from any cause, lenalidomide discontinuation, or hematologic grade 4 or nonhematologic grade 3 to 4 adverse event (AE). Of 199 evaluable patients, 101 received Rd-R and 98 continuous Rd. Median follow-up was 37 months. EFS was 10.4 vs 6.9 months (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51-0.95; P = .02); median progression-free survival, 20.2 vs 18.3 months (HR, 0.78; 95% CI, 0.55-1.10; P = .16); and 3-year overall survival, 74% vs 63% (HR, 0.62; 95% CI, 0.37-1.03; P = .06) with Rd-R vs Rd, respectively. Rate of ≥1 nonhematologic grade ≥3 AE was 33% vs 43% (P = .14) in Rd-R vs Rd groups, with neutropenia (21% vs 18%), infections (10% vs 12%), and skin disorders (7% vs 3%) the most frequent; constitutional and central nervous system AEs mainly related to dexamethasone were more frequent with Rd. Lenalidomide was discontinued for AEs in 24% vs 30% and reduced in 45% vs 62% of patients receiving Rd-R vs Rd, respectively. In intermediate-fit patients, switching to reduced-dose lenalidomide maintenance without dexamethasone after 9 Rd cycles was feasible, with similar outcomes to standard continuous Rd. This trial was registered at www.clinicaltrials.gov as #NCT02215980.

This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes.

Purpose: Despite the improvement of therapeutic regimens, several patients with multiple myeloma (MM) still experience early relapse (ER). This subset of patients currently represents an unmet medical need. Experimental Design: We pooled data from seven European multicenter phase II/III clinical trials enrolling 2,190 patients with newly diagnosed MM from 2003 to 2017. Baseline patient evaluation included 14 clinically relevant features. Patients with complete data (n = 1,218) were split into training (n = 844) and validation sets (n = 374). In the training set, a univariate analysis and a multivariate logistic regression model on ER within 18 months (ER18) were made. The most accurate model was selected on the validation set. We also developed a dynamic version of the score by including response to treatment. Results: The Simplified Early Relapse in Multiple Myeloma (S-ERMM) score was modeled on six features weighted by a score: 5 points for high lactate dehydrogenase or t(4;14); 3 for del17p, abnormal albumin, or bone marrow plasma cells >60%; and 2 for λ free light chain. The S-ERMM identified three patient groups with different risks of ER18: Intermediate (Int) versus Low (OR = 2.39, P < 0.001) and High versus Low (OR = 5.59, P < 0.001). S-ERMM High/Int patients had significantly shorter overall survival (High vs. Low: HR = 3.24, P < 0.001; Int vs. Low: HR = 1.86, P < 0.001) and progression-free survival-2 (High vs. Low: HR = 2.89, P < 0.001; Int vs. Low: HR = 1.76, P < 0.001) than S-ERMM Low. The Dynamic S-ERMM (DS-ERMM) modulated the prognostic power of the S-ERMM. Conclusions: On the basis of simple, widely available baseline features, the S-ERMM and DS-ERMM properly identified patients with different risks of ER and survival outcomes.

Background Combined therapy with carfilzomib, bendamustine, and dexamethasone was evaluated in this multicenter phase 1/2 trial conducted within the European Myeloma Network (EMN09 trial). Methods Sixty-three patients with relapsed/refractory multiple myeloma who had received ≥2 lines of prior therapy were included. The phase 1 portion of the study determined the maximum tolerated dose of carfilzomib with bendamustine set at 70 mg/m2 on days 1 and 8. After 8 cycles, responding patients received maintenance therapy with carfilzomib and dexamethasone until progression. Results On the basis of the phase 1 results, the recommended phase 2 dose for carfilzomib was 27 mg/m2 twice weekly in weeks 1, 2, and 3. Fifty-two percent of patients achieved a partial response or better, and 32% reached a very good partial response or better. The clinical benefit rate was 93%. After a median follow-up of 21.9 months, the median progression-free survival was 11.6 months, and the median overall survival was 30.4 months. The reported grade ≥3 hematologic adverse events (AEs) were lymphopenia (29%), neutropenia (25%), and thrombocytopenia (22%). The main nonhematologic grade ≥3 AEs were pneumonia, thromboembolic events (10%), cardiac AEs (8%), and hypertension (2%). Conclusions In heavily pretreated patients who have relapsed/refractory multiple myeloma, combined carfilzomib, bendamustine, and dexamethasone is an effective treatment option administered in the outpatient setting. Infection prophylaxis and attention to patients with cardiovascular predisposition are required.

Despite remarkable advances in the treatment of multiple myeloma in the last decades, the prognosis of patients harboring high-risk cytogenetic abnormalities remains dismal as compared to that of standard-risk patients. Proteasome inhibitors demonstrated to partially ameliorate the prognosis of high-risk patients. We pooled together data from two phase I/II trials on transplant-ineligible patients with multiple myeloma receiving upfront carfilzomib cyclophosphamide and dexamethasone followed by carfilzomib maintenance. The aim of this analysis was to compare treatment outcomes in patients with standard- versus high-risk cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) analysis. High risk was defined by the presence of at least one chromosomal abnormality, including t(4;14), del17p and t(14;16). Overall, 94 patients were included in the analysis: 57 (61%) in the standard-risk and 37 (39%) in the high-risk group. Median follow-up was 38 months. In standard- vs. high-risk patients, we observed similar progression-free survival (3-year PFS: 52% vs. 43%, respectively; p=0.50), overall survival (3-year OS: 78% vs. 73%; p=0.38), and overall response rate (88% vs 95%; p=0.47), with no statistical differences between the two groups. No difference in terms of progression-free survival was observed between patients with or without del17p. Carfilzomib, used both as induction and maintenance agent for transplant-ineligible newly diagnosed multiple myeloma patients, mitigated the poor prognosis carried by high-risk cytogenetics and resulted into similar progression-free survival and overall survival, as compared to standard-risk patients. ClinicalTrials.gov IDs: NCT01857115 (IST-CAR-561) and NCT01346787 (IST-CAR-506).

No abstract available

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

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a wide range of tumor-induced alterations, which affect both the innate and adaptive arms of the immune response, and accumulate during disease progression. In recent years, the development of targeted therapies, such as the B-cell receptor signaling inhibitors and the Bcl-2 protein inhibitor venetoclax, has dramatically changed the treatment landscape of CLL. Despite their remarkable anti-tumor activity, targeted agents have some limitations, which include the development of drug resistance mechanisms and the inferior efficacy observed in high-risk patients. Therefore, additional treatments are necessary to obtain deeper responses and overcome drug resistance. Allogeneic hematopoietic stem cell transplantation (HSCT), which exploits immune-mediated graft-versus-leukemia effect to eradicate tumor cells, currently represents the only potentially curative therapeutic option for CLL patients. However, due to its potential toxicities, HSCT can be offered only to a restricted number of younger and fit patients. The growing understanding of the complex interplay between tumor cells and the immune system, which is responsible for immune escape mechanisms and tumor progression, has paved the way for the development of novel immune-based strategies. Despite promising preclinical observations, results from pilot clinical studies exploring the safety and efficacy of novel immune-based therapies have been sometimes suboptimal in terms of long-term tumor control. Therefore, further advances to improve their efficacy are needed. In this context, possible approaches include an earlier timing of immunotherapy within the treatment sequencing, as well as the possibility to improve the efficacy of immunotherapeutic agents by administering them in combination with other anti-tumor drugs. In this review, we will provide a comprehensive overview of main immune defects affecting patients with CLL, also describing the complex networks leading to immune evasion and tumor progression. From the therapeutic standpoint, we will go through the evolution of immune-based therapeutic approaches over time, including i) agents with broad immunomodulatory effects, such as immunomodulatory drugs, ii) currently approved and next-generation monoclonal antibodies, and iii) immunotherapeutic strategies aiming at activating or administering immune effector cells specifically targeting leukemic cells (e.g. bi-or tri-specific antibodies, tumor vaccines, chimeric antigen receptor T cells, and checkpoint inhibitors).

The authors sincerely apologize for the inaccuracies made during the revision that a product line has been associated with the wrong company [...]

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.