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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.

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 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.

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).

Proteasome inhibitors (PIs) represent a recently developed drug class that inhibit the ubiquitin-proteasome system, thus interfering with the intracellular machinery who has the duty of misfolded proteins disposal. Myeloma plasma cells are structurally aimed at the production of large quantities of immunoglobulins. This explains their vulnerability to any perturbation of intracellular protein homeostasis. Bortezomib is the first-in-class PI and nowadays, in combination with other compounds, is the cornerstone of multiple myeloma (MM) treatment in several settings. Bortezomib has several attractive features for its inclusion in the induction phase of therapy: high efficacy, rapid cytoreduction, absence of nephrotoxicity, fast reduction of plasmacytomas, and fast pain control. However, the safety profile of bortezomib is characterized by a not negligible peripheral neuropathy. Newer PIs, such as carfilzomib and ixazomib, have been developed and each offers specific advantages. Carfilzomib is extremely efficient in proteasome inhibition. This results in high efficacy but suffers from a significant cardiotoxicity. Ixazomib is the first oral PI with a proteasome inhibition profile similar to bortezomib, with lower neurotoxicity. PIs mechanism of action is complementary with other drug classes, and this explains the synergism between PIs and other drugs, in particular steroids and immunomodulators. PIs are frequently used in doublets and triplets. Also, they can be associated with anti-CD38 monoclonal antibodies. This review summarizes the principal biological and clinical features of PIs in the MM treatment.

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).

The treatment of transplant-eligible multiple myeloma patients in Italy consists in an induction phase based on bortezomib plus thalidomide plus dexamethasone (VTd), followed by a single or tandem autologous stem cell transplantation (ASCT), followed by lenalidomide maintenance. This approach offers an overall response rate of 93% and a CR rate of 58% with acceptable toxicity. Lenalidomide maintenance adds a significant increase in disease control, with a progression free survival after ASCT of 53 months, and an overall survival of 86 months. Second primary malignancies represent the most concerning toxicity of lenalidomide maintenance with a 6.9% incidence. However, the benefit in terms of increased myeloma control largely outweigh this complication. The incorporation of daratumumab in this treatment schema will further improve these clinical results.

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

In multiple myeloma, novel treatments with proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) have prolonged survival but the disease remains incurable. At relapse, next-generation sequencing has shown occasional mutations of drug targets but has failed to identify unifying features that underlie chemotherapy resistance. We studied 42 patients refractory to both PIs and IMiDs. Whole-exome sequencing was performed in 40 patients, and RNA sequencing (RNA-seq) was performed in 27. We found more mutations than were reported at diagnosis and more subclonal mutations, which implies ongoing evolution of the genome of myeloma cells during treatment. The mutational landscape was different from that described in published studies on samples taken at diagnosis. The TP53 pathway was the most frequently inactivated (in 45% of patients). Conversely, point mutations of genes associated with resistance to IMiDs were rare and were always subclonal. Refractory patients were uniquely characterized by having a mutational signature linked to exposure to alkylating agents, whose role in chemotherapy resistance and disease progression remains to be elucidated. RNA-seq analysis showed that treatment or mutations had no influence on clustering, which was instead influenced by karyotypic events. We describe a cluster with both amp(1q) and del(13) characterized by CCND2 upregulation and also overexpression of MCL1, which represents a novel target for experimental treatments. Overall, high-risk features were found in 65% of patients. However, only amp(1q) predicted survival. Gene mutations of IMiD and PI targets are not a preferred mode of drug resistance in myeloma. Chemotherapy resistance of the bulk tumor population is likely attained through differential, yet converging evolution of subclones that are overall variable from patient to patient and within the same patient.

BACKGROUND: Bortezomib- and lenalidomide-containing regimens are well-established therapies in multiple myeloma (MM). However, despite their extensive use, head-to-head comparisons have never been performed. Therefore, we compared bortezomib and lenalidomide in fixed-duration therapies for relapsed MM. METHODS: In this open-label, phase III study, we randomized MM patients at first relapse to receive either 9 cycles of bortezomib-cyclophosphamide-dexamethasone (VCD) or lenalidomide-cyclophosphamide-dexamethasone (RCD). The primary endpoint was the achievement of a very good partial response (VGPR) or better at six weeks after 9 treatment cycles. FINDINGS: From March 2011 to February 2015, 155 patients were randomized. The primary endpoint was met by 12 patients (15%) in the VCD arm and 14 patients (18%) in the RCD arm (p=0·70). Median progression-free survival (PFS) was 16·3 (95% CI: 12·1-22·4) with VCD and 18·6 months (95% CI: 14·7-25.5) with RCD, and the 2-year overall survival (OS) was 75% (95% CI: 66%-86%) and 74% (95% CI: 64%-85%), respectively. By subgroup analysis, no differences in PFS were observed in bortezomib and lenalidomide- naive patients, nor in patients who received a bortezomib-based regimen in first line. Adverse events were consistent with the well-established safety profiles of bortezomib and lenalidomide. INTERPRETATION: Bortezomib and lenalidomide treatments were equally effective in terms of depth of response, PFS, and OS in MM patients at first relapse. Nevertheless, the two drugs have a different safety profile. Clinical Trial Number: This study is registered as EUDRACT 2010- 021557-40. Funding Statement: Associazione Italiana per la Ricerca sul Cancro - AIRC grant IG-10419; Associazione Italiana contro le Leucemie-Linfomi e Mieloma (AIL); Fondazione Adiuvare, Lugano. Declaration of Interests: VM has received honoraria and travel grants from Janssen, Celgene, Bristol-Myers Squibb, Amgen. AC has not competing interests. MG has received honoraria and travel grants from Janssen, Celgene, Bristol-Myers Squibb. IA has not competing interests. SP has not competing interests. CCarniti SP has not competing interests. FP has received honoraria and travel grants from Janssen and Celgene. FG has not competing interests. RZ has not competing interests. SS has not competing interests. MM has not competing interests. AN has not competing interests. CCrippa has not competing interests. AMC has received honoraria and travel grants from Janssen and Celgene. LB has not competing interests. PC has honoraria from advisory board and speaking fees from Celgene, Janssen, Novartis, Roche, Takeda, Sanofi, Abbvie, Amgen, Gilead, and Klowa Kirin. Ethics Approval Statement: The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Ethics committees at each study site reviewed and approved the protocol.

Multiple myeloma (MM) therapy is evolving, and several new drugs are now available, extending patients' life and exposure to different compounds and toxicities. We conducted a cross-sectional observational study enrolling 93 consecutive patients on active treatment for MM, aiming to assess their ocular complications. All the patients underwent a comprehensive ophthalmic evaluation. In our cohort, prevalence of low visual acuity was in line with similar age healthy population reported in registry studies. Interestingly, we recorded a higher prevalence of lens opacities (46%) and dry eye syndrome (53%). Nevertheless, we did not find any significant association between ocular disorders and anti-myeloma treatments, even steroid therapy. This observation suggests that other factors besides treatments, such as M-protein deposition in eye structures, may have a role in developing ocular toxicities. Since MM patients are elderly patients at higher risk of age-related eye disorders, we recommend periodic ophthalmic assessment in daily practice.

We evaluated 71 patients treated with allogeneic hematopoietic cell transplantation (allo-HCT) for multiple myeloma (MM). Forty-three patients (61%) received allo-HCT after the first line of therapy. Fifty-eight patients (82%) had chemosensitive disease at the time of allo-HCT. A HLA-matched related or unrelated donor was available for 68 patients (96%). Non-myeloablative or reduced-intensity conditioning regimen and peripheral blood hematopoietic cells as a graft source were used in most patients. The cumulative incidence of grade II–IV acute GVHD at day +100 and chronic GVHD at 5 years was 13% (95% CI 7–23%) and 35% (95% CI 24–46), respectively. Non-relapse mortality and relapse/progression incidence at 5 years were 12% (95% CI 5–23) and 65% (95% CI 49–76), respectively. With a median follow-up in survivors of 100 months (range 16–186), the 5-year PFS and OS were 39% (95% CI 27–52) and 60% (95% CI 55–77), respectively. On multivariate analysis: age >55 years was associated with both a reduced PFS (RR 2.11, 95% CI 1.15–3.87) and OS (RR 5.53, 95% CI 2.22–13.76); chemorefractory disease at allo-HCT was associated with both reduced PFS (RR 3.09, 95% CI 1.37–7.00) and OS (RR 3.19, 95% CI 1.23–8.22). At relapse, 24 patients (56%) received bortezomib, 28 (65%) lenalidomide, 11 (26%) pomalidomide, 16 (37%) donor lymphocytes infusion as part of salvage therapy after allo-HCT relapse. Median PFS from time of salvage treatment was 7 months (range 0–113 months) for bortezomib-based therapy, 14 months (range 0–79 months) for lenalidomide and 10 months (range 1–28) for pomalidomide. Allo-HCT is a feasible and effective strategy in selected patients with MM and could be an effective platform for subsequent therapies.

BACKGROUND The authors describe a family with a high penetrance of plasma cell dyscrasias, suggesting inheritance of an autosomal dominant risk allele. METHODS The authors performed whole-exome sequencing and reported on a combined approach aimed at the identification of causative variants and risk loci, using the wealth of data provided by this approach. RESULTS The authors identified gene mutations and single-nucleotide polymorphisms of potential significance, and pinpointed a known risk locus for myeloma as a potential area of transmissible risk in the family. CONCLUSIONS To the authors' knowledge, the current study is the first to provide a whole-exome sequencing approach to such cases, and a framework analysis that could be applied to further understanding of the inherited risk of developing plasma cell dyscrasias. Cancer 2017. © 2017 American Cancer Society.

Background. Despite the improvement of therapeutic regimens, a relevant proportion of multiple myeloma (MM) patients (pts) experience early relapse (ER) [Majithia, Leukemia 2016] and represents an unmet medical need. It is therefore of high clinical interest to identify baseline factors that may predict ER. Aims To design models predictive of ER (defined as pts with a time-to-progression ≤18 or ≤ 24 months). To assess the accuracy of every model on an independent validation set. To build a score to predict ER. Methods Data were obtained from 2326 pts enrolled in 8 multi-center clinical trials: NCT01093196, NCT01346787, NCT01857115, NCT01190787, NCT00551928, NCT01091831, NCT01063179 and 2005-004730-41. Here, we included 14 baseline features (fts): age, creatinine, albumin (alb), b2microglobulin (b2m), bone marrow plasma cell (PCbm) were evaluated as continuous variables; free light chain (FLC, λ vs K), M-component subtype (IgA vs others), Revised International Staging System (R-ISS stage II/III vs I), lactate dehydrogenase levels >/≤ upper limit of normal (LDHULN), presence vs absence of chromosomal abnormalities detected by FISH [del17p, t(4;14), t(14;16), t(11;14)], and presence of plasmacytomas as categorical values. Trials were assigned to training and validation set to have a superimposed median (μe) age and follow-up in the two subsets. From the training set, a univariate analysis (UV) on outcome was performed according to both Chi-square and Kruskal tests, as appropriate. Features with p Results ER≤18 models. 10/14 fts were selected based on UV analysis: age, FLC, PCbm, del17p, t(4/14), t(14/16), alb and b2m, LDHULN and R-ISS stage. Pts with complete data were included in the training set (n=923; μe age =66 years [y]; ER=35%) and the validation set (n=313; μe age=67 y; ER=36%), respectively. In the MV incorporating the R-ISS, the R-ISS II/III vs I (OR=1.75, 95% CI:1.26-2.44) and increased PCbm (OR=1.05, 95% CI:1.02-1.08) increased the risk of ER. When the MV analysis was performed including single fts instead of R-ISS, increased PCbm (OR=1.05, 95% CI:1.02-1.08), λ FLC (OR=1.34, 95% CI:1.01-1.79), LDHULN (OR=1.80, 95% CI:1.16-2.81), presence of both del17q (OR=1.58, 95% CI:1.07-2.33) and t(4/14) (OR=2.01, 95% CI:1.36-3.01) increased the probability of ER; increased alb (OR=0.75, 95% CI:0.61-0.94), reduced the risk of ER (table 1). ER≤24 models. 8/14 fts were selected based on UV analysis: FLC, PCbm, del17p, t(4/14), alb and b2m levels, LDHULN and R-ISS stage. Pts with complete data were included in the training set (n=1009; μe age=67 y; ER=45%) and in the validation set (n=352; μe age=67 y, ER=45%). In MV analysis, including R-ISS, both R-ISS (OR=1.88, 95% CI:1.39-2.55) and PCbm (OR=1.04, 95% CI:1.02-1.06) impacted on outcome. When the MV analysis was performed including single fts, λ FLC (OR=1.31, 95% CI:1.01-1.69), PCbm (OR=1.04, 95% CI:1.02-1.07), del17p (OR=1.86, 95% CI:1.30-2.65) and t(4/14) (OR=2.00, 95% CI:1.38-2.88) retained their impact on outcome (table 1). Validation. Each MV model was tested on the validation set. Among the 4 MV models, the ER≤18 incorporating individual fts resulted in the highest AUC (0.66) and was therefore used to build up a prognostic score. Score. The ER score was calculated as 0.047 × PCbm + 0.589 × LDHULN + 0.459 × del17q (IF present) + 0.705 × t(4/14) (IF present) + 0.293 × FLC (IF FLC =λ) - 0.284 × alb. The ER score was calculated as 3 groups of pts with different risks of ER: L (42% of pts; risk of ER18=23%), M (33% of pts; risk of ER18=39%) and H (26% of pts; risk of ER18 =55%). Discussion. This is the first analysis proposing a score that includes standard baseline fts and aims at identifying pts at high risk of ER in the context of novel agent-based therapy. Based on our score, 26% of pts can be defined at high risk. To improve the clinical applicability, the construction of a simplified model with categorized variables is ongoing. Disclosures Petrucci: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Offidani: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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Di Raimondo:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy. Liberati:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Novartis: Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Omedé:Janssen: Membership on an entity's Board of Directors or advisory committees. Mannina:Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy. Caravita di Toritto:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation costs, Research Funding; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation costs; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accomodation costs; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Patriarca:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Benevolo:Novartis Pharmaceuticals: Consultancy. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra-Zeneca: Consultancy, Honoraria; Sunesys: Consultancy, Honoraria. Hajek:Amgen: Honoraria, Other: Consultant or advisory relationship, Research Funding; Celgene: Honoraria, Other: Consultant or advisory relationship, Research Funding; AbbVie: Other: Consultant or advisory relationship; Bristol-Myers Squibb: Honoraria, Other: Consultant or advisory relationship, Research Funding; Novartis: Other: Consultant or advisory relationship, Research Funding; PharmaMar: Honoraria, Other: Consultant or advisory relationship; Takeda: Honoraria, Other: Consultant or advisory relationship, Research Funding; Janssen: Honoraria, Other: Consultant or advisory relationship, Research Funding. Spencer:Sanofi: Other: Consulting/advisory role; Specialised Therapeutics Australia: Consultancy, Honoraria; Amgen: Other: Consulting/advisory role, Research Funding; AbbVie: Other: Consulting/advisory role, Research Funding; Haemalogix: Other: Consulting/advisory role; Janssen Oncology: Other: Consulting/advisory role, Research Funding, Speakers Bureau; Servier: Other: Consulting/advisory role; Secura Bio: Other: Consulting/advisory role; Takeda: Other: Consulting/advisory role, Research Funding; Celgene: Other: Consulting/advisory role, Research Funding, Speakers Bureau. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SkylineDx: Research Funding. Boccadoro:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Gay:AbbVie: 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; 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma.

INTRODUCTION: Cancer pathogenesis is usually characterized by a long evolutionary process where genomic driver events accumulate over time, conferring advantage to distinct subclones, allowing their expansion and progression. METHODS: To investigate the multiple myeloma (MM) evolutionary history, we characterized the mutational processes' landscape and activity over time utilizing a large cohort of 89 whole genomes and 973 exomes. To improve the accuracy of mutational signatures analysis, we analyzed both the 3' and 5' nucleotide context of each mutation and we developed the novel fitting algorithm mmSig, which fits the entire mutational catalogue of each patient with the mutational signatures involved in MM pathogenesis. The contribution of each mutational signature was then corrected based on the cosine similarity between the original 96-mutational profile and the reconstructed profile generated without that signature. To reconstruct the genetic evolutionary history of each patient's cancer, we integrated two approaches. First dividing all mutations into clonal (early) or subclonal (late), then subdivided the clonal mutations into duplicated mutations (present on two alleles and therefore acquired before the duplication) or non-duplicated mutations (detected on a single allele), reflecting either pre-gain and post-gain mutations on the minor allele, or post-gain mutations acquired on one of the duplicated alleles. RESULTS Eight mutational signatures were identified, seven of which showed significant similarity with the most recent mutational signature catalogue (i.e SBS1, SBS2, SBS5, SBS8, SBS9, SBS13 and SBS18). The new mutational signature (named SBS-MM1) was observed only among relapsed patients exposed to alkylating agents (i.e melphalan). The etiology of this specific signature was further confirmed by analyzing recent whole genomes public data from human-induced pluripotent stem cells exposed to melphalan (Kucab et al, Cell 2019). Reconstructing the chronological activity of each mutational signature, we identified four different routes to acquire the full mutational spectrum in MM based on the differential temporal activity of AID (SBS9) and APOBEC (SBS2 and SBS13). Our data indicate that AID activity is not limited to the first contact with the GC, but persists in the majority of patients, behaving similarly to a B-memory cells, capable of re-entering the germinal center upon antigen stimulation to undergo clonal expansion several times before MM diagnosis. Next, we confirmed the clock-like nature (i.e constant mutation rate) of SBS5 in MM and other post-germinal center disorders such as chronic lymphocytic leukemia and B-cell lymphomas. Based on the SBS5 mutation rates and the corrected ratio between duplicated and non-duplicated mutations within large chromosomal gains, we could time the acquisition of the first copy number gain during the life history of each MM patient. Intriguingly, the first MM chromosomal duplication was acquired on average 38 years (ranges 11-64) before sample collection. In 23/27 (85%) cases the first multi gain event occurred before 30 years of age, and in 13/27 (48%) before 20 years reflecting a long and slow process potentially influenced and accelerated by extrinsic and intrinsic factors. DISCUSSION Our analysis provides a glimpse into the early stages of myelomagenesis, where acquisition of the first key drivers precedes cancer diagnosis by decades. Defining the time window when transformation occurs opens up for new avenues of research: to identify causal mechanisms of disease initiation and evolution, to better define the optimal time to start therapy, and ultimately develop early prevention strategies. Disclosures Bolli: CELGENE: Honoraria; JANSSEN: Honoraria; GILEAD: Other: Travel expenses. Corradini:Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Gilead: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; BMS: Other: Travel Costs. Anderson:Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Sanofi-Aventis: Other: Advisory Board. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Papaemmanuil:Celgene: Research Funding. Avet-Loiseau:takeda: Consultancy, Other: travel fees, lecture fees, Research Funding; celgene: Consultancy, Other: travel fees, lecture fees, Research Funding. Munshi:Adaptive: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Abbvie: Consultancy. Landgren:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Bortezomib-melphalan-prednisone (VMP) and continuous lenalidomide-dexamethasone (Rd) represent the standard treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (MM). To date, no randomized trial has compared VMP to Rd, and there is no evidence of the optimal treatment for newly diagnosed MM, particularly in patients with high-risk cytogenetics [del(17p), t(4;14) or t(14;16)]. We pooled together data from patients with newly diagnosed MM treated with VMP or Rd induction followed by lenalidomide maintenance 10 mg (Rd-R) enrolled in the GIMEMA-MM-03-05 and EMN01 trials, to evaluate the efficacy of these treatments in different subgroups of patients, focusing on those with standard- and high-risk cytogenetics. Overall, 474 patients were analyzed (VMP: 257 patients; Rd-R: 217 patients). No differences in progression-free survival (hazard ratio=0.96) and overall survival (hazard ratio=1.08) were observed between standard-risk patients treated with VMP or Rd-R, whereas among the high-risk patients, the probabilities of progression (hazard ratio=0.54) and death (hazard ratio=0.73) were lower in the patients treated with VMP than in those treated with Rd-R. In particular, standard-risk patients >75 years benefited less from VMP than from Rd-R (hazard ratio for progression-free survival=0.96; hazard ratio for overall survival=1.81). In this non-randomized analysis, VMP and Rd-R were equally effective in younger (≤75 years), standard-risk patients, while older ones (>75 years) benefited more from Rd-R. In high-risk patients, VMP improved progression-free survival and overall survival irrespective of age. The source trials are registered at ClinicalTrials.gov (NCT01063179 and NCT01093196).

Background Several new drugs are approved for treatment of patients with multiple myeloma (MM), but no validated biomarkers are available for the prediction of a clinical outcome. We aimed to establish whether pretreatment blood and bone marrow plasma concentrations of major cytokines and angiogenic factors (CAFs) of patients from a phase 3 trial of a MM treatment could have a prognostic and predictive value in terms of response to therapy and progression-free and overall survival and whether these patients could be stratified for their prognosis. Methods Blood and bone marrow plasma levels of Ang-2, FGF-2, HGF, VEGF, PDGF-β, IL-8, TNF-α, TIMP-1, and TIMP-2 were determined at diagnosis in MM patients enrolled in the GIMEMA MM0305 randomized controlled trial by an enzyme-linked immunosorbent assay (ELISA). These levels were correlated both reciprocally and with the type of therapy and patients’ characteristics and with a group of non-MM patients as controls. Results No significant differences were detected between the blood and bone marrow plasma levels of angiogenic cytokines. A cutoff for each CAF was established. The therapeutic response of patients with blood plasma levels of CAFs lower than the cutoff was better than the response of those with higher levels in terms of percentage of responding patients and quality of response. Conclusion FGF-2, HGF, VEGF, and PDGF-β plasma levels at diagnosis have predictive significance for response to treatment. The stratification of patients based on the levels of CAFs at diagnosis and their variations after therapy is useful to characterize different risk groups concerning outcome and response to therapy. Trial registration Clinical trial information can be found at the following link: NCT01063179 Electronic supplementary material The online version of this article (10.1186/s13045-018-0691-4) contains supplementary material, which is available to authorized users.

Maintenance therapy after autologous stem cell transplantation, as well as continuous regimens for older, transplant ineligible patients, are emerging as an effective strategy to control the minimal residual disease that persists after response to initial treatments and is the main cause of relapse in patients affected by multiple myeloma (MM). However, though such approaches have consistently demonstrated in clinical trials to be able to delay disease recurrence, thus improving progression-free survival and, at least in some studies, overall survival, the use of these long term therapies (LTTs) in the daily clinical practice is not uniformly applied and some questions remains unanswered. This article aims to provide a synthetic discussion of the most consistent data on novel agent-based LTTs in newly diagnosed MM, to recognize the best candidate for these treatments and to describe a landscape of their possible future application.

Allogeneic hematopoietic cell transplantation (alloHCT) represents a treatment option for multiple myeloma (MM) patients. As shown in several studies, alloHCT is highly effective, but it is hampered by a high toxicity, mainly related to the graft-versus-host disease (GVHD), a complex immunological reaction ascribable to the donor’s immune system. The morbidity and mortality associated with GVHD can weaken the benefits of this procedure. On the other side, the high therapeutic potential of alloHCT is also related to the donor’s immune system, through immunological activity known as the graft-versus-myeloma effect. Clinical research over the past two decades has sought to enhance the favorable part of this balance, along with the reduction in treatment-related toxicity. Frontline alloHCT showed promising results and a potential for a cure in the past. Currently, thanks to the improved results of first-line therapies and the availability of effective second- or third-line salvage therapies, alloHCT is reserved for selected high-risk patients and is considered a clinical option. For donor lymphocyte infusion, bortezomib or lenalidomide have been used as consolidation or maintenance therapies post-transplant—none has become standard of care. For those patients who relapse, the best treatment should be evaluated considering the patient’s clinical status and the previous lines of therapy. The use of newer drugs, such as monoclonal antibodies or other immunotherapies in the post-transplant setting, deserves further investigation. However, acceptable toxicity and a synergic effect with the newer immune system could be hopefully expected.

In Multiple myeloma (MM) no treatment has a curative potential and even complete response to novel agents such as proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) are followed by relapse over time. Next generation sequencing (NGS) has showed how MM at diagnosis is defined by several somatic mutations, but only few drivers, even fewer "druggable" mutations, and many found at a subclonal level. At relapse, targeted studies have shown occasional mutations in drug target genes but the genomic and transcriptomic determinants of chemoresistance in MM remains elusive. We selected 42 MM patients refractory to both lenalidomide and PIs. Whole exome sequencing was performed in 40 of them, and RNAseq in 27. Clinical annotation was available for all patients. Standard analysis pipelines where applied to analyze mutations, copy number alterations (CNAs), mutational signatures, gene expression and expressed mutations. Patients received a median of 3 lines of treatment, with median overall survival of 14.6 months from sampling. We found a median of 77.5 mutations per patient, which is more than what reported at diagnosis (Bolli et al, Nature Communications 2014;5:2997). 100% of samples showed evidence of subclonality, and 37% of them exhibited a higher number of subclonal than clonal variants. Therefore, even at this advanced stage the MM genome is evolving and is composed of different subclones that may display different chemosensitivity. The mutational landscape was also different. TP53 mutations were the second most common after KRAS (20% and 17.5%, respectively). Interestingly TP53 mutations all clustered in patients receiving bortezomib as the last line of treatment. Only 2 patients showed a CRBN mutation, both subclonal. Combining mutations and CNA analysis, the TP53 pathway was the most frequently inactivated (45% of patients). Altogether, mutations or deletions of genes in the CRBN E3 ubiquitin ligase complex were found in 32.5% of patients, while proteasomal subunit genes were infrequently hit. Refractory cases were also uniquely characterized by a novel signature linked to exposure to alkylating agents, whose activity was more pronounced after high-dose melphalan suggesting a mutagenic effect of the drug on residual cells at the time of transplant. Whether this has any pathogenetic role on the disease course remains to be elucidated. RNAseq analysis did not show any influence of treatment or mutational data on the clustering of samples, which was mainly influenced by karyotypic events. The main cluster was composed by non-hyperdiploid patients with both amp(1q) and del(13): these showed CCND2 and MCL1 upregulation, the latter representing a marker of venetoclax resistance and novel target of experimental treatments. Only 26.3% of mutations were expressed, and this correlated with the clonality level of the mutation. However, most mutations in driver genes were expressed, with the notable exception of those causing nonsense mediated decay. Overall, classical high-risk features or CRBN pathway mutations were found in 65% of the cohort. However, only amp(1q) predicted survival in our cohort. The lack of prognostic value of high-risk lesions is likely explained by a higher prevalence of such features in double-refractory stages. Our data suggest that gene mutation is not a preferred mode of evolution of drug resistance in MM. Chemoresistance of the bulk tumor population is likely attained though differential, yet converging evolution of different subclones that are overall highly variable from patient to patient and within the same patient. Disclosures Kastritis: Prothena: Honoraria; Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria. Dimopoulos:Sanofi Oncology: Research Funding. Cavo:bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: 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 accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Corradini:Janssen: Honoraria, Other: Travel Costs; Takeda: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Gilead: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Celgene: Honoraria, Other: Travel Costs; Amgen: Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel Costs; KiowaKirin: Honoraria; Kite: Honoraria; BMS: Other: Travel Costs; Sanofi: Honoraria; Servier: Honoraria; Roche: Honoraria; Novartis: Honoraria, Other: Travel Costs. Bolli:Celgene: Honoraria; Novartis: Honoraria; Gilead: Other: travel expenses.

Background Risk-adapted therapy is a common strategy in curable hematologic malignancies: standard-risk patients receive less intensive treatment, whereas high-risk patients require a more intensive approach. This model cannot be applied in multiple myeloma (MM), which is still incurable. Continuous treatment (CT) is a key strategy for MM treatment, since it improves duration of remission. However, the role of CT according to standard- or high-risk baseline prognosis remains an open question. Patients and methods We performed a pooled analysis of 2 phase III trials (GIMEMA-MM-03-05 and RV-MM-PI-209) that randomized patients to CT vs fixed-duration therapy (FDT). Results In the overall patient population (n = 550), CT improved progression-free survival1 (PFS1) (HR 0.54), PFS2 (HR 0.61) and overall survival (OS) (HR 0.71) vs FDT. CT improved PFS1 both in R-ISS I (HR 0.49) and R-ISS II/III patients (HR 0.55). Four-year PFS1 was 38% in R-ISS II/III patients receiving CT and 25% in R-ISS I patients receiving FDT, with similar trends for PFS2 and OS. High-risk patients benefited more from proteasome-inhibitor plus immunomodulatory-based CT than immunomodulatory alone. Conclusion Good prognosis patients receiving FDT lose their prognostic advantage over high-risk patients receiving CT and high-risk patients may benefit from more intensive maintenance including proteasome inhibitors and immunomodulators.

We report the long-term clinical outcomes of a retrospective multicenter study that enrolled 169 patients with multiple myeloma (MM) in first relapse after failing autologous stem cell transplantation (SCT). After HLA typing at relapse, 79 patients with a suitable donor, 72 (91%) of whom eventually underwent salvage allogeneic SCT (allo-SCT), were compared with 90 patients without a donor who were treated with multiple lines of salvage treatment with bortezomib and/or immunomodulatory agents. At a median follow-up of 30 months (range, 2-180 months) for all patients and 110 months (range, 38-180 months) for surviving patients, 7-year progression-free survival (PFS) was 18% in the donor group and 0% in the no-donor group (hazard ratio [HR], 2.495; 95% confidence interval [CI], 1.770-3.517; P .0001). Seven-year overall survival (OS) was 31% in the donor group and 9% in the no-donor group (HR, 1.835; 95% CI, 1.306-2.577; P .0001). By multivariate analysis, chemosensitivity to salvage treatments and presence of a suitable donor were significantly associated with better PFS and OS. The long-term follow-up of this study confirms the significant PFS benefit and provides new evidence of an OS advantage for patients with MM who have a suitable donor and undergo allo-SCT. Allo-SCT should be considered as a treatment option in young relapsed patients with high-risk disease features after first-line treatment.

This multicentre, open-label phase 1/2 trial determined safety and efficacy of weekly carfilzomib plus cyclophosphamide-dexamethasone (wKCyd) in newly diagnosed multiple myeloma (NDMM) patients aged ⩾65 years or transplant ineligible. Patients received wKCyd for up to nine 28-day cycles, followed by maintenance with carfilzomib until progression/intolerance. The phase 1 portion used a 3+3 dose-escalation scheme to determine the maximum tolerated dose of weekly carfilzomib: 12 patients received wKCyd with carfilzomib doses of 45, 56 and 70 mg/m

Introduction: Novel targeted therapies and monoclonal antibodies can be combined with allogeneic stem cell transplantation (allo-SCT) at different time-points: 1) before the transplant to reduce tumour burden, 2) as part of the conditioning in place of or in addition to conventional agents 3) after the transplant to allow long-term disease control. Areas covered: This review focuses on the current integration of new drugs with allo-SCT for the treatment of major hematological malignancies for which allo-SCT has been a widely-adopted therapy. Expert opinion: After having been used as single agent salvage treatments in relapsed patients after allo-SCT or in combination with donor lymphocyte infusions, many new drugs have also been safely employed before allo-SCT as a bridge to transplantation or after it as planned consolidation/maintenance. This era of new drugs has opened new important opportunities to ‘smartly’ combine ‘targeted drugs and cell therapies’ in new treatment paradigms that may lead to higher cure rates or longer disease control in patients with hematological malignancies.

The authors describe a family with a high penetrance of plasma cell dyscrasias, suggesting inheritance of an autosomal dominant risk allele.The authors performed whole-exome sequencing and reported on a combined approach aimed at the identification of causative variants and risk loci, using the wealth of data provided by this approach.The authors identified gene mutations and single-nucleotide polymorphisms of potential significance, and pinpointed a known risk locus for myeloma as a potential area of transmissible risk in the family.To the authors' knowledge, the current study is the first to provide a whole-exome sequencing approach to such cases, and a framework analysis that could be applied to further understanding of the inherited risk of developing plasma cell dyscrasias. Cancer 2017;123:3701-3708. © 2017 American Cancer Society.

Allogeneic (allo) hematopoietic cell transplantation (HCT) currently represents the only potentially curative therapy for patients affected by multiple myeloma (MM). Up to 30% of patients in western countries do not have a matched donor. Haploidentical HCT (haplo-HCT) may be an option, but currently, there are little available data regarding this treatment. We analyzed survival outcomes of 30 heavily pretreated MM patients who received haplo-HCT with post-transplantation cyclophosphamide as graft-versus-host-disease (GVHD) prophylaxis. Median neutrophil and platelet engraftments at day +30 were 87% (95% confidence interval [CI], 66% to 95%) and 60% (95% CI, 40% to 75%), respectively. The cumulative incidences of relapse or progression of disease (PD) and nonrelapse mortality at 18 months were 42% (95% CI, 23% to 59%) and 10% (95% CI, 2% to 24%), respectively. The cumulative incidence of grade II to IV acute GVHD at day +100 was 29% (95% CI, 14% to 47%). The cumulative incidence of chronic GVHD at 18 months was 7% (95% CI, 1% to 21%). With a median follow-up in survivors of 25 months (range, 15 to 73 months), the 18-month progression-free survival (PFS) and overall survival (OS) were 33% (95% CI, 17% to 50%) and 63% (95% CI, 44% to 78%), respectively. No differences were observed between peripheral blood and bone marrow graft in terms of engraftment, GVHD, or PD incidence. Chemorefractory disease at transplantation was associated with a lower/reduced 18-month PFS (9% versus 47%, P = .01) and OS (45% versus 74%, P = .03). This was explained by a higher PD incidence (55% versus 33%, P = .05). In this multicenter study, we report encouraging results with haplo-HCT for patients with heavily pretreated MM.