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Background: Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed., Methods: In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)-negative status., Results: At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P = 0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group., Conclusions: The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Bortezomib-based induction followed by high-dose melphalan (200 mg/m 2 ) 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 (<60 years vs 60-65 years) and randomly assigned (1:1:1) to KRd plus ASCT (four 28-day induction cycles with carfilzomib plus lenalidomide plus dexamethasone [KRd], melphalan at 200 mg/m 2 and autologous stem-cell transplantation [MEL200-ASCT], followed by four 28-day KRd consolidation cycles), KRd12 (12 28-day KRd cycles), or KCd plus ASCT (four 28-day induction cycles with carfilzomib plus cyclophosphamide plus dexamethasone [KCd], MEL200-ASCT, and four 28-day KCd consolidation cycles). Carfilzomib 36 mg/m 2 was administered intravenously on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg administered orally on days 1-21; cyclophosphamide 300 mg/m 2 administered orally on days 1, 8, and 15; and dexamethasone 20 mg administered orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23. Thereafter, patients were stratified according to induction-consolidation treatment and randomly assigned (1:1) to maintenance treatment with carfilzomib plus lenalidomide or lenalidomide alone. Carfilzomib 36 mg/m 2 was administered intravenously on days 1-2 and 15-16 every 28 days for up to 2 years; lenalidomide 10 mg was administered orally on days 1-21 every 28 days until progression or intolerance in both groups. The primary endpoints were the proportion of patients with at least a very good partial response after induction with KRd versus KCd and progression-free survival with carfilzomib plus lenalidomide versus lenalidomide alone as maintenance treatment, both assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02203643. Study recruitment is complete, and all patients are in the follow-up or maintenance phases., Findings: Between Feb 23, 2015, and April 5, 2017, 474 patients were randomly assigned to one of the induction-intensification-consolidation groups (158 to KRd plus ASCT, 157 to KRd12, and 159 to KCd plus ASCT). The median duration of follow-up was 50·9 months (IQR 45·7-55·3) from the first randomisation. 222 (70%) of 315 patients in the KRd group and 84 (53%) of 159 patients in the KCd group had at least a very good partial response after induction (OR 2·14, 95% CI 1·44-3·19, p=0·0002). 356 patients were randomly assigned to maintenance treatment with carfilzomib plus lenalidomide (n=178) or lenalidomide alone (n=178). The median duration of follow-up was 37·3 months (IQR 32·9-41·9) from the second randomisation. 3-year progression-free survival was 75% (95% CI 68-82) with carfilzomib plus lenalidomide versus 65% (58-72) with lenalidomide alone (hazard ratio [HR] 0·64 [95% CI 0·44-0·94], p=0·023). During induction and consolidation, the most common grade 3-4 adverse events were neutropenia (21 [13%] of 158 patients in the KRd plus ASCT group vs 15 [10%] of 156 in the KRd12 group vs 18 [11%] of 159 in the KCd plus ASCT group); dermatological toxicity (nine [6%] vs 12 [8%] vs one [1%]); and hepatic toxicity (13 [8%] vs 12 [8%] vs none). Treatment-related serious adverse events were reported in 18 (11%) of 158 patients in the KRd-ASCT group, 29 (19%) of 156 in the KRd12 group, and 17 (11%) of 159 in the KCd plus ASCT group; the most common serious adverse event was pneumonia, in seven (4%) of 158, four (3%) of 156, and five (3%) of 159 patients. Treatment-emergent deaths were reported in two (1%) of 158 patients in the KRd plus ASCT group, two (1%) of 156 in the KRd12 group, and three (2%) of 159 in the KCd plus ASCT group. During maintenance, the most common grade 3-4 adverse events were neutropenia (35 [20%] of 173 patients on carfilzomib plus lenalidomide vs 41 [23%] of 177 patients on lenalidomide alone); infections (eight [5%] vs 13 [7%]); and vascular events (12 [7%] vs one [1%]). Treatment-related serious adverse events were reported in 24 (14%) of 173 patients on carfilzomib plus lenalidomide versus 15 (8%) of 177 on lenalidomide alone; the most common serious adverse event was pneumonia, in six (3%) of 173 versus five (3%) of 177 patients. One patient died of a treatment-emergent adverse event in the carfilzomib plus lenalidomide group., Interpretation: Our data show that KRd plus ASCT showed superiority in terms of improved responses compared with the other two treatment approaches and support the prospective randomised evaluation of KRd plus ASCT versus standards of care (eg, daratumumab plus bortezomib plus thalidomide plus dexamethasone plus ASCT) in transplant-eligible patients with multiple myeloma. Carfilzomib plus lenalidomide as maintenance therapy also improved progression-free survival compared with the standard-of-care lenalidomide alone., Funding: Amgen, Celgene/Bristol Myers Squibb., Translation: For the Italian translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests FG has received honoraria from Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, and GlaxoSmithKline; and served on the advisory boards for Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, Roche, Adaptive Biotechnologies, Oncopeptides, and bluebird bio. PM has received honoraria from Celgene, Janssen, Takeda, Bristol Myers Squibb, Amgen, Novartis, Gilead, Jazz, Sanofi, AbbVie, and GlaxoSmithKline; and served on the advisory boards for Celgene, Janssen, Takeda, Bristol Myers Squibb, Amgen, Jazz, Sanofi, AbbVie, and GlaxoSmithKline. AB has served on the advisory boards for Janssen, Celgene, Amgen, and GlaxoSmithKline; and received consultancy fees from Takeda. MGa has received, in the past 2 years, honoraria from Bristol Myers Squibb/Celgene, Janssen, and Takeda. MO has received honoraria from and served on the scientific advisory boards for Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Sanofi, and Takeda. EZ has received honoraria from and served on the advisory boards for Janssen, Bristol Myers Squibb, Takeda, Sanofi, Amgen, GlaxoSmithKline, and Oncopeptides. SB has received honoraria from and served on the scientific advisory boards for Celgene, Janssen, Takeda, Bristol Myers Squibb, Amgen, and Novartis. MC has received advisory fees from Celgene, Janssen, and Takeda; and received research funding from Celgene. FP has served on advisory boards for Celgene, Janssen, and GlaxoSmithKline. MD has received honoraria for lectures from Sanofi and GlaxoSmithKline; and served on advisory boards for GlaxoSmithKline. NG has received research grants from Celgene and Janssen Pharmaceutical; received sponsorship for clinical studies from Janssen Pharmaceutical and Millennium Pharmaceutical; served on advisory boards for Celgene, Takeda, and Janssen Pharmaceutical; and received support for attending meetings from Janssen Pharmaceutical, Celgene, and Bristol Myers Squibb. AP has received support for meetings fees and travel and lodging expenses from Amgen, Celgene, and Janssen; and received non-financial support from Celgene, Janssen, Roche, Takeda, and Amgen. BG has received honoraria from Janssen, Amgen, Celgene, and Takeda; and served on the advisory boards for Celgene, Janssen, Sanofi, Amgen, GlaxoSmithKline, and Takeda. RZ has served on advisory boards for Celgene, Janssen, GlaxoSmithKline, Amgen, and Takeda. MTP has received honoraria from and served on advisory boards for Celgene, Janssen-Cilag, Bristol Myers Squibb, Takeda, Amgen, Sanofi, and Karyopharm. PC has received honoraria from AbbVie, ADC Therapeutics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GlaxoSmithKline, Incyte, Janssen, Kyowa Kirin, Nerviano Medical Science, Novartis, Roche, Sanofi, and Takeda; received support for attending meetings and for travel from Novartis, Janssen, Celgene, Bristol Myers Squibb, Takeda, Gilead/Kite, Amgen, and AbbVie; and participated on a data safety monitoring board or advisory board for ADC Therapeutics. MC has received honoraria from Janssen, Celgene, Bristol Myers Squibb, GlaxoSmithKline, Amgen, Takeda, AbbVie, Sanofi, and Roche; served on the advisory boards for Janssen, Celgene, Bristol Myers Squibb, GlaxoSmithKline, Amgen, Takeda, AbbVie, Sanofi, Roche, and Adaptive Biotechnologies. MB has received honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, and AbbVie; served on the advisory boards for Janssen and GlaxoSmithKline; and received research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, and Mundipharma. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Pieter SonneveldConsulting or Advisory Role: Celgene, Janssen, Amgen, Karyopharm Therapeutics, CARsgen TherapeuticsResearch Funding: Janssen, Amgen, Skyline Diagnostics Meletios A. DimopoulosHonoraria: Amgen, Takeda, Janssen-Cilag, Bristol Myers Squibb, BeigeneConsulting or Advisory Role: Amgen, Janssen-Cilag, Takeda, Bristol Myers Squibb, Beigene Meral BeksacConsulting or Advisory Role: Amgen, Janssen, Sanofi, Oncopeptides, TakedaTravel, Accommodations, Expenses: Amgen, Janssen, Takeda, Sanofi Meral BeksacConsulting or Advisory Role: Celgene, Janssen-Cilag, Amgen, Takeda, Sanofi Pasteur, OncopeptidesSpeakers' Bureau: Amgen, Celgene, Janssen-Cilag, Sanofi Pasteur Heinz LudwigConsulting or Advisory Role: Amgen, Janssen-Cilag, Sanofi, Seattle GeneticsSpeakers' Bureau: Celgene, Bristol Myers Squibb, Janssen-Cilag, Amgen, TakedaResearch Funding: Takeda, Amgen Sonja ZweegmanConsulting or Advisory Role: Janssen-Cilag, Takeda, Celgene, Sanofi, OncopeptidesResearch Funding: Janssen-Cilag, Takeda, CelgeneTravel, Accommodations, Expenses: Janssen-Cilag, Takeda, Celgene Elena ZamagniHonoraria: Janssen-Cilag, Celgene, Amgen, Bristol Myers Squibb, Takeda, GlaxoSmithKline, Oncopeptides, SanofiConsulting or Advisory Role: Celgene, Janssen-Cilag, Amgen, SanofiTravel, Accommodations, Expenses: Janssen-Cilag, Celgene, Amgen Ruth WesterHonoraria: Sanofi Roman HajekConsulting or Advisory Role: Takeda, Amgen, Celgene, AbbVie, BMS, PharmaMar, Janssen-Cilag, NovartisSpeakers' Bureau: Takeda, AmgenResearch Funding: Novartis, BMS, Amgen, Celgene, Takeda Lucia PantaniHonoraria: Celgene, Janssen, Takeda, Amgen Francesca GayHonoraria: Amgen, Bristol Myers Squibb, Celgene, Takeda, AbbVie, Janssen, GlaxoSmithKlineConsulting or Advisory Role: AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Oncopeptides, Roche, Takeda, Janssen, Bluebird bio Stefania OlivaHonoraria: Amgen, Celgene/Bristol Myers Squibb, JanssenConsulting or Advisory Role: Adaptive Biotechnologies, Janssen, Amgen, Takeda Vincent van de VeldenResearch Funding: BD Biosciences, Pfizer, Janssen, Novartis/Navigate, Agilent/DAKOPatents, Royalties, Other Intellectual Property: Patent EuroFlow MRD antibody tubes. No financial relationship KaLung WuConsulting or Advisory Role: Janssen Oncology Gerard BosEmployment: CiMaasLeadership: CiMaasStock and Other Ownership Interests: CIMaasHonoraria: CiMaas Mark-David LevinHonoraria: AbbVie, Celgene, Janssen, TakedaTravel, Accommodations, Expenses: Takeda, Janssen Annemiek BroijlHonoraria: Amgen, Sanofi, Celgene, Bristol Myers Squibb/Celgene, JanssenTravel, Accommodations, Expenses: Bristol Myers Squibb/Celgene Monique MinnemaConsulting or Advisory Role: Janssen-Cilag, Alnylam, Gilead SciencesSpeakers' Bureau: Celgene/Bristol Myers SquibbTravel, Accommodations, Expenses: Celgene Anders WaageHonoraria: Janssen OncologySpeakers' Bureau: Janssen Oncology Cecilie BlimarkHonoraria: Bristol Myers Squibb/Celgene, Janssen, Takeda, AmgenConsulting or Advisory Role: Adaptive Biotechnologies, Janssen, GlaxoSmithKline Niels W. C. J. van de DonkConsulting or Advisory Role: Janssen, Celgene, Bristol Myers Squibb, Novartis, Amgen, Servier, Takeda, BayerSpeakers' Bureau: Janssen Research & Development, Celgene, Amgen, Bristol Myers SquibbResearch Funding: Janssen, Celgene, Amgen, Novartis, Bristol Myers Squibb, Cellectis Massimo OffidaniHonoraria: BMS, Janssen, CelgeneConsulting or Advisory Role: Janssen Giuseppe A. PalumboConsulting or Advisory Role: Novartis, Janssen Oncology, AOP Orphan Pharmaceuticals, AbbVie, AstraZeneca, Celgene/Bristol Myers SquibbSpeakers' Bureau: Novartis, Celgene/Bristol Myers Squibb, AbbVieTravel, Accommodations, Expenses: Takeda, Novartis Andrew SpencerHonoraria: Janssen-Cilag, BMSConsulting or Advisory Role: Janssen-Cilag, BMSSpeakers' Bureau: Janssen-CilagResearch Funding: Janssen-Cilag Mario BoccadoroHonoraria: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, AbbVieConsulting or Advisory Role: Janssen, GlaxoSmithKlineResearch Funding: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, Mundipharma Michele CavoHonoraria: Janssen, Bristol Myers Squibb, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm Therapeutics, Adaptive BiotechnologiesConsulting or Advisory Role: Janssen, Bristol Myers Squibb, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm Therapeutics, Adaptive BiotechnologiesSpeakers' Bureau: Janssen, CelgeneNo other potential conflicts of interest were reported.

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 < 0.001), 5-year overall survival was 86% versus 69%, respectively (HR 0.41; p < 0.001). MRD negativity was associated with reduced risk of progression or death in all subgroups, including ISS-III (HR 0.37) and high-risk fluorescence in situ hybridization (FISH) patients (HR 0.38;). In the 1-year maintenance MRD population, 42% of MRD-positive patients at pre-maintenance became MRD-negative after lenalidomide exposure. In conclusion, MRD by MFC is a strong prognostic factor. Lenalidomide maintenance further improved MRD-negativity rate.

To understand the profile of best responders (complete response or better [≥CR]) to carfilzomib, we described the characteristics, progression-free survival (PFS), overall survival (OS) data, and the safety of patients who achieved ≥CR to carfilzomib-based treatment in ASPIRE and ENDEAVOR. In post hoc analyses from ASPIRE and ENDEAVOR, median PFS and OS were longer for ≥CR patients versus those who achieved a very good partial response or partial response (VGPR/PR). In the carfilzomib arm of ASPIRE, median PFS was 50.4 months for ≥CR versus 22.1 months for VGPR/PR; median OS was 67.0 versus 44.2 months, respectively. In the carfilzomib arm of ENDEAVOR, median PFS was 34.0 for ≥CR versus 20.4 months for VGPR/PR; median OS was non-estimable. Despite the longer treatment duration, fewer patients with ≥CR versus VGPR/PR experienced treatment-emergent adverse events that led to discontinuation of carfilzomib-based treatment in ASPIRE or ENDEAVOR. Low serum lactate dehydrogenase was the only factor associated with achieving ≥CR vs patients not achieving CR in ASPIRE in multivariate regression analyses. No association was found between cytogenetic risk status and reaching ≥CR. Carfilzomib treatment may lead to rapid and deep responses, irrespective of most patient characteristics.

Purpose: Duration of first remission is important for the survival of patients with multiple myeloma., Experimental Design: From the CoMMpass study (NCT01454297), 926 patients with newly diagnosed multiple myeloma, characterized by next-generation sequencing, were analyzed to evaluate those who experienced early progressive disease (PD; time to progression, TTP ≤18 months)., Results: After a median follow-up of 39 months, early PD was detected in 191/926 (20.6%) patients, 228/926 (24.6%) patients had late PD (TTP >18 months), while 507/926 (54.8%) did not have PD at the current follow-up. Compared with patients with late PD, patients with early PD had a lower at least very good partial response rate (47% vs. 82%, P < 0.001) and more frequently acquired double refractoriness to immunomodulatory drugs (IMiD) and proteasome inhibitors (PI; 21% vs. 8%, P < 0.001). Patients with early PD were at higher risk of death compared with patients with late PD and no PD (HR, 3.65; 95% CI, 2.7-4.93; P < 0.001), showing a dismal median overall survival (32.8 months). In a multivariate logistic regression model, independent factors increasing the early PD risk were TP53 mutation (OR, 3.78, P < 0.001), high lactate dehydrogenase levels (OR, 3.15, P = 0.006), λ-chain translocation (OR, 2.25, P = 0.033), and IGLL5 mutation (OR, 2.15, P = 0.007). Carfilzomib-based induction (OR, 0.15, P = 0.014), autologous stem-cell transplantation (OR, 0.27, P < 0.001), and continuous therapy with PIs and IMiDs (OR, 0.34, P = 0.024) mitigated the risk of early PD., Conclusions: Early PD identifies a high-risk multiple myeloma population. Further research is needed to better identify baseline features predicting early PD and the optimal treatment approaches for patients at risk., (©2020 American Association for Cancer Research.)

Background: Survival of multiple myeloma patients has considerably improved in the last decades thanks to the introduction of many new drugs, including immunomodulatory agents, proteasome inhibitors and, more recently, monoclonal antibodies., Methods: We analyzed the most recent literature focusing on the clinical and pharmacologic aspects of monoclonal antibody-based therapies in multiple myeloma, including monoclonal antibodies directed against plasma cell antigens, as well as checkpoint blockade therapy directed against immune inhibitory molecules, used as single agents or in combination therapy., Results: Anti-CD38 monoclonal antibodies including daratumumab, isatuximab and MOR202 have shown outstanding results in relapsed and/or refractory multiple myeloma patients. The addition of daratumumab to bortezomib-dexamethasone or lenalidomidedexamethasone substantially improved patients' outcome in this patient population. The anti- SLAMF7 molecule elotuzumab in combination with lenalidomide-dexamethasone showed to be superior to lenalidomide-dexamethasone alone, without adding meaningful toxicity. Checkpoint blockade therapy in combination with immunomodulatory agents produced objective responses in more than 50% of treated patients. However, this combination was also associated with an increase in toxicity and a thorough safety evaluation is currently ongoing., Conclusion: Monoclonal antibodies are reshaping the standard of care for multiple myeloma and ongoing trials will help physicians to optimize their use in order to further improve patients' outcome., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Importance: Several trials demonstrated the impact of novel agent-based maintenance in newly diagnosed multiple myeloma (NDMM), but there is no current evidence demonstrating the superiority of one regimen over the other, owing to the lack of direct/indirect comparisons., Objective: To analyze and compare the effectiveness of different maintenance regimens in NDMM via a network meta-analysis., Data Sources: We performed 2 independent searches in PubMed and Cochrane databases, and then we identified all the records registered after 1999 and on or before November 20, 2017., Study Selection: By blinded review, we identified prospective phase 3 randomized trials evaluating novel agent-based maintenance in patients with NDMM; the included studies compared at least 2 maintenance approaches; comparators included placebo and no maintenance. From 364 screened records, 11 studies were included., Data Extraction and Synthesis: We followed (independent extraction) the guidelines provided by the PRISMA Report and the EQUATOR Network. The evidence was synthesized using a network meta-analysis (NMA). To allow comparison of all treatments, no maintenance was selected as common comparator and the effect of placebo was assumed to be the same as no treatment. The best option was identified by a Bayesian consistency model based on hazard ratio (HR), 95% credible interval (CrI), probability of being the best treatment (PbBT), and median ranking distribution (MedR)., Main Outcomes and Measures: Outcomes of interest were progression-free survival (PFS) and overall survival (OS)., Results: Eleven trials and 8 treatments including a total of 5073 participants were included. By PFS analysis, lenalidomide-based regimens (lenalidomide-prednisone, lenalidomide alone) were identified as the most effective options (HR, 0.39 [95% CrI, 0.28-0.53] and 0.47 [95% CrI, 0.39-0.55], respectively; MedR, 1 and 2; overall PbBT, 74%). Four treatments (thalidomide-interferon, thalidomide-bortezomib, bortezomib-prednisone, thalidomide alone) showed an HR in favor of maintenance. By OS analysis, lenalidomide alone was identified as the best option (HR, 0.76; 95% CrI, 0.51-1.16; MedR, 2; PbBT, 38%), followed by bortezomib-thalidomide and bortezomib-prednisone. Similar features were noticed in the restricted network including transplant trials, in the sensitivity analysis, and in most of the prognostic subgroups., Conclusions and Relevance: Based on PFS and OS results of this NMA, lenalidomide maintenance appears to be the best treatment option, by synthesizing the available evidence of novel agent-based maintenance in the past 20 years.

There are currently no direct head-to-head clinical trials evaluating bortezomib-melphalan-prednisone (VMP) versus lenalidomide and low-dose dexamethasone (Rd). VMP (257 cases) and Rd (222 cases) arms of two randomized phase III trials were employed to assess the treatment influence on outcome in untreated elderly MM patients. Progression free survival (PFS) and overall survival (OS) were the primary and secondary end-points, respectively, and were investigated according to treatments administered over a 60-months follow-up period. While VMP significantly reduced the disease progression rate between enrolment and 12 months of follow-up, no difference between the two schedules was found between 12 and 32 months. After 32 months, Rd-treated patients had a lower incidence of disease progression. A statistically significant higher OS rate was seen in the VMP arm, which was maintained after data adjustment for potential confounders. Both approaches showed acceptable toxicity profiles. The profound tumor reduction by VMP over Rd justifies the initial higher PFS rate in favor of the bortezomib schedule, while the Rd regimen overcomes this evident initial drawback in reducing the tumor burden by long-term drug administration, gaining a subsequent improved disease control. VMP is associated with a significant reduced risk of death. This study may help physicians make a more informed therapy choice., (© 2016 Wiley Periodicals, Inc.)

Objective: There is no strong evidence to guide therapeutic approach to multiple myeloma (MM) patients who experience first relapse. The treatment choice can be difficult since currently all patients are exposed to novel agents as thalidomide, bortezomib and lenalidomide., Methods: In this retrospective analysis, we evaluated the best therapeutic sequence, the role of retreatment, and the most beneficial cutoff of first remission in order to choose retreatment, analyzing 476 patients relapsed after first-line therapy., Results: Bortezomib-based regimens upfront followed by lenalidomide-based regimens at first relapse resulted in significantly better second progression-free survival (2ndPFS), PFS2, and overall survival (OS) compared to the opposite sequence. Changing therapy resulted in significantly better 2ndPFS in the whole population, whereas PFS2 was significantly longer only in patients who underwent maintenance therapy. Moreover, until PFS1 was shorter than 27 months, changing therapy at first relapse significantly extended 2ndPFS and PFS2 compared to retreatment, whereas similar outcomes were observed between the two strategies, when PFS1 was longer than 27 months., Conclusion: Lacking randomized trials, our study could help to choose the most appropriate therapy algorithm in patients with MM., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We analyzed 50 patients who achieved at least a very good partial response in the RV-MM-EMN-441 study. Patients received consolidation with autologous stem-cell transplantation (ASCT) or cyclophosphamide-lenalidomide-dexamethasone (CRD), followed by Lenalidomide-based maintenance. We assessed minimal residual disease (MRD) by multi-parameter flow cytometry (MFC) and allelic-specific oligonucleotide real-time quantitative polymerase chain reaction (ASO-RQ-PCR) after consolidation, after 3 and 6 courses of maintenance, and thereafter every 6 months until progression. By MFC analysis, 19/50 patients achieved complete response (CR) after consolidation, and 7 additional patients during maintenance. A molecular marker was identified in 25/50 patients, 4/25 achieved molecular-CR after consolidation, and 3 additional patients during maintenance. A lower MRD value by MFC was found in ASCT patients compared with CRD patients (p=0.0134). Tumor burden reduction was different in patients with high-risk vs standard-risk cytogenetics (3.4 vs 5.2, ln-MFC; 3 vs 6 ln-PCR, respectively) and in patients who relapsed vs those who did not (4 vs 5, ln-MFC; 4.4 vs 7.8 ln-PCR). MRD progression anticipated clinical relapse by a median of 9 months while biochemical relapse by a median of 4 months. MRD allows the identification of a low-risk group, independently of response, and a better characterization of the activity of treatments.

High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) remains the standard of care for patients younger than 65 years of age with multiple myeloma (MM). However, this therapeutic approach has undergone substantial advances in this last decade, mainly due to the introduction of new drugs such as thalidomide, lenalidomide and bortezomib. These new drugs, in different combinations, have shown to significantly increase response rates after induction therapy and ASCT. Moreover, the positive results obtained with these agents in consolidation and maintenance strategies after ASCT strongly support the concept of continuous therapy, whose ultimate goal is the long-term control of the disease and the improvement of outcome. Preliminary data from studies investigating next generation proteasome inhibitors, such as carfilzomib and ixazomib, used upfront as well as at subsequent therapeutic lines, demonstrate the possibility of achieving molecular remission in most of the patients. The deeper responses obtained with new drugcombinations questioned the role of ASCT, and large, ongoing, phase 3 trials will shed light on the role and the timing of ASCT., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: High-dose melphalan plus autologous stem-cell transplantation (ASCT) is the standard approach in transplant-eligible patients with newly diagnosed myeloma. Our aims were to compare consolidation with high-dose melphalan plus ASCT versus chemotherapy (cyclophosphamide and dexamethasone) plus lenalidomide, and maintenance with lenalidomide plus prednisone versus lenalidomide alone., Methods: We did an open-label, randomised, multicentre, phase 3 study at 59 centres in Australia, Czech Republic, and Italy. We enrolled transplant-eligible patients with newly diagnosed myeloma aged 65 years or younger. Patients received a common induction with four 28-day cycles of lenalidomide (25 mg, days 1-21) and dexamethasone (40 mg, days 1, 8, 15, and 22) and subsequent chemotherapy with cyclophosphamide (3 g/m(2)) followed by granulocyte colony-stimulating factor for stem-cell mobilisation and collection. Using a 2 × 2 partial factorial design, we randomised patients to consolidation with either chemotherapy plus lenalidomide (six cycles of cyclophosphamide [300 mg/m(2), days 1, 8, and 15], dexamethasone [40 mg, days 1, 8, 15, and 22], and lenalidomide [25 mg, days 1-21]) or two courses of high-dose melphalan (200 mg/m(2)) and ASCT. We also randomised patients to maintenance with lenalidomide (10 mg, days 1-21) plus prednisone (50 mg, every other day) or lenalidomide alone. A simple randomisation sequence was used to assign patients at enrolment into one of the four groups (1:1:1:1 ratio), but the treatment allocation was disclosed only when the patient reached the end of the induction and confirmed their eligibility for consolidation. Both the patient and the treating clinician did not know the consolidation and maintenance arm until that time. The primary endpoint was progression-free survival assessed by intention-to-treat. The trial is ongoing and some patients are still receiving maintenance. This study is registered at ClinicalTrials.gov, number NCT01091831., Findings: 389 patients were enrolled between July 6, 2009, and May 6, 2011, with 256 eligible for consolidation (127 high-dose melphalan and ASCT and 129 chemotherapy plus lenalidomide) and 223 eligible for maintenance (117 lenalidomide plus prednisone and 106 lenalidomide alone). Median follow-up was 52·0 months (IQR 30·4-57·6). Progression-free survival during consolidation was significantly shorter with chemotherapy plus lenalidomide compared with high-dose melphalan and ASCT (median 28·6 months [95% CI 20·6-36·7] vs 43·3 months [33·2-52·2]; hazard ratio [HR] for the first 24 months 2·51, 95% CI 1·60-3·94; p<0·0001). Progression-free survival did not differ between maintenance treatments (median 37·5 months [95% CI 27·8-not evaluable] with lenalidomide plus prednisone vs 28·5 months [22·5-46·5] with lenalidomide alone; HR 0·84, 95% CI 0·59-1·20; p=0·34). Fewer grade 3 or 4 adverse events were recorded with chemotherapy plus lenalidomide than with high-dose melphalan and ASCT; the most frequent were haematological (34 [26%] of 129 patients vs 107 [84%] of 127 patients), gastrointestinal (six [5%] vs 25 [20%]), and infection (seven [5%] vs 24 [19%]). Haematological serious adverse events were reported in two (2%) patients assigned chemotherapy plus lenalidomide and no patients allocated high-dose melphalan and ASCT. Non-haematological serious adverse events were reported in 13 (10%) patients assigned chemotherapy plus lenalidomide and nine (7%) allocated high-dose melphalan and ASCT. During maintenance, adverse events did not differ between groups. The most frequent grade 3 or 4 adverse events were neutropenia (nine [8%] of 117 patients assigned lenalidomide plus prednisone vs 14 [13%] of 106 allocated lenalidomide alone), infection (eight [8%] vs five [5%]), and systemic toxicities (seven [6%] vs two [2%]). Non-haematological serious adverse events were reported in 13 (11%) patients assigned lenalidomide plus prednisone versus ten (9%) allocated lenalidomide alone. Four patients died because of adverse events, three from infections (two during induction and one during consolidation) and one because of cardiac toxic effects., Interpretation: Consolidation with high-dose melphalan and ASCT remains the preferred option in transplant-eligible patients with multiple myeloma, despite a better toxicity profile with chemotherapy plus lenalidomide., Funding: Celgene., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: Continuous therapy (CT) prolongs progression-free survival 1 (PFS1; time from random assignment until the first progression or death), but chemotherapy-resistant relapse may negatively impact overall survival (OS). Progression-free survival 2 (PFS2; time from random assignment until the second progression or death) may represent an additional tool to estimate outcome. This study evaluates the benefit of novel agent-based CT versus fixed duration of therapy (FDT) in patients with newly diagnosed myeloma., Methods: We included patients enrolled onto three phase III trials that randomly assigned patients to novel agent-based CT versus FDT. Primary analyses were restricted to the intent-to-treat population eligible for CT (patients progression free and alive at 1 year after random assignment). Primary end points were PFS1, PFS2, and OS. All hazard ratios (HRs) and 95% CIs were adjusted for several potential confounders using Cox models., Results: In the pooled analysis of the three trials, 604 patients were randomly assigned to CT and 614 were assigned to FDT. Median follow-up was 52 months. In the intent-to-treat CT population, CT (n = 417), compared with FDT (n = 410), significantly improved PFS1 (median, 32 v 16 months, respectively; HR, 0.47; 95% CI, 0.40 to 0.56; P < .001), PFS2 (median, 55 v 40 months, respectively; HR, 0.61; 95% CI, 0.50 to 0.75; P < .001), and OS (4-year OS, 69% v 60%, respectively; HR, 0.69; 95% CI, 0.54 to 0.88; P = .003)., Conclusion: In this pooled analysis, CT significantly improved PFS1, PFS2, and OS. The improvement in PFS2 suggests that the benefit reported during first remission is not cancelled by a shorter second remission. PFS2 is a valuable end point to estimate long-term clinical benefit and should be included in future trials., (© 2015 by American Society of Clinical Oncology.)

Background: This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma., Methods: We randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival., Results: The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P<0.001; and 4-year overall survival, 81.6% vs. 65.3%; hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P=0.02). Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P<0.001), but 3-year overall survival was not significantly prolonged (88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P=0.14). Grade 3 or 4 neutropenia was significantly more frequent with high-dose melphalan than with MPR (94.3% vs. 51.5%), as were gastrointestinal adverse events (18.4% vs. 0%) and infections (16.3% vs. 0.8%); neutropenia and dermatologic toxic effects were more frequent with lenalidomide maintenance than with no maintenance (23.3% vs. 0% and 4.3% vs. 0%, respectively)., Conclusions: Consolidation therapy with high-dose melphalan plus stem-cell transplantation, as compared with MPR, significantly prolonged progression-free and overall survival among patients with multiple myeloma who were 65 years of age or younger. Lenalidomide maintenance, as compared with no maintenance, significantly prolonged progression-free survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00551928.).

Introduction: Despite the introduction of novel agents, such as thalidomide, lenalidomide and bortezomib, multiple myeloma (MM) remains an incurable disease and new therapies are needed. mAbs are a new promising anticancer treatment option., Areas Covered: This review will focus on mAbs that are currently under evaluation in Phase II and III clinical trials, as single agent and in combination with established treatment options., Expert Opinion: mAbs are a new strategy against MM, and they have demonstrated encouraging results in preclinical models. mAbs have a relatively benign side-effect profile and work synergistically with traditional chemotherapies and with immunomodulatory drugs and proteasome inhibitors.

Multiple myeloma management has undergone profound changes in the past thanks to advances in our understanding of the disease biology and improvements in treatment and supportive care approaches. This article presents recommendations of the European Myeloma Network for newly diagnosed patients based on the GRADE system for level of evidence. All patients with symptomatic disease should undergo risk stratification to classify patients for International Staging System stage (level of evidence: 1A) and for cytogenetically defined high- versus standard-risk groups (2B). Novel-agent-based induction and up-front autologous stem cell transplantation in medically fit patients remains the standard of care (1A). Induction therapy should include a triple combination of bortezomib, with either adriamycin or thalidomide and dexamethasone (1A), or with cyclophosphamide and dexamethasone (2B). Currently, allogeneic stem cell transplantation may be considered for young patients with high-risk disease and preferably in the context of a clinical trial (2B). Thalidomide (1B) or lenalidomide (1A) maintenance increases progression-free survival and possibly overall survival (2B). Bortezomib-based regimens are a valuable consolidation option, especially for patients who failed excellent response after autologous stem cell transplantation (2A). Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients (1A). Melphalan-prednisone-lenalidomide with lenalidomide maintenance increases progression-free survival, but overall survival data are needed. New data from the phase III study (MM-020/IFM 07-01) of lenalidomide-low-dose dexamethasone reached its primary end point of a statistically significant improvement in progression-free survival as compared to melphalan-prednisone-thalidomide and provides further evidence for the efficacy of lenalidomide-low-dose dexamethasone in transplant-ineligible patients (2B).

A sequential approach including bortezomib induction, intermediate-dose melphalan, and autologous stem cell transplantation (ASCT), followed by lenalidomide consolidation-maintenance, has been evaluated. Efficacy and safety data have been analyzed on intention-to-treat and results updated. Newly diagnosed myeloma patients 65 to 75 years of age (n = 102) received 4 cycles of bortezomib-pegylated liposomal doxorubicin-dexamethasone, tandem melphalan (100 mg/m(2)) followed by ASCT (MEL100-ASCT), 4 cycles of lenalidomide-prednisone consolidation (LP), and lenalidomide maintenance (L) until disease progression. The complete response (CR) rate was 33% after MEL100-ASCT, 48% after LP and 53% after L maintenance. After a median follow-up of 66 months, median time-to-progression (TTP) was 55 months and median progression-free survival 48 months. Median overall survival (OS) was not reached, 5-year OS was 63%. In CR patients, median TTP was 70 months and 5-year OS was 83%. Median survival from relapse was 28 months. Death related to adverse events (AEs) occurred in 8/102 patients during induction or transplantation. Rate of death related to AEs was higher in patients ≥70 years compared with younger (5/26 vs 3/76, P = .024). Bortezomib-induction followed by ASCT and lenalidomide consolidation-maintenance is a valuable option for elderly myeloma patients, with the greatest benefit in those younger than 70 years of age.

Multiple myeloma remains a fatal plasma cell malignancy. However, new insights into the disease biology and immunology have identified molecular mechanisms, underling functional interactions between plasma cells and the bone marrow microenvironment that have become molecular targets of so-called "new drugs" such as thalidomide, lenalidomide, and bortezomib. Recently, the combinations of new drugs with melphalan and prednisone in elderly patients, and with autologous stem cell transplantation in induction and/or maintenance schedules in younger patients have significantly prolonged overall survival. Optimal combinations and timing are a matter of debate. Moreover, management of side effects is a key clinical target to improve long-term quality of life. Many randomized phase III studies are currently in progress to address these issues. Whether these new advancements in myeloma treatment will eventually translate into a long chronic phase or a monoclonal gammopathy of undetermined significance-like status for the majority of patients remains, however, still unanswered., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Although treatment for multiple myeloma (MM) has considerably improved in the past decade, MM continues to be an incurable hematological malignancy that causes most patients to eventually relapse and die from their illness. Thus, the identification of effective salvage strategies remains a priority., Methods: In this trial, the authors evaluated the safety and efficacy of bortezomib and dexamethasone [V: on days 1 and 15 (1.3 mg/mq); D: on days 1-2 and 15-16, every 28-day cycle until progression (20 mg/d)] as maintenance therapy (MT) in patients with advanced MM who responded to salvage therapy that used a bortezomib-containing regimen., Results: Forty-nine MM patients were enrolled in this study between October of 2004 and April of 2008. All patients who were included in this study were responsive to a prior salvage therapy with bortezomib and had a measurable disease. The bortezomib and dexamethasone MT improved the quality of responses to complete remission in 4 patients and very good partial response in 3 patients. In addition, 10 patients experienced at least a 50% improvement in their symptoms. The median time to progression (TTP) was 16 months with a progression-free survival of 61% after 1 year. The overall response after 1 year was 76%, and the cumulative incidence of death due to disease progression, which was adjusted for competitive risk events, was 14%. Non-dose-limiting toxicities included neuropathy (predominantly grade 1), herpes zoster reactivation, pneumonia, and gastrointestinal affections (constipation and diarrhea). Three patients developed grade 2 neuropathy, which required a bortezomib dose reduction to 1.0 mg/mq. No grade 3 or 4 toxicities were recorded., Conclusions: The use of bortezomib and dexamethasone as MT in advanced MM was effective and well tolerated. The twice-monthly bortezomib infusion appeared to reduce the incidence of grade 3 and 4 neuropathies in comparison to similar experiences in other settings., (Copyright © 2010 American Cancer Society.)

For many years, the oral combination melphalan-prednisone (MP) has been considered the standard of care for patients with multiple myeloma (MM) not eligible for autologous stem cell transplantation. In the era of novel agents, the introduction of immunomodulatory drugs and proteasome inhibitors has challenged the role of MP and led to new standards of care for this disease. Five randomized phase III studies compared the traditional MP with the MP plus thalidomide (MPT). All these studies showed a prolonged time to progression (TTP) with the 3-drug combination. However, in only two of these trials this advantage translated into an improvement in overall survival (OS). In another randomized trial, MP plus bortezomib (VMP) was correlated with an increase in both TTP and OS compared with MP. Preliminary data showed the superiority of the association of VMP plus thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) vs VMP and melphalan-prednisone-lenalidomide followed by lenalidomide maintenance (MPR-R) compared to MP. Promising results have also been reported with the combination of lenalidomide plus low-dose dexamethasone. The availability of different efficacious regimens provided clinicians with the opportunity of tailoring the proper and specific approach for each patient. The choice should be based on patients' comorbidities and biologic age, while taking into account the expected toxicity profiles of each treatment regimen. Moreover, an accurate management of therapy-related adverse events and a gentler approach, particularly for patients older than 75 years, with appropriate age-adjusted dose reductions, should be considered to further improve outcome., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The objective of this case-matched study was to compare the efficacy and toxicity of the addition of clarithromycin (Biaxin) to lenalidomide/low-dose dexamethasone (BiRd) vs. lenalidomide/low-dose dexamethasone (Rd) for newly diagnosed myeloma. Data from 72 patients treated at the New York Presbyterian Hospital-Cornell Medical Center were retrospectively compared with an equal number of matched pair mates selected among patients seen at the Mayo Clinic who received Rd. Case matching was blinded and was performed according to age, gender, and transplant status. On intention-to-treat analysis, complete response (45.8% vs. 13.9%, P < 0.001) and very-good-partial-response or better (73.6% vs. 33.3%, P < 0.001) were significantly higher with BiRd. Time-to-progression (median 48.3 vs. 27.5 months, P = 0.071), and progression-free survival (median 48.3 vs. 27.5 months, P = 0.044) were higher with BiRd. There was a trend toward better OS with BiRd (3-year OS: 89.7% vs. 73.0%, P = 0.170). Main grade 3-4 toxicities of BiRd were hematological, in particular thrombocytopenia (23.6% vs. 8.3%, P = 0.012). Infections (16.7% vs. 9.7%, P = 0.218) and dermatological toxicity (12.5% vs. 4.2%, P = 0.129) were higher with Rd. Results of this case-matched analysis suggest that there is significant additive value when clarithromycin is added to Rd. Randomized phase III trials are needed to confirm these results., (© 2010 Wiley-Liss, Inc.)

Background: The goal of this retrospective study was to compare the efficacy and toxicity of lenalidomide-dexamethasone (len/dex) vs. melphalan-prednisone-lenalidomide (MPR) as upfront therapy for newly diagnosed elderly patients with myeloma., Methods: Data from 51 patients enrolled in an Italian phase I/II trial and treated with MPR were analyzed and compared with data from 38 patients, seen at the Mayo Clinic, treated with len/dex and enrolled in phase II/III trials., Results: On intention-to-treat analysis, time to progression (median: 24.7 vs. 27.5 months in MPR and len/dex groups, respectively, P = 0.903), progression-free survival (median: 24.7 vs. 27.5 months in MPR and len/dex groups, respectively, P = 0.926), and overall survival (2-yr overall survival: 86.2% in MPR vs. 89.1% in len/dex, P = 0.730) were not significantly different between the two groups. Results were confirmed when the analysis was restricted to MPR and len/dex matched pair mates. Hematologic grade 3-4 toxicities were more common with MPR (neutropenia: 66.7% vs. 21.1%, P < 0.001; thrombocytopenia: 31.4% vs. 2.6%, P < 0.001). Grade 3-4 gastrointestinal events (13.2% vs. 3.9%, P = 0.132), thrombotic events (13.2% vs. 5.9%, P = 0.279), and fatigue (10.5% vs. 3.9%, P = 0.395) were more common with len/dex., Conclusions: Results show that both MPR and len/dex are efficacious regimens for elderly patients with myeloma. Randomized trials are needed to confirm these results.

Background: Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen., Design and Methods: This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1-4, prednisone at a dose of 1.5 mg/kg also on days 1-4 and thalidomide at a dose of 50-100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1-4 and 1.6, 3.2, or 4.8 g on days 5-35., Results: Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3-4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient., Conclusions: This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1-4 followed by 4.8 g p.o. on days 5-35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs.

Treatment of myeloma has dramatically changed after introduction of novel agents, such as thalidomide, lenalidomide and bortezomib, with a significant improvement in response rate and survival of patients with myeloma. For newly diagnosed patients not eligible for transplant, the standards of care are now considered melphalan and prednisone (MP) plus thalidomide and MP plus bortezomib. Ongoing randomized trials are evaluating lenalidomide plus MP and lenalidomide plus dexamethasone. For newly diagnosed patients eligible for transplant, new induction regimens included the combination of high-dose dexamethasone plus thalidomide, high-dose dexamethasone plus lenalidomide (RD) and high-dose dexamethasone plus bortezomib (VD). The combinations RD, VD and bortezomib plus pegylated-liposomal-doxorubicin have received the US Food and Drug Administration approval for the treatment of relapsed myeloma. Different efficacious regimens are therefore now available for patients with myeloma. Disease control leads to improvement of all myeloma-related complications (anemia, bone disease, immune dysfunction and renal impairment), but physicians should take into account the choice of the therapeutic strategy, the expected toxicity profile of each of these regimens, together with the patient's biologic age and comorbidities. Supportive care is an essential part of myeloma therapy, both for the treatment of myeloma-related complications, together with anti-myeloma treatment, and for the management of treatment-emergent adverse events. This chapter will provide an overview of frequency and management of main complications related to the disease itself and to the use of new drugs in newly diagnosed and relapsed patients with myeloma.

The objective of this case-control study was to compare the efficacy and toxicity of lenalidomide plus dexamethasone (len/dex) versus thalidomide plus dexamethasone (thal/dex) as initial therapy for newly diagnosed myeloma. We retrospectively studied 411 newly diagnosed patients treated with len/dex (228) or thal/dex (183) at the Mayo Clinic. The differences were similar in a matched-pair analysis that adjusted for age, sex, transplantation status, and dexamethasone dose. The proportions of patients achieving at least a partial response to len/dex and thal/dex were 80.3% versus 61.2%, respectively (P < .001); very good partial response rates were 34.2% and 12.0%, respectively (P < .001). Patients receiving len/dex had longer time to progression (median, 27.4 vs 17.2 months; P = .019), progression-free survival (median, 26.7 vs 17.1 months; P = .036), and overall survival (median not reached vs 57.2 months; P = .018). A similar proportion of patients in the 2 groups experienced at least one grade 3 or 4 adverse event (57.5% vs 54.6%, P = .568). Main grade 3 or 4 toxicities of len/dex were hematologic, mainly neutropenia (14.6% vs 0.6%, P < .001); the most common toxicities in thal/dex were venous thromboembolism (15.3% vs 9.2%, P = .058) and peripheral neuropathy (10.4% vs 0.9%, P < .001). Len/dex appears well-tolerated and more effective than thal/dex. Randomized trials are needed to confirm these results.

PURPOSE To evaluate the effect of bortezomib as induction therapy before autologous transplantation, followed by lenalidomide as consolidation-maintenance in myeloma patients. PATIENTS AND METHODS Newly diagnosed patients age 65 to 75 years were eligible. Induction (bortezomib, doxorubicin, and dexamethasone [PAD]) included four 21-day cycles of bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11), pegylated liposomal doxorubicin (30 mg/m(2) on day 4), and dexamethasone (40 mg/d; cycle 1: days 1 to 4, 8 to 11, and 15 to 18; cycles 2 to 4: days 1 to 4). Autologous transplantation was tandem melphalan 100 mg/m(2) (MEL100) and stem-cell support. Consolidation included four 28-day cycles of lenalidomide (25 mg/d on days 1 to 21 every 28 days) plus prednisone (50 mg every other day), followed by maintenance with lenalidomide (LP-L; 10 mg/d on days 1 to 21) until relapse. Primary end points were safety (incidence of grade 3 to 4 adverse events [AEs]) and efficacy (response rate). Results A total of 102 patients were enrolled. In a per-protocol analysis, after PAD, 58% of patients had very good partial response (VGPR) or better, including 13% with complete response (CR); after MEL100, 82% of patients had at least VGPR and 38% had CR; and after LP-L, 86% of patients had at least VGPR and 66% had CR. After median follow-up time of 21 months, the 2-year progression-free survival rate was 69%, and the 2-year overall survival rate was 86%. During induction, treatment-related mortality was 3%; grade 3 to 4 AEs included thrombocytopenia (17%), neutropenia (10%), peripheral neuropathy (16%), and pneumonia (10%). During consolidation-maintenance, grade 3 to 4 AEs were neutropenia (16%), thrombocytopenia (6%), pneumonia (5%), and cutaneous rash (4%). CONCLUSION Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance, is an effective regimen.

Multiple myeloma (MM) is a neoplastic disorder affecting elderly people. The treatment for all patients with MM was, for about 40 years, based on the combination of melphalan plus prednisone, with a very low rate of complete remissions and a survival that remained unacceptably low (about 36 months). Diverse factors, including comorbidity, performance status, decreased physiologic reserve, and potential undertreatment, contribute to these poor outcomes. Recently, however, the reduced treatment-related morbidity and mortality associated with autologous stem-cell transplantation and the availability of effective new drugs with acceptable toxicity, such as thalidomide, lenalidomide and bortezomib, have greatly modified the traditional treatment paradigms in older patients with MM, challenging, in some cases, the definition of elderly and rapidly transforming the traditional palliative treatments to a new global therapeutic strategy, with the final objective of significantly improving the quality and the duration of life for elderly people with this disease. In this review, we report updated data for the front-line treatment of MM in the elderly population, examining the role of new drugs combined with melphalan or their incorporation within more complex combinations, including other so-called conventional drugs such as (pegylated)-doxorubicin, cyclophosphamide, and dexamethasone. We also assess the role of autologous and allogeneic stem-cell transplantation with adjusted conditioning regimens in selected elderly patients.

Background: Initial analysis of the combination melphalan, prednisone, plus lenalidomide (MPR) showed significant antimyeloma activity in patients with untreated multiple myeloma, with neutropenia and thrombocytopenia as the most frequent side effects. This updated analysis reassessed the kinetics of neutropenia and thrombocytopenia as well as the safety and efficacy of MPR., Patients and Methods: A total of 21 patients with newly diagnosed myeloma received melphalan 0.18 mg/kg on days 1-4, prednisone 2 mg/kg on days 1-4, and lenalidomide 10 mg daily on days 1-21 for nine 28-day cycles, followed by maintenance therapy with lenalidomide 10 mg daily on days 1-21., Results: Grade 3/4 neutropenia occurred in 52% of the patients, and granulocyte colonystimulating factor was administered in 43%. The mean neutrophil counts at the start of each MPR cycle, during nadir, and after 6 months of maintenance were 2.69 x 109/L, 1.43 x 109/L, and 2.11 x 109/L, respectively. Grade 3/4 thrombocytopenia occurred in 24% of the patients. Platelet transfusions were required by 1 patient (5%) with a platelet count of 16 x 109/L; however, no thrombocytopenia-associated bleeding was reported. The mean platelet counts at the start of each cycle, during nadir, and after 6 months of maintenance were 174 x 109/L, 121 x 109/L, and 158 x 109/L, respectively. Median follow-up was 29.6 months, median progression-free survival was 28.5 months, and 2-year overall survival was 91%., Conclusion: MPR is a promising regimen with manageable hematologic toxicity.

Patients with multiple myeloma aged older than 65 years have traditionally received an oral regimen combining melphalan and prednisone (MP). The introduction of novel agents, such as immunomodulatory drugs and proteasome inhibitors, has substantially changed the treatment paradigm of this disease. Five randomized phase III studies, comparing MP plus thalidomide (MPT) versus MP, have shown that MPT increased time to progression (TTP); however, only two of these five studies showed improvement in overall survival (OS). One randomized study has shown that MP plus bortezomib (MPV) increases both TTP and OS compared with MP. Both MPT and MPV are now regarded as the new standards of care for elderly patients. Other promising results have been reported with MP plus lenalidomide or lenalidomide plus dexamethasone, or the combination of cyclophosphamide, thalidomide, and dexamethasone. Reduced-intensity transplantation can be an option for some patients, especially when novel agents are incorporated into pre-transplant induction and post-transplant consolidation. For patients aged older than 75 years a gentler approach should be used, and doses of standard MPT or MPV should be reduced. An accurate management of treatment-related adverse events with prompt dose-reduction can greatly reduce the rate of early discontinuation and significantly improve treatment efficacy. The choice of treatment should be tailored according to the patient's biologic age and comorbidities, and the expected toxicity profile of the regimen.

The initial analysis of the oral combination melphalan, prednisone, and thalidomide (MPT) in newly diagnosed patients with myeloma showed significantly higher response rate and longer progression-free survival (PFS) than did the standard melphalan and prednisone (MP) combination and suggested a survival advantage. In this updated analysis, efficacy and safety end points were updated. Patients were randomly assigned to receive oral MPT or MP alone. Updated analysis was by intention to treat and included PFS, overall survival (OS), and survival after progression. After a median follow-up of 38.1 months, the median PFS was 21.8 months for MPT and 14.5 months for MP (P = .004). The median OS was 45.0 months for MPT and 47.6 months for MP (P = .79). In different patient subgroups, MPT improved PFS irrespective of age, serum concentrations of beta(2)-microglobulin, or high International Staging System. Thalidomide or bortezomib administration as salvage regimens significantly improved survival after progression in the MP group (P = .002) but not in the MPT group (P = .34). These data confirm activity of MPT for PFS but failed to show any survival advantage. New agents in the management of relapsed disease could explain this finding. The study is registered at www.clinicaltrials.gov as #NCT00232934.

Recent studies have demonstrated that novel therapeutic combinations are challenging melphalan and prednisone (MP) as the standard of care in elderly patients with multiple myeloma. Combination regimens containing bortezomib or thalidomide can achieve response rates, especially complete response rates, which are superior to those seen with standard MP alone, and offer new possibilities for this patient population.

Purpose: Lenalidomide has shown significant antimyeloma activity in clinical studies. Oral melphalan, prednisone, and thalidomide have been regarded as the standard of care in elderly multiple myeloma patients. We assessed dosing, efficacy, and safety of melphalan, prednisone, and lenalidomide (MPR) in newly diagnosed elderly myeloma patients., Patients and Methods: Oral melphalan was administered in doses ranging from 0.18 to 0.25 mg/kg on days 1 to 4, prednisone at a 2-mg/kg dose on days 1 to 4, and lenalidomide at doses ranging from 5 to 10 mg on days 1 to 21, every 28 days for nine cycles, followed by maintenance therapy with lenalidomide alone. Aspirin was given as a prophylaxis for thrombosis., Results: Fifty-four patients were enrolled and evaluated after completing the assigned treatment schedule. The maximum tolerated dose was defined as 0.18 mg/kg melphalan and 10 mg lenalidomide. With these doses, 81% of patients achieved at least a partial response, 47.6% achieved a very good partial response, and 23.8% achieved a complete immunofixation-negative response. In all patients, 1-year event-free and overall survival rates were 92% and 100%, respectively. At the maximum tolerated dose, grade 3 adverse events included neutropenia (38.1%), thrombocytopenia (14.2%), febrile neutropenia (9.5%), vasculitis (9.5%), and thromboembolism (4.8%); grade 4 adverse events were neutropenia (14.2%) and thrombocytopenia (9.5%)., Conclusion: Oral MPR therapy is a promising first-line treatment for elderly myeloma patients. Hematologic adverse events were frequent but manageable. A low incidence of nonhematologic adverse events was noted. Aspirin appears to provide adequate antithrombosis prophylaxis.

Background: Bortezomib and thalidomide have shown synergy with melphalan and dexamethasone. We used this 4-drug combination as conditioning before autologous hematopoietic cell infusions., Patients and Methods: Twenty-six patients with advanced-stage myeloma were treated with melphalan 50 mg/m(2) and bortezomib 1.3 mg/m(2) on days -6 and -3 in association with thalidomide 200 mg and dexamethasone 20 mg on days -6 through -3, followed by hematopoietic cell support on day 0., Results: Nonhematologic toxicities included pneumonia, febrile neutropenia, and peripheral neuropathy. All patients had undergone autologous transplantation at diagnosis, and 13 patients (50%) underwent an additional transplantation at relapse. Responses occurred in 17 of 26 patients (65%), including 1 complete remission, 3 near complete remissions (12%), and 2 very good partial remissions (8%). Response rate was higher than that induced by the previous line of treatment in 12 patients (46%)., Conclusion: Melphalan/bortezomib/thalidomide/dexamethasone showed encouraging antimyeloma activity in patients with advanced-stage myeloma.