Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a mult

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. 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 (ISS), 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/m2 administered intravenously or subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32) combined with melphalan (9 mg/m2 administered orally on days 1-4) and prednisone (60 mg/m2 administered orally on days 1-4) or autologous HSCT after high-dose melphalan (200 mg/m2), stratified by site and ISS disease stage. In centres with a double HSCT 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/m2 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. 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%]). 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. Janssen and Celgene.

Cavo M ，Gay F ，Beksac M ，Pantani L ，Petrucci MT ，Dimopoulos MA ，Dozza L ，van der Holt B ，Zweegman S ，Oliva S ，van der Velden VHJ ，Zamagni E ，Palumbo GA ，Patriarca F ，Montefusco V ，Galli M ，Maisnar V ，Gamberi B ，Hansson M ，Belotti A ，Pour L ，Ypma P ，Grasso M ，Croockewit A ，Ballanti S ，Offidani M ，Vincelli ID ，Zambello R ，Liberati AM ，Andersen NF ，Broijl A ，Troia R ，Pascarella A ，Benevolo G ，Levin MD ，Bos G ，Ludwig H ，Aquino S ，Morelli AM ，Wu KL ，Boersma R ，Hajek R ，Durian M ，von dem Borne PA ，Caravita di Toritto T ，Zander T ，Driessen C ，Specchia G ，Waage A ，Gimsing P ，Mellqvist UH ，van Marwijk Kooy M ，Minnema M ，Mandigers C ，Cafro AM ，Palmas A ，Carvalho S ，Spencer A ，Boccadoro M ，Sonneveld P ... -  《Lancet Haematology》

Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for

Bortezomib-based induction followed by high-dose melphalan (200 mg/m2) and autologous stem-cell transplantation (MEL200-ASCT) and maintenance treatment with lenalidomide alone is the current standard of care for young and fit patients with newly diagnosed multiple myeloma. We aimed to evaluate the efficacy and safety of different carfilzomib-based induction and consolidation approaches with or without transplantation and of maintenance treatment with carfilzomib plus lenalidomide versus lenalidomide alone in newly diagnosed multiple myeloma. 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/m2 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/m2 was administered intravenously on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg administered orally on days 1-21; cyclophosphamide 300 mg/m2 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/m2 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. 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. 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. Amgen, Celgene/Bristol Myers Squibb. For the Italian translation of the abstract see Supplementary Materials section.

Gay F ，Musto P ，Rota-Scalabrini D ，Bertamini L ，Belotti A ，Galli M ，Offidani M ，Zamagni E ，Ledda A ，Grasso M ，Ballanti S ，Spadano A ，Cea M ，Patriarca F ，D'Agostino M ，Capra A ，Giuliani N ，de Fabritiis P ，Aquino S ，Palmas A ，Gamberi B ，Zambello R ，Petrucci MT ，Corradini P ，Cavo M ，Boccadoro M ... -  《-》

Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial.

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. 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. 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. 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. Celgene.

Gay F ，Oliva S ，Petrucci MT ，Conticello C ，Catalano L ，Corradini P ，Siniscalchi A ，Magarotto V ，Pour L ，Carella A ，Malfitano A ，Petrò D ，Evangelista A ，Spada S ，Pescosta N ，Omedè P ，Campbell P ，Liberati AM ，Offidani M ，Ria R ，Pulini S ，Patriarca F ，Hajek R ，Spencer A ，Boccadoro M ，Palumbo A ... -  《-》

Carfilzomib induction, consolidation, and maintenance with or without autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: pre-planned cytogenetic subgroup analysis of the randomised, phase 2 FORTE trial.

Patients with newly diagnosed multiple myeloma and high-risk cytogenetic abnormalities (HRCA) represent an unmet medical need. In the FORTE trial, lenalidomide and dexamethasone plus carfilzomib (KRd) induction resulted in a higher proportion of patients with at least a very good partial response as compared with carfilzomib, cyclophosphamide, and dexamethasone (KCd), and carfilzomib plus lenalidomide maintenance prolonged progression-free survival compared with lenalidomide maintenance. In this prespecified analysis of the FORTE trial, we described the outcomes of enrolled patients according to their cytogenetic risk. The UNITO-MM-01/FORTE was a randomised, open-label, phase 2 trial done at 42 Italian academic and community practice centres, which enrolled transplant-eligible patients with newly diagnosed multiple myeloma aged 18-65 years. Eligible patients had newly diagnosed multiple myeloma based on standard International Myeloma Working Group criteria, a Karnofsky performance status of at least 60%, and had not received any previous treatment with anti-myeloma therapy. At enrolment, 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 autologous stem-cell transplantation (ASCT; four 28-day induction cycles with KRd, melphalan at 200 mg/m2 and ASCT [MEL200-ASCT], followed by four 28-day KRd consolidation cycles), 12 28-day KRd cycles, or KCd plus ASCT (four 28-day induction cycles with KCd, MEL200-ASCT, and four 28-day KCd consolidation cycles), using a web-based system (block randomisation, block size of 12). Carfilzomib was administered at 20 mg/m2 on days 1 and 2 of cycle 1, followed by 36 mg/m2 intravenously administered on days 8, 9, 15, and 16 of cycle 1, and then 36 mg/m2 intravenously administered for all subsequent doses on days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg was administered orally on days 1-21; cyclophosphamide 300 mg/m2 was administered orally on days 1, 8, and 15; and dexamethasone 20 mg was administered orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23. After the consolidation phase, patients were stratified according to induction-consolidation treatment and randomly assigned (1:1; block size of 8) to maintenance treatment with carfilzomib plus lenalidomide or lenalidomide alone. Carfilzomib 36 mg/m2 was administered intravenously on days 1-2 and days 15-16, every 28 days for up to 2 years, and 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. In this preplanned analysis, we included patients enrolled in the FORTE trial with complete cytogenetic data on del(17p), t(4;14), t(14;16), del(1p), gain(1q) (3 copies), and amp(1q) (≥4 copies) assessed by fluorescence in-situ hybridisation analysis on CD138-positive sorted cells. We assessed progression-free survival, overall survival, minimal residual disease negativity, and 1-year sustained minimal residual disease negativity according to the presence of zero, one, and two or more HRCA across treatment groups. The FORTE trial is ongoing, and registered with ClinicalTrials.gov, NCT02203643. Between Feb 23, 2015, and April 5, 2017, 477 patients were enrolled, of whom 396 (83%) had complete cytogenetic data and were analysed (176 [44%] of whom were women and 220 [56%] were men). The median follow-up from first randomisation was 51 months (IQR 46-56). 4-year progression-free survival was 71% (95% CI 64-78) in patients with zero HRCA, 60% (95% CI 52-69) in patients with one HRCA, and 39% (95% CI 30-50) in patients with two or more HRCA. Compared with patients with zero HRCA, the risk of progression or death was similar in patients with one HRCA (hazard ratio [HR] 1·33 [95% CI 0·90-1·97]; p=0·15) and higher in patients with two or more HRCA (HR 2·56 [95% CI 1·74-3·75]); p<0·0001) across the induction-intensification-consolidation groups. Moreover, the risk of progression or death was also higher in patients with two or more HRCA versus those with one HRCA (HR 1·92 [95% CI 1·34-2·76]; p=0·0004). 4-year overall survival from the first randomisation was 94% (95% CI 91-98) in patients with zero HRCA, 83% (95% CI 76-90) in patients with one HRCA, and 63% (95% CI 54-74) in patients with two or more HRCA. Compared with patients with zero HRCA, the risk of death was significantly higher in patients with one HRCA (HR 2·55 [95% CI 1·22-5·36]; p=0·013) and two or more HRCA (HR 6·53 [95% CI 3·24-13·18]; p<0·0001). Patients with two or more HRCA also had a significantly higher risk of death than those with one HRCA (HR 2·56 [95% CI 1·53-4·28]; p=0·0004). The rates of 1-year sustained minimal residual disease negativity were similar in patients with zero HRCA (53 [35%] of 153] and with one HRCA (57 [41%] of 138) and were lower in patients with two or more HRCA (25 [24%] of 105). The median duration of follow-up from second randomisation was 37 months (IQR 33-42). 3-year progression-free survival from the second randomisation was 80% (95% CI 74-88) in patients with zero HRCA, 68% (95% CI 59-78) in patients with one HRCA, and 53% (95% CI 42-67) in patients with two or more HRCA. The risk of progression or death was higher in patients with one HRCA (HR 1·68 [95% CI 1·01-2·80]; p=0·048) and two or more HRCA (2·74 [95% CI 1·60-4·69], p=0·0003) than in patients with zero HRCA. This preplanned analysis of the FORTE trial showed that carfilzomib-based induction-intensification-consolidation regimens are effective strategies in patients with standard risk (zero HRCA) and high-risk (one HRCA) myeloma, resulting in similar rates of progression-free survival and 1-year sustained minimal residual disease negativity. Despite promising progression-free survival, patients with ultra-high-risk disease (those with 2 or more HRCA) still have an increased risk of progression and death and therefore represent an unmet medical need. Amgen and Celgene/Bristol Myers Squibb.

Mina R ，Musto P ，Rota-Scalabrini D ，Paris L ，Gamberi B ，Palmas A ，Aquino S ，de Fabritiis P ，Giuliani N ，De Rosa L ，Gozzetti A ，Cellini C ，Bertamini L ，Capra A ，Oddolo D ，Vincelli ID ，Ronconi S ，Pavone V ，Pescosta N ，Cea M ，Fioritoni F ，Ballanti S ，Grasso M ，Zamagni E ，Belotti A ，Boccadoro M ，Gay F ... -  《-》

Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomise

Bortezomib, lenalidomide, and dexamethasone (VRd) is a standard therapy for newly diagnosed multiple myeloma. Carfilzomib, a next-generation proteasome inhibitor, in combination with lenalidomide and dexamethasone (KRd), has shown promising efficacy in phase 2 trials and might improve outcomes compared with VRd. We aimed to assess whether the KRd regimen is superior to the VRd regimen in the treatment of newly diagnosed multiple myeloma in patients who were not being considered for immediate autologous stem-cell transplantation (ASCT). In this multicentre, open-label, phase 3, randomised controlled trial (the ENDURANCE trial; E1A11), we recruited patients aged 18 years or older with newly diagnosed multiple myeloma who were ineligible for, or did not intend to have, immediate ASCT. Participants were recruited from 272 community oncology practices or academic medical centres in the USA. Key inclusion criteria were the absence of high-risk multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0-2. Enrolled patients were randomly assigned (1:1) centrally by use of permuted blocks to receive induction therapy with either the VRd regimen or the KRd regimen for 36 weeks. Patients who completed induction therapy were then randomly assigned (1:1) a second time to either indefinite maintenance or 2 years of maintenance with lenalidomide. Randomisation was stratified by intent for ASCT at disease progression for the first randomisation and by the induction therapy received for the second randomisation. Allocation was not masked to investigators or patients. For 12 cycles of 3 weeks, patients in the VRd group received 1·3 mg/m2 of bortezomib subcutaneously or intravenously on days 1, 4, 8, and 11 of cycles 1-8, and day 1 and day 8 of cycles nine to twelve, 25 mg of oral lenalidomide on days 1-14, and 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. For nine cycles of 4 weeks, patients in the KRd group received 36 mg/m2 of intravenous carfilzomib on days 1, 2, 8, 9, 15, and 16, 25 mg of oral lenalidomide on days 1-21, and 40 mg of oral dexamethasone on days 1, 8, 15, and 22. The coprimary endpoints were progression-free survival in the induction phase, and overall survival in the maintenance phase. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of their assigned treatment. The trial is registered with ClinicalTrials.gov, NCT01863550. Study recruitment is complete, and follow-up of the maintenance phase is ongoing. Between Dec 6, 2013, and Feb 6, 2019, 1087 patients were enrolled and randomly assigned to either the VRd regimen (n=542) or the KRd regimen (n=545). At a median follow-up of 9 months (IQR 5-23), at a second planned interim analysis, the median progression-free survival was 34·6 months (95% CI 28·8-37·8) in the KRd group and 34·4 months (30·1-not estimable) in the VRd group (hazard ratio [HR] 1·04, 95% CI 0·83-1·31; p=0·74). Median overall survival has not been reached in either group. The most common grade 3-4 treatment-related non-haematological adverse events included fatigue (34 [6%] of 527 patients in the VRd group vs 29 [6%] of 526 in the KRd group), hyperglycaemia (23 [4%] vs 34 [6%]), diarrhoea (23 [5%] vs 16 [3%]), peripheral neuropathy (44 [8%] vs four [<1%]), dyspnoea (nine [2%] vs 38 [7%]), and thromboembolic events (11 [2%] vs 26 [5%]). Treatment-related deaths occurred in two patients (<1%) in the VRd group (one cardiotoxicity and one secondary cancer) and 11 (2%) in the KRd group (four cardiotoxicity, two acute kidney failure, one liver toxicity, two respiratory failure, one thromboembolic event, and one sudden death). The KRd regimen did not improve progression-free survival compared with the VRd regimen in patients with newly diagnosed multiple myeloma, and had more toxicity. The VRd triplet regimen remains the standard of care for induction therapy for patients with standard-risk and intermediate-risk newly diagnosed multiple myeloma, and is a suitable treatment backbone for the development of combinations of four drugs. US National Institutes of Health, National Cancer Institute, and Amgen.

Kumar SK ，Jacobus SJ ，Cohen AD ，Weiss M ，Callander N ，Singh AK ，Parker TL ，Menter A ，Yang X ，Parsons B ，Kumar P ，Kapoor P ，Rosenberg A ，Zonder JA ，Faber E Jr ，Lonial S ，Anderson KC ，Richardson PG ，Orlowski RZ ，Wagner LI ，Rajkumar SV ... -  《-》