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Background: 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., Methods: 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/m 2 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/m 2 on days 1 and 2 of cycle 1, followed by 36 mg/m 2 intravenously administered on days 8, 9, 15, and 16 of cycle 1, and then 36 mg/m 2 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/m 2 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/m 2 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., Findings: 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., Interpretation: 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., Funding: Amgen and Celgene/Bristol Myers Squibb., Competing Interests: Declaration of interests RM has received honoraria from Janssen, Celgene, Takeda, and Amgen; has served on the advisory boards for Janssen, Celgene, Takeda, Bristol Myers Squibb, and Amgen; and has received consultancy fees from Janssen, Takeda, and Sanofi. PM has received honoraria from Celgene, Janssen, Takeda, Bristol Myers Squibb, Amgen, Novartis, Gilead, Jazz, Sanofi, AbbVie, and GlaxoSmithKlin; and has served on scientific advisory boards for Celgene, Janssen, Takeda, Bristol Myers Squibb, Amgen, Jazz, Sanofi, AbbVie, and GlaxoSmithKline. LP has received honoraria from Celgene, Takeda, Amgen, Bristol Myers Squibb, and Janssen; has served on the advisory boards for Celgene, Bristol Myers Squibb, Amgen, and Janssen; and has received consultancy fees from Janssen. BG has received honoraria from Amgen, Bristol Myers Squibb, Janssen, and Takeda; and has served on the advisory boards for Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Sanofi, and Takeda. AP has served on the advisory board for Amgen; has received support for meeting fees, travel, and lodging expenses from Amgen, Celgene, and Janssen; and has received non-financial support from Celgene, Janssen, Roche, Takeda, and Amgen. NG has received research grants from Celgene and Janssen Pharmaceutical; has received sponsorship for clinical studies from Janssen Pharmaceutical and Millennium Pharmaceutical; has served on the advisory boards for Celgene, Takeda, and Janssen Pharmaceutical; and has received support for attending meetings from Janssen Pharmaceutical, Celgene, and Bristol Myers Squibb. AG has received honoraria from Celgene, Takeda, Amgen, and Janssen; and has served on the advisory boards for Takeda and Janssen. MC has received advisory fees from Celgene, Janssen, and Takeda; and has received research funding from Celgene. SB has received honoraria from Sanofi, Celgene, Takeda, and Janssen. EZ has received honoraria from and served on the advisory boards for Janssen, Bristol Myers Squibb, Takeda, Sanofi, Amgen, GlaxoSmithKline, and Oncopeptides. AB has served on the advisory boards for Amgen, Janssen, Celgene, GlaxoSmithKline, and Takeda. MB has received honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, and AbbVie; has served on the advisory boards for Janssen and GlaxoSmithKline; and has received research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, and Mundipharma. FG has received honoraria from Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, and GlaxoSmithKline; and has served on the advisory boards for Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, Roche, Adaptive Biotechnologies, Oncopeptides, bluebird bio, and Pfizer. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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.)