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 patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial

Gay, Francesca; Musto, Pellegrino; Rota–Scalabrini, Delia; Bertamini, Luca; Belotti, Angelo; Galli, Mónica; Offidani, Massimo; Zamagni, Elena; Ledda, Antonio; Grasso, Mariella; Ballanti, Stelvio; Spadano, Antonio; Cea, Michele; Patriarca, Francesca; D’Agostino, Mattia; Capra, Andréa; Giuliani, Nicola; Fabritiis, Paolo de; Aquino, Sara; Palmas, Angelo; Gamberi, Barbara; Zambello, Renato; Petrucci, Maria Teresa; Corradini, Paolo; Cavo, Michèle; Boccadoro, Mario

doi:10.1016/s1470-2045(21)00535-0

Cited by 163 publications

(163 citation statements)

References 30 publications

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“…(30) The addition of carfilzomib to lenalidomide maintenance also demonstrated benefit in high-risk NDMM patients. (27) Based on the results of previous studies, high-risk patients are likely to receive maximum benefit when treated with doublet or triplet maintenance regimens. (27,29,30) While additional studies with a larger number of patients are warranted to determine the impact of ixazomib and lenalidomide maintenance therapy in high-risk patients, our results and those of previous studies suggest that maintenance therapy may be beneficial across all cytogenetic risk groups.…”

Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of Combination Maintenance Therapy with Ixazomib and Lenalidomide in Patients with Posttransplant Myeloma

Patel

Shah

Liu

et al. 2022

Clinical Cancer Research

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The current recommended treatment for newly-diagnosed multiple myeloma involves induction treatment with a triplet or quadruplet regimen such as lenalidomide-bortezomibdexamethasone, followed by ASCT and maintenance therapy. While this approach offers improved PFS and quality of life, it is non-curative for most patients. Currently, maintenance therapy with lenalidomide post ASCT is recommended, as this has been observed to improve outcomes after ASCT. In this study, we evaluated the combination of lenalidomide and ixazomib as an all oral maintenance therapy to determine whether it would further improve clinical response in myeloma patients after ASCT, without significantly increasing toxicity. Our results demonstrate a better than expected PFS and suggest that myeloma patients may benefit further with combination maintenance therapy.Research.

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Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of Combination Maintenance Therapy with Ixazomib and Lenalidomide in Patients with Posttransplant Myeloma

Patel

Shah

Liu

et al. 2022

Clinical Cancer Research

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“…In the phase II FORTE trial, aiming to explore different carfilzomib-based induction and consolidation therapies with or without ASCT, patients randomized to receive four cycles of carfilzomib, lenalidomide, and dexamethasone (KRd) as induction had significantly higher ≥ VGPR, the primary endpoint, compared to patients treated with four cycles of carfilzomib, cyclophosphamide, and dexamethasone (KCd) (70% vs. 53%, OR = 2.14, p = 0.0002) [ 19 ].…”

Section: Where We Are With Induction Therapymentioning

confidence: 99%

“…After a median follow-up comparable to that of the MMRC study (60.5 months), 5-year PFS was 45.1% in all populations, being about 60% in MRD-negative and 35% in MRD-positive patients [ 32 ]. In the randomized phase II FORTE trial consolidation, four KRd cycles were found to be more effective than a consolidation with KCd in terms of quality of response (at least CR documented in 54% and 42% of patients receiving KRd and KCd after consolidation, respectively), MRD negativity (62% vs. 43%), and 1-year sustained MRD negativity (47% vs. 25%) [ 19 ]. Quadruplet regimens including daratumumab such as D-VTd and D-VRd (two cycles) administered after ASCT were able to improve responses in the CASSIOPEIA and GRIFFIN studies.…”

Section: Where We Are With Consolidation Therapy Post-asctmentioning

confidence: 99%

“…However, no significant differences in terms of PFS between KRd12 and KCd-ASCT were reported. Remarkably, in patients with MRD negativity after consolidation, 4-year PFS was 83%, 69%, and 63% in the KRd-ASCT, KRd12, and KCd-ASCT arms, respectively, whereas PFS was similar in the three groups in patients who achieved a 1-year sustained MRD negativity [ 19 ]. The phase II randomized CARDAMON trial has explored four courses of KCd as induction followed by ASCT or intensification with four cycles KCd.…”

Section: A Look At Asct In the Era Of Novel Drugs New Regimens And Ca...mentioning

confidence: 99%

“…On the other hand, a prospective study (BMTSS) in which 1906 patients who underwent ASCT were followed for a median of nine years showed a decrease in late mortality related to myeloma, infection, and cardiac events over the past 25 years [ 6 ]. In transplant-eligible (TE) NDMM patients, ASCT remains the standard of care recommended by international guidelines such as by ASCO [ 7 ] and ESMO [ 8 ] since a significant benefit of ASCT vs. conventional therapy was demonstrated, not only in patients receiving “old” chemotherapies in the control arm [ 9 , 10 , 11 , 12 , 13 , 14 ], but also in those treated with new triplet combinations including proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) [ 15 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Autologous Stem Cell Transplantation in Multiple Myeloma: Where Are We and Where Do We Want to Go?

Morè

Corvatta²,

Manieri

et al. 2022

Cells

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The introduction of high-dose therapy in the 1990s as well as the development of drugs such as thalidomide, lenalidomide, and bortezomib in the 2000s led to an impressive improvement in outcome of patients with multiple myeloma (MM) eligible for autologous stem cell transplantation (ASCT). Clinical trials conducted in the first ten years of the twenty-first century established as standard therapy for these patients a therapeutic approach including induction, single or double ASCT, consolidation, and maintenance therapy. More recently, incorporating second-generation proteasome inhibitors carfilzomib and monoclonal antibody daratumumab into each phase of treatment significantly improved the efficacy of ASCT in terms of measurable residual disease (MRD) negativity, Progression Free Survival (PFS), and Overall Survival (OS). The availability of techniques such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for MRD assessment allowed the design of MRD-based response-adjusted trials that will define, in particular, the role of consolidation and maintenance therapies. In this review, we will provide an overview of the most recent evidence and the future prospects of ASCT in MM patients.

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Elotuzumab and Weekly Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Without Transplant Intent

et al. 2022

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IMPORTANCETreatment of newly diagnosed multiple myeloma (NDMM) with a quadruplet regimen consisting of a monoclonal antibody, proteasome inhibitor, immunomodulatory imide, and corticosteroid has been associated with improved progression-free survival (PFS) compared with triplet regimens. The optimal quadruplet combination, and whether this obviates the need for frontline autologous stem cell transplant (ASCT), remains unknown. We evaluated elotuzumab and weekly carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) without ASCT in NDMM.OBJECTIVE To investigate the efficacy of Elo-KRd using a measurable residual disease (MRD)-adapted design in NDMM regardless of ASCT eligibility. DESIGN, SETTING, AND PARTICIPANTSThis multicenter, single-arm, phase 2 study enrolled patients between July 2017 and February 2021. Median follow-up was 29 months.INTERVENTIONS Twelve to 24 cycles of Elo-KRd; consecutive MRD-negative results at 10 −6 by next-generation sequencing (NGS) after cycles 8 (C8) and 12 determined the duration of Elo-KRd. This was followed by Elo-Rd (no carfilzomib) maintenance therapy until disease progression. MAIN OUTCOMES AND MEASURESThe primary end point was the rate of stringent complete response (sCR) and/or MRD-negativity (10 −5 ) after C8 Elo-KRd. Secondary end points included safety, rate of response, MRD status, PFS, and overall survival (OS). As an exploratory analysis, MRD was assessed using liquid chromatography mass spectrometry (MS) on peripheral blood samples. RESULTS Forty-six patients were enrolled (median age 62 years, 11 [24%] aged >70 years). Overall, 32 (70%) were White, 6 (13%) were Black, 3 (6%) were more than 1 race, and 5 (11%) were of unknown race. Thirty-three (72%) were men and 13 (28%) were women. High-risk cytogenetic abnormalities were present in 22 (48%) patients. The rate of sCR and/or MRD-negativity after C8 was 26 of 45 (58%), meeting the predefined statistical threshold for efficacy. Responses deepened over time, with the MRD-negativity (10 −5 ) rate increasing to 70% and MS-negativity rate increasing to 65%; concordance between MRD by NGS and MS increased over time. The most common (>10%) grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively). There was 1 grade 5 myocardial infarction. The estimated 3-year PFS was 72% overall and 92% for patients with MRD-negativity (10 −5 ) at C8. CONCLUSIONS AND RELEVANCEAn MRD-adapted design using elotuzumab and weekly KRd without ASCT showed a high rate of sCR and/or MRD-negativity and durable responses. This approach provides support for further evaluation of MRD-guided deescalation of therapy to decrease treatment exposure while sustaining deep responses.

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Cited by 163 publications

References 30 publications

Safety and Efficacy of Combination Maintenance Therapy with Ixazomib and Lenalidomide in Patients with Posttransplant Myeloma

Safety and Efficacy of Combination Maintenance Therapy with Ixazomib and Lenalidomide in Patients with Posttransplant Myeloma

Autologous Stem Cell Transplantation in Multiple Myeloma: Where Are We and Where Do We Want to Go?

Elotuzumab and Weekly Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Without Transplant Intent

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