Dataset Information

A phase 1b study of once-weekly carfilzomib combined with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma.

ABSTRACT: Twice-weekly carfilzomib with lenalidomide-dexamethasone (Rd) is an effective regimen for newly diagnosed multiple myeloma (NDMM). Here we evaluated once-weekly carfilzomib with Rd (once-weekly KRd) in NDMM patients. The NDMM patients were enrolled regardless of transplant eligibility. Patients received carfilzomib on days 1, 8, and 15; lenalidomide 25?mg on days 1-21; and dexamethasone 40?mg on carfilzomib days (also day 22 for cycles 1-8) for ?18, 28-day?cycles. Enrollment initiated in a carfilzomib 20/70?mg/m² (20?mg/m² on cycle one, day 1; 70?mg/m² thereafter) NDMM dose-expansion arm, which was suspended because of serious adverse events. After evaluation of dose-limiting toxicities in a two-step-up dose-evaluation cohort, an NDMM dose-expansion arm (carfilzomib 20/56?mg/m² ) was opened. Fifty-one NDMM patients were enrolled in dose-finding and dose-expansion cohorts. Results are presented for the carfilzomib 56?mg/m² NDMM dose-expansion arm (n = 33). The grade???3 treatment-emergent AE (TEAE) rate was 63.6%. Twenty-five patients underwent stem cell collection; 18 proceeded to auto stem cell transplant, and five resumed KRd on study after autoSCT. The overall response rate (ORR) based on best overall response by cycle four was 97.0% (?very good partial response [VGPR], 69.7%) in the NDMM 20/56?mg/m² cohort. In patients who did not receive autoSCT (n = 15), the median number of cycles was 16.0; ORR was 93.3% (?VGPR, 80.0%). At a median follow-up of 8.1 months, median progression-free survival was not reached. Once-weekly KRd (carfilzomib 56?mg/m² ) had a favorable safety profile and promising activity in NDMM, supporting the use of this regimen in this setting.

SUBMITTER: Alsina M

PROVIDER: S-EPMC7898514 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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A phase 1b study of once-weekly carfilzomib combined with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma.

Alsina Melissa M Landgren Ola O Raje Noopur N Niesvizky Ruben R Bensinger William I WI Berdeja Jesus G JG Kovacsovics Tibor T Vesole David H DH Fang Belle B Kimball Amy S AS Siegel David S DS

American journal of hematology 20201215 2

Twice-weekly carfilzomib with lenalidomide-dexamethasone (Rd) is an effective regimen for newly diagnosed multiple myeloma (NDMM). Here we evaluated once-weekly carfilzomib with Rd (once-weekly KRd) in NDMM patients. The NDMM patients were enrolled regardless of transplant eligibility. Patients received carfilzomib on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on carfilzomib days (also day 22 for cycles 1-8) for ≤18, 28-day cycles. Enrollment initiated in a carfi ...[more]

PMID: 33125764

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Project description:ImportanceCarfilzomib-lenalidomide-dexamethasone therapy yields deep responses in patients with newly diagnosed multiple myeloma (NDMM). It is important to gain an understanding of this combination's tolerability and impact on minimal residual disease (MRD) negativity because this end point has been associated with improved survival.ObjectiveTo assess the safety and efficacy of carfilzomib-lenalidomide-dexamethasone therapy in NDMM and high-risk smoldering multiple myeloma (SMM).Design, setting, and participantsClinical and correlative pilot study at the National Institutes of Health Clinical Center. Patients with NDMM or high-risk SMM were enrolled between July 11, 2011, and October 9, 2013. Median follow-up was 17.3 (NDMM) and 15.9 months (SMM).InterventionsEight 28-day cycles were composed of carfilzomib 20/36 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on days 1 through 21; and dexamethasone 20/10 mg (cycles 1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, and 23. Patients who achieved at least stable disease subsequently received 24 cycles of lenalidomide extended dosing.Main outcomes and measuresPrimary end points were neuropathy of grade 3 or greater (NDMM) and at least very good partial response rates (SMM). Minimal residual disease was also assessed.ResultsOf 45 patients with NDMM, none had neuropathy of grade 3 or greater. Of 12 patients with high-risk SMM, the most common of any-grade adverse events were lymphopenia (12 [100%]) and gastrointestinal disorders (11 [92%]). All patients with SMM achieved at least a very good partial response during the study period. Among the 28 patients with NDMM and the 12 with SMM achieving at least a near-complete response, MRD negativity was found in 28 of 28 (100% [95% CI, 88%-100%]), 11 of 12 (92% [95% CI, 62%-100%]) (multiparametric flow cytometry), 14 of 21 (67% [95% CI, 43%-85%]), and 9 of 12 (75% [95% CI, 43%-94%]) (next-generation sequencing), respectively. In patients with NDMM, 12-month progression-free survival for MRD-negative vs MRD-positive status by flow cytometry and next-generation sequencing was 100% vs 79% (95% CI, 47%-94%; P < .001) and 100% vs 95% (95% CI, 75%-99%; P = .02), respectively.Conclusions and relevanceCarfilzomib-lenalidomide-dexamethasone therapy is tolerable and demonstrates high rates of MRD negativity in NDMM, translating into longer progression-free survival in patients achieving MRD negativity. Carfilzomib-lenalidomide-dexamethasone therapy also demonstrates efficacy in high-risk SMM.

Dataset Information

A phase 1b study of once-weekly carfilzomib combined with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma.

Publications

A phase 1b study of once-weekly carfilzomib combined with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma.

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