Carfilzomib, Lenalidomide, and Dexamethasone Followed by Lenalidomide Maintenance for Prevention of Symptomatic Multiple Myeloma in Patients With High-risk Smoldering Myeloma: A Phase 2 Nonrandomized Controlled Trial

Abstract

Importance: High-risk smoldering myeloma has a 5-year risk of progression to symptomatic multiple myeloma of approximately 75%. Treatment with lenalidomide decreases the risk of progression; however, novel triplet regimens are superior, and earlier disease may be more treatment sensitive.

Objective: To evaluate the use of carfilzomib, lenalidomide, and dexamethasone (KRd) with lenalidomide maintenance therapy as early intervention in high-risk smoldering myeloma and to determine the rates of minimal residual disease (MRD)-negative complete response (CR).

Design, setting, and participants: In this single-arm, single-center, phase 2 nonrandomized controlled trial, responses were evaluated at every cycle during KRd treatment and every 3 cycles subsequently. Bone marrow biopsies and imaging were performed by cycle 8 and then annually. The study enrolled patients from May 29, 2012, to July 23, 2020, at the National Institutes of Health Clinical Center, a highly specialized tertiary cancer center. Patient key eligibility criteria included a diagnosis of high-risk smoldering myeloma based on the Mayo Clinic, Spanish, and/or Rajkumar, Mateos, and Landgren criteria.

Interventions: Patients received eight 4-week cycles of intravenous carfilzomib 36 mg/m2 (first 2 doses, 20 mg/m2), dexamethasone (20 mg, cycles 1-4; 10 mg, cycles 5-8 twice weekly), and lenalidomide 25 mg (days 1-21) followed by twenty-four 28-day cycles of maintenance lenalidomide 10 mg (days 1-21). Stem cell harvest and storage were optional.

Main outcomes and measures: The primary outcome was the MRD-negative CR rate. Key secondary outcomes included duration of MRD-negative CR and progression to multiple myeloma.

Results: A total of 54 patients (median age, 59 years [range, 40-79 years]; 30 men [55.6%]; and 2 Asian [3.7%], 15 Black [27.8%], 1 Hispanic [1.9%], and 36 White [66.7%] patients) were enrolled, with a median potential follow-up time of 31.9 months (range, 6.7-102.9 months). The MRD-negative CR rate was 70.4% (95% CI, 56.4%-82.0%), with a median sustained duration of 5.5 years (95% CI, 3.7 years to not estimable). The 8-year probability of being free from progression to multiple myeloma was 91.2% (95% CI, 67.4%-97.9%), and no deaths occurred. Nonhematologic grade 3 adverse events occurred in 21 patients (38.9%) and included thromboembolism, rash, and lung infection, with no grade 4 events.

Conclusions and relevance: Results of this phase 2 nonrandomized controlled trial suggest that treatment of high-risk smoldering myeloma with novel triplet regimens, such as KRd and lenalidomide maintenance therapy, may alter the natural history of smoldering myeloma by significantly delaying development of end-organ disease. Randomized clinical trials are needed to confirm this favorable benefit-to-risk profile.

Trial registration: ClinicalTrials.gov Identifier: NCT01572480.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Korde reported receiving research funding from Amgen and being on the advisory board for MedImmune/AstraZeneca outside the submitted work. Dr Bhutani reported serving on a speakers bureau for Amgen, Bristol Myers Squibb, and Takeda and as a consultant for Sanofi Genzyme; receiving research funding from Janssen, MedImmune, Takeda, Prothena, Celgene/Bristol Myers Squibb, Cerecor, and Cellularity; receiving nonfinancial support from Sanofi Genzyme; and receiving personal fees from Bristol Myers Squibb during the conduct of the study. Dr Manasanch reported receiving research support from Sanofi, Quest Diagnostics, Novartis, JW Pharma, and Merck and consultant fees from Takeda, Celgene, Sanofi, Janssen, GlaxoSmithKline, and Adaptive Biotechnologies outside the submitted work. Dr Landgren reported receiving research funding from the National Institutes of Health, the National Cancer Institute, the US Food and Drug Administration, the Multiple Myeloma Research Foundation, the International Myeloma Foundation, the Leukemia and Lymphoma Society, the Perelman Family Foundation, the Rising Tide Foundation, Amgen, Celgene, Janssen, Takeda, Glenmark, Seattle Genetics, and Karyopharm; honoraria from serving on advisory boards for Adaptive, Amgen, Binding Site, Bristol Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer; and serving on Takeda, Merck, Janssen, and Theradex independent data monitoring committees outside the submitted work. Dr Mailankody reported receiving trial support from Takeda, Janssen, Bristol Myers Squibb, Allogene Therapeutics, and Fate Therapeutics and personal fees from PleXus Education and Physician Education Resource outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Patient Flow Diagram

KRd indicates carfilzomib, lenalidomide, and dexamethasone.

Figure 2.. Kaplan-Meier Estimates for Progression to Clinical Multiple Myeloma (Clinical Progression-Free Survival [PFS]) and Progression by M Protein or Serum-Free Light Chains (Biochemical PFS)

A, For the clinical PFS outcome (development of multiple myeloma), the median was not reached, with 2 events reported. B, For the biochemical PFS outcome, the median was not reached, with 6 events reported. The plus sign (+) denotes censoring of patients.