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

Dickran Kazandjian*, Elizabeth Hill, Alexander Dew, Candis Morrison, Joseph Roswarski, Neha Korde, Michael Emanuel, Ani Petrosyan, Manisha Bhutani, Katherine R. Calvo, Alina Dulau-Florea, Mary Kwok, Min Jung Lee, Sunmin Lee, Liza Lindenberg, Sham Mailankody, Elisabet Manasanch, Irina Maric, Esther Mena, Nisha PatelNishant Tageja, Jane B. Trepel, Baris Turkbey, Hao Wei Wang, Weixin Wang, Constance Yuan, Yong Zhang, Raul Braylan, Peter Choyke, Maryalice Stetler-Stevenson, Seth M. Steinberg, William D. Figg, Mark Roschewski, Ola Landgren

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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: Identifier: NCT01572480.

Original languageEnglish
Pages (from-to)1678-1685
Number of pages8
JournalJAMA Oncology
Issue number11
StatePublished - Nov 2021
Externally publishedYes


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