Carfilzomib, Lenalidomide, and Dexamethasone Followed by Lenalidomide Maintenance for Prevention of Symptomatic Multiple Myeloma in Patients With High-risk Smoldering Myeloma
Authors: 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 Patel, Nishant 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
Journal: JAMA Oncology (2021)

<h3>Importance</h3> 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. <h3>Objective</h3> 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). <h3>Design, Setting, and Participants</h3> 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. <h3>Interventions</h3> Patients received eight 4-week cycles of intravenous carfilzomib 36 mg/m<sup>2</sup>(first 2 doses, 20 mg/m<sup>2</sup>), 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. <h3>Main Outcomes and Measures</h3> The primary outcome was the MRD-negative CR rate. Key secondary outcomes included duration of MRD-negative CR and progression to multiple myeloma. <h3>Results</h3> 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. <h3>Conclusions and Relevance</h3> 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. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01572480