Bortezomib, lenalidomide, and dexamethasone with or without elotuzumab in patients with untreated, high-risk multiple myeloma (SWOG-1211): primary analysis of a randomised, phase 2 trial

Summary Background The introduction of immunomodulatory agents, proteasome inhibitors, and autologous haematopoietic stem-cell transplantation has improved outcomes for patients with multiple myeloma, but patients with high-risk multiple myeloma have a poor long-term prognosis. We aimed to address optimal treatment for these patients. Methods SWOG-1211 is a randomised phase 2 trial comparing eight cycles of lenalidomide (25 mg orally on days 1–14 every 21 days), bortezomib (1·3 mg/m2 subcutaneously on days 1, 4, 8, and 11 every 21 days), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days; RVd) induction followed by dose-attenuated RVd maintenance (bortezomib 1 mg/m2 subcutaneously on days 1, 8, and 15; lenalidomide 15 mg orally on days 1–21; dexamethasone 12 mg orally on days 1, 18, and 15 every 28 days) until disease progression with or without elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1–2, on days 1 and 11 for cycles 3–8, and on days 1 and 15 during maintenance). Patients were randomly assigned (1:1) to either RVd or RVd-elotuzumab. High-risk multiple myeloma was defined by one of the following: gene expression profiling high risk (GEPhi), t(14;16), t(14;20), del(17p) or amp1q21, primary plasma cell leukaemia and elevated serum lactate dehydrogenase (two times the upper limit of normal or more). The primary endpoint was progression-free survival, and all analyses were done on intention-to-treat basis among eligible patients who were evaluable for response. This study is registered with ClinicalTrials.gov , NCT01668719 . Findings 100 (RVd n=52, RVd-elotuzumab n=48) patients were enrolled between Oct 27, 2013, and May 15, 2016, across 26 cooperative group institutions in the USA. Median age was 64 years (IQR 57–70, range 36–85). 74 (75%) of 99 had International Staging System stage II or stage III disease, 47 (47%) of 99 had amp1q21, 37 (37%) of 100 had del17p, 11 (11%) of 100 had t(14;16), eight (9%) of 90 were GEPhi, seven (7%) of 100 had primary plasma cell leukaemia, five (5%) of 100 had t(14;20), four (4%) of 100 had elevated serum lactate dehydrogenase, and 17 (17%) had two or more features. With a median follow-up of 53 months (IQR 46–59), no difference in median progression-free survival was observed (RVd 33·64 months [95% CI 19·55–not reached], RVd-elotuzumab 31·47 months [18·56–53·98]; hazard ratio 0·968 [80% CI 0·697–1·344]; one-sided p=0·45]. 37 (71%) of 52 patients in the RVd group and 37 (77%) of 48 in the RVd-elotuzumab group had grade 3 or worse adverse events. No significant differences in the safety profile were observed, although some notable results included grade 3–5 infections (four [8%] of 52 in the RVd group, eight [17%] of 48 in the RVd-elotuzumab group), sensory neuropathy (four [8%] of 52 in the RVd group, six [13%] of 48 in the RVd-elotuzumab group), and motor neuropathy (one [2%] of 52 in the RVd group, four [8%] of 48 in the RVd-elotuzumab group). There were no treatment-related deaths in the RVd group and one death in the RVd-elotuzumab group for which study treatment was listed as possibly contributing by the investigator. Interpretation In the first randomised study of high-risk multiple myeloma reported to date, the addition of elotuzumab to RVd induction and maintenance did not improve patient outcomes. However, progression-free survival in both study groups exceeded the original statistical assumptions and supports the role for continuous proteasome inhibitors and immunomodulatory drug combination maintenance therapy for this patient population. Funding National Institutes of Health, National Cancer Institute, Bristol Myers Squibb, Celgene, Leukemia and Lymphoma Society.