A randomized, open-label, multicenter phase 2 study of daratumumab monotherapy for patients (pts) with intermediate or high-risk smoldering multiple myeloma (SMM): CENTAURUS

INTRODUCTION: While current guidelines recommend monitoring pts every 3-6 months for active MM before initiating treatment, early intervention to delay or prevent evolution of SMM to active disease could benefit pts. Daratumumab (DARA) is a humanized anti-CD38 monoclonal antibody approved as monotherapy and combined with standard of care regimens for relapsed or refractory MM (RRMM). We hypothesized that DARA may delay SMM progression to symptomatic MM. We report preliminary data from a phase 2 study (Centuarus : NCT02316106) of DARA in pts with intermediate or high-risk SMM. METHODS: Pts had SMM for $<5$ years, no prior anti-SMM or antimyeloma therapy, and no evidence of MM or primary amyloid light chain amyloidosis. Intermediate or high-risk SMM was defined as $\geq 10\%$ to $<60\%$ plasma cells in bone marrow and $\geq 1$ of the following : serum M-protein $\geq 3$ g/dL; urine M-protein $>500$ mg/24 h; abnormal involved :uninvolved free light chain (FLC) ratio ($<0.126$ or $>8$) with serum M-protein $<3$ g/dL but $\geq 1$ g/dL; and/or involved serum FLC $\geq 100$ mg/L with abnormal FLC ratio ($<0.126$ or $>8$), but not $\geq 100$. Pts were randomized to 1 of 3 treatment arms of DARA 16 mg/kg IV in 8-week cycles : long intense (Long; weekly [QW] in Cycle 1, every other week in Cycle 2-3, every 4 weeks in Cycle 4-7, and every 8 weeks [Q8W] up to Cycle 20), intermediate (Int; QW in Cycle 1, Q8W to Cycle 20), and short intense (Short; QW for 1 cycle). Co-primary endpoints were complete response (CR) rate and progressive disease (PD; as defined by 2014 IMWG criteria for SMM)/death rate (proportion of pts who progressed to MM or died per pt-year). Other endpoints were overall response rate (ORR) and progression-free survival (PFS). We report a prespecified interim analysis of CR, which occurred 6 months after randomization of last pt; prespecified interim analysis of PD/death rate is planned at 12 months after randomization of last pt. RESULTS: 123 pts were enrolled (41 in each arm). Median (range) time since initial SMM diagnosis was 6.83 (0.4-56) months. Number of pts with $\geq 2$ risk factors at screening was balanced between arms (81% for Long and Int; 83% for Short), but more pts with high bone marrow aspirate plasma cell percentage ($\geq 30$-$<60\%$) were enrolled in Long (26%) vs Int (14%) and Short (16%). In Arm Long, Int, and Short, 10%, 10%, and 5% of pts discontinued treatment, respectively, for adverse events (AEs; 5%, 2%, and 5%), PD (2%, 5%, and 0%), pt refused further treatment (2% in Int) and withdrawal of consent (2% in Long). Common ($>25\%$) treatment-emergent AEs (TEAEs) were fatigue, cough, headache, and insomnia; common ($>1$ pt) grade 3/4 TEAEs were hypertension and hyperglycemia. No hematologic TEAE was $>10\%$ across arms. Rates of grade 3/4 infection (pneumonia or sepsis) were $\leq 5\%$. Infusion-related reactions occurred in 56%, 37%, and 55% of pts; 2% in Long, 0% in Int, and 3% in Short were grade 3/4. At clinical cut-off, no deaths were observed. With median follow-up of 9.6 (range, 0-17.9) months, ORR was higher in Long than Int and Short (Table 1). Median PFS was not reached in any arm; 12-month PFS rates were 98%, 93%, and 89% in Long, Int, and Short, respectively. Updated data including prespecified analysis of PD/death rate will be presented. CONCLUSIONS: DARA was well tolerated in SMM, with a safety profile similar to that in RRMM. Efficacy follow-up is ongoing. A phase 3 study ($\text{Smm3}_{001}$) of long intense dosing with subcutaneous DARA in high-risk SMM pts is planned.