P04: DARATUMUMAB PLUS BORTEZOMIB AND DEXAMETHASONE VERSUS BORTEZOMIB AND DEXAMETHASONE ALONE IN PATIENTS WITH PREVIOUSLY TREATED MULTIPLE MYELOMA: OVERALL SURVIVAL RESULTS FROM THE PHASE 3 CASTOR TRIAL

Abstract

Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 approved in combination with standard-of-care regimens for pts with newly diagnosed multiple myeloma (NDMM) and as monotherapy and in combination with standard-of-care regimens for pts with relapsed/refractory multiple myeloma (RRMM). In the primary analysis of the phase 3 CASTOR study (median follow-up, 7.4 months), DARA plus bortezomib and dexamethasone (D-Vd) significantly prolonged progression-free survival (PFS) versus bortezomib and dexamethasone (Vd) alone in pts with RRMM, and key secondary endpoints (including time to disease progression, rate of very good partial response or better, overall response rate, and minimal residual disease [MRD]–negativity rate) showed a statistically significant benefit favoring D-Vd. Here, we report final overall survival (OS) and updated MRD-negativity and safety results after ~6 years of follow-up. Methods: Pts with RRMM and ≥1 prior line of therapy were randomized 1:1 to receive D-Vd or Vd. All pts received up to 8 (21-day) cycles of Vd (V 1.3 mg/m2 SC on Days 1, 4, 8, and 11; d 20 mg PO or IV on Days 1, 2, 4, 5, 8, 9, 11, and 12). Pts in the D-Vd group also received DARA (16 mg/kg IV QW in Cycles 1-3, Q3W in Cycles 4-8, and Q4W thereafter until disease progression or unacceptable toxicity). The primary endpoint was PFS; OS was a secondary endpoint. Results: In total, 498 pts were randomized (D-Vd, n=251; Vd, n=247). Median (range) age was 64 (30-88) years; pts had received a median (range) of 2 (1-10) prior lines of therapy. At a median (range) follow-up of 72.6 (0.0-79.8) months, the CASTOR study showed a statistically significant and clinically meaningful improvement in OS with D-Vd versus Vd (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.59-0.92; P=0.0075 [crossing the prespecified stopping boundary of P=0.0323]), representing a 26% reduction in the risk of death with D-Vd (Figure). Median OS was 49.6 (95% CI, 42.2-62.3) months with D-Vd versus 38.5 (95% CI, 31.2-46.2) months with Vd. Prespecified subgroup analyses showed an OS improvement with D-Vd versus Vd across most subgroups, including pts aged ≥65 years; pts who had received 1 or 2 prior lines of therapy; pts with International Staging System stage III disease, high-risk cytogenetic abnormalities, or prior bortezomib treatment; and pts who were refractory to their last prior line of therapy. The most pronounced OS benefit of D-Vd was seen in pts with 1 prior line of therapy (HR, 0.56; 95% CI, 0.39-0.80). D-Vd achieved significantly higher rates of MRD negativity (10–5) versus Vd (15.1% vs 1.6%; P<0.0001). The most common (≥10%) grade 3/4 treatment-emergent adverse events (TEAEs; D-Vd/Vd) were thrombocytopenia (46.1%/32.9%), anemia (16.0%/16.0%), neutropenia (13.6%/4.6%), lymphopenia (10.3%/2.5%), and pneumonia (10.7%/10.1%). Rates of discontinuation due to TEAEs were low and similar between treatment groups (D-Vd, 10.7%; Vd, 9.3%). No new safety concerns were identified with extended follow-up. Conclusion: Treatment with D-Vd significantly prolonged OS compared with Vd alone. These results, together with the OS results observed with DARA in combination with lenalidomide and dexamethasone in the phase 3 POLLUX study, demonstrate for the first time an OS benefit with DARA-containing regimens in RRMM. The greatest OS benefit of D-Vd was observed in pts with 1 prior line of therapy. Our results support early use of D-Vd to maximize pt benefit.