OAB-002: Daratumumab improves depth of response and progression free survival in transplant-ineligible, high-risk, newly diagnosed multiple myeloma (NDMM)

Introduction Patients with high-risk NDMM who are ineligible for autologous stem cell transplant (ASCT) have limited first-line treatment options, and new regimens to improve their outcomes are needed. Daratumumab (Dara) is approved in combination with lenalidomide and dexamethasone (D-Rd) and in combination with bortezomib, melphalan, and prednisone (D-VMP) in ASCT-ineligible NDMM patients, based on the randomized clinical trials (RCTs), MAIA and ALCYONE, respectively. A recent meta-analysis of data from these two RCTs along with ASCT-eligible patients from the CASSIOPEIA RCT demonstrated that incorporation of Dara was associated with improved progression free survival (PFS) in high-risk NDMM patients. The current study builds upon these findings by focusing on the more homogenous population of ASCT-ineligible high-risk patients from MAIA and ALCYONE RCTs, using longer follow-up data, adjusting for patient-level imbalances in baseline characteristics, and evaluating additional efficacy endpoints. Methods A stratified pooled analysis of patient-level data for ASCT-ineligible NDMM patients with high cytogenetic risk [i.e., del(17p), t(4;14), or t(14;16)] from MAIA and ALCYONE RCTs was conducted, adjusting for cytogenetic abnormality subtype, baseline performance status, International Staging System stage, type of multiple myeloma, and renal impairment. The impact of Dara on PFS and rates of complete response or better (≥CR), minimal residual disease (MRD)-negative CR, very good partial response or better (≥VGPR), and overall response (ORR), compared to control treatment, was assessed using the study identifier as the stratification factor. Results There were 101 patients in Dara and 89 patients in the control cohort. Median follow-up was 43.7 months. In the adjusted analysis, the risk of progression or death was reduced by 41% in the Dara cohort vs control (hazard ratio [95% confidence interval (CI)] = 0.59 [0.41-0.85]). At 36 months, the proportion of patients who did not progress and were still alive was 41.3% in the Dara and 19.9% in the control cohort. Deeper response was observed in the Dara cohort with higher rates, and adjusted odd ratios (95% CI) for ≥CR (41.6% vs. 22.5%; 2.63 [1.34-5.16]), MRD-negative CR (24.8% vs. 5.6%; 5.50 [1.97-15.34]), ≥VGPR (75.3% vs. 46.1%; 4.03 [2.09-7.78]), and ORR (92.1% vs. 74.2%; 4.88 [1.94-12.27]) compared to control. Conclusion Addition of Dara to backbone regimens resulted in 41% reduction in risk of progression or death among ASCT-ineligible high-risk NDMM patients. Additionally, patients in the Dara cohort had a two-fold higher likelihood of achieving ≥CR and a five-fold higher likelihood of achieving MRD-negative CR relative to control. This study provides additional evidence that the use of Dara based first-line treatment benefits high-risk NDMM patients.