Analysis of Transplant-Eligible Patients (Pts) Who Received Frontline Daratumumab (DARA)-Based Quadruplet Therapy for the Treatment of Newly Diagnosed Multiple Myeloma (NDMM) with High-Risk Cytogenetic Abnormalities (HRCA) in the Griffin and Master Studies

Introduction: DARA as monotherapy and combination therapy is approved across lines of treatment for multiple myeloma. The single-arm phase 2 MASTER study (NCT03224507) evaluated DARA + carfilzomib/lenalidomide/dexamethasone (D-KRd), which demonstrated promising clinical efficacy in transplant-eligible NDMM. The primary endpoint analysis (median follow-up, 25.1 mo) showed that minimal residual disease (MRD) negativity at the 10^–5 threshold was achieved by 80% of D-KRd pts (Costa, et al. JCO. 2021). The randomized phase 2 GRIFFIN study (NCT02874742) evaluated DARA + lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible NDMM; the primary endpoint analysis (median follow-up, 13.5 mo) showed that the rate of stringent complete response by the end of consolidation was significantly higher for D-RVd versus RVd (42.4% vs 32.0%; 1-sided P = 0.068, meeting the prespecified 1-sided α of 0.1) (Voorhees, et al. Blood. 2020). Here, we present an analysis of pts with HRCA, defined as having ≥1 genetic abnormality: del17p, t(4;14), t(14;16), t(14;20), and/or gain/amp1q (≥3 copies of chromosome 1q21) from MASTER (median follow-up, 31.1 mo) and GRIFFIN (median follow-up, 49.6 mo).

Methods: In MASTER, enrolled pts (no age limit with enrichment for high-risk disease) received 4 D-KRd induction cycles, autologous stem cell transplant (ASCT), and 0, 4 or 8 D-KRd consolidation cycles with treatment cessation upon achievement of 2 consecutive MRD-negative assessments, or lenalidomide (R) maintenance therapy if 2 consecutive MRD-negative assessments were not achieved. Pts received 28-day cycles of K (20/56 mg/m² IV Days [D] 1, 8, 15), R (25 mg PO D1-21), d (40 mg PO or IV D1, 8, 15, and 22), and DARA (16 mg/kg IV: D1, 8, 15, and 22 for Cycles 1-2; D1 and 15 for Cycles 3-6; and D1 for Cycles 7+). In GRIFFIN, enrolled pts (age ≤70 years) were randomized 1:1 to receive 4 D-RVd/RVd induction cycles, ASCT, 2 D-RVd/RVd consolidation cycles, and up to 2 years of maintenance with R ± DARA. For induction/consolidation (21-day cycles), pts received R (25 mg PO on Days 1-14), V (1.3 mg/m² SC on Days 1, 4, 8, and 11), and d (40 mg PO QW) ± DARA (16 mg/kg IV QW in Cycles 1-4 and D1 of Cycles 5-6). During maintenance (28-day cycles), pts received R (10 mg PO D1-21; if tolerated, 15 mg Cycles 10+) ± DARA (16 mg/kg IV Q8W or Q4W, or 1800 mg SC Q4W per protocol amendments). Following completion of study therapy, pts could continue R maintenance per local standard of care. Before the randomized phase, a safety run-in was conducted to assess D-RVd dose-limiting toxicities.

Results: Among pts in MASTER (D-KRd, n = 123), 43% (n = 53) had standard risk (0 HRCA), 37% (n = 46) had high risk (1 HRCA), and 20% (n = 24) had ultra-high risk (≥2 HRCA) NDMM. Among 120 pts in GRIFFIN who received D-RVd (n = 104 randomized phase pts and n = 16 safety run-in pts), 56% (n = 67) had NDMM with 0 HRCA, 28% (n = 34) had 1 HRCA, 11% (n = 13) had ≥2 HRCA, and 5% (n = 6) were not evaluable. In an analysis of best response on study, rates of complete response or better (≥CR) for pts with 0, 1, and ≥2 HRCA were 91%, 89%, and 71% for D-KRd pts in MASTER, respectively, and 91%, 79%, and 62% for D-RVd pts in GRIFFIN. MRD-negativity rates at the 10^–5 threshold were 80%, 86%, and 83% for D-KRd for pts with 0, 1, and ≥2 HRCA, respectively, and MRD-negativity rates at the 10^–6 threshold were 68%, 80%, and 67%. For D-RVd pts, MRD-negativity rates at the 10^–5 threshold were 76%, 56%, and 62% for pts with 0, 1, and ≥2 HRCA, respectively, and MRD-negativity rates at 10^–6 were 45%, 26%, and 15%. MRD negativity (10^‒5) with ≥CR occurred in 76%, 79%, and 67% of D-KRd pts with 0, 1, and ≥2 HRCA, respectively, and 75%, 53%, and 54% of D-RVd pts. In MASTER, 24-month progression-free survival (PFS) rates were 92%, 96%, and 66% for D-KRd pts with 0, 1, and ≥2 HRCA, respectively (Figure A). In GRIFFIN, 24-month PFS rates were 97%, 94%, and 64% for D-RVd pts with 0, 1, ≥2 HRCA, respectively, and 48-month PFS rates were 94%, 91%, and 54% (Figure B).

Conclusions: In MASTER and GRIFFIN, pts with NDMM and 0 HRCA or 1 HRCA who received DARA-based quadruplet therapy achieved high rates of ≥CR, MRD negativity, and 2-year PFS rates. These data support use of DARA-based quadruplet therapy as frontline treatment among pts with high cytogenetic risk. However, among pts with NDMM and ≥2 HRCA, results were not similar, and the subgroup was small suggesting that more research is needed for pts with the poor prognosis of ultra–high-risk disease.