Abstract
High cytogenetic risk abnormalities confer poor outcomes in multiple myeloma patients. In POLLUX, daratumumab/lenalidomide/dexamethasone (D-Rd) demonstrated significant clinical benefit versus lenalidomide/dexamethasone (Rd) in relapsed/refractory multiple myeloma (RRMM) patients. We report an updated subgroup analysis of POLLUX based on cytogenetic risk. The cytogenetic risk was determined using fluorescence in situ hybridization/karyotyping; patients with high cytogenetic risk had t(4;14), t(14;16), or del17p abnormalities. Minimal residual disease (MRD; 10–5) was assessed via the clonoSEQ® assay V2.0. 569 patients were randomized (D-Rd, n = 286; Rd, n = 283); 35 (12%) patients per group had high cytogenetic risk. After a median follow-up of 44.3 months, D-Rd prolonged progression-free survival (PFS) versus Rd in standard cytogenetic risk (median: not estimable vs 18.6 months; hazard ratio [HR], 0.43; P < 0.0001) and high cytogenetic risk (median: 26.8 vs 8.3 months; HR, 0.34; P = 0.0035) patients. Responses with D-Rd were deep, including higher MRD negativity and sustained MRD-negativity rates versus Rd, regardless of cytogenetic risk. PFS on subsequent line of therapy was improved with D-Rd versus Rd in both cytogenetic risk subgroups. The safety profile of D-Rd by cytogenetic risk was consistent with the overall population. These findings demonstrate the improved efficacy of daratumumab plus standard of care versus standard of care in RRMM, regardless of cytogenetic risk.
Highlights
Introduction Daratumumab is a humanIgGκ monoclonal antibody targeting CD38 with a direct on-tumor1–4 and immunomodulatory5–7 mechanism of action
With longer follow-up, daratumumab to Rd (D-Rd) continued to reduce the risk of disease progression or death by 56% and significantly increased the overall response rate (ORR; 93% vs 76%; P < 0.0001) and rates of complete response (CR) or better (57% vs 23%; P < 0.0001), very good partial response (VGPR) or better (80% vs 49%; P < 0.0001), and minimal residual disease (MRD) negativity (10–5 sensitivity threshold; 30% vs 5%; P < 0.000001) versus Rd alone10
Among patients with standard cytogenetic risk, time to VGPR or better and CR or better were decreased with D-Rd versus Rd
Summary
Introduction Daratumumab is a humanIgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. In the phase 3 POLLUX study in patients with RRMM, adding daratumumab to Rd (D-Rd) more than doubled complete response (CR) or better rates, induced a > fourfold increase in the rate of minimal residual disease (MRD) negativity at the 10–5 sensitivity threshold, and reduced the risk of disease progression or death by 63% versus Rd alone at a median follow-up of 13.5 months. With longer follow-up (median: 44.3 months), D-Rd continued to reduce the risk of disease progression or death by 56% and significantly increased the overall response rate (ORR; 93% vs 76%; P < 0.0001) and rates of CR or better (57% vs 23%; P < 0.0001), very good partial response (VGPR) or better (80% vs 49%; P < 0.0001), and MRD negativity (10–5 sensitivity threshold; 30% vs 5%; P < 0.000001) versus Rd alone. In patients with high cytogenetic risk, treatment choice is driven by the duration, quality, and depth of response offered; updated IMWG guidelines recommend treatment with regimens containing bortezomib or lenalidomide in these patients
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