Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma

Abstract

Key Points• Daratumumab plus lenalidomide/dexamethasone elicited an overall response rate of 81% (63% very good partial response or better).• Adverse events were manageable and in accord with the individual toxicity profiles of daratumumab and lenalidomide/ dexamethasone.Daratumumab, a human CD38 immunoglobulin G1 kappa (IgG1k) monoclonal antibody, has activity as monotherapy in multiple myeloma (MM). This phase 1/2 study investigated daratumumab plus lenalidomide/dexamethasone in refractory and relapsed/refractory MM. Part 1 (dose escalation) evaluated 4 daratumumab doses plus lenalidomide (25 mg/day orally on days 1-21 of each cycle) and dexamethasone (40 mg/week). Part 2 (dose expansion) evaluated daratumumab at the recommended phase 2 dose (RP2D) plus lenalidomide/dexamethasone. Safety, efficacy, pharmacokinetics, immunogenicity, and accelerated daratumumab infusions were studied. In part 1 (13 patients), no dose-limiting toxicities were observed, and 16 mg/kg was selected as the R2PD. In part 2 (32 patients), median time since diagnosis was 3.2 years, with a median of 2 prior therapies (range, 1-3 prior therapies), including proteasome inhibitors (91%), alkylating agents (91%), autologous stem cell transplantation (78%), thalidomide (44%), and lenalidomide (34%); 22% of patients were refractory to the last line of therapy. Grade 3 to 4 adverse events ( ‡5%) included neutropenia, thrombocytopenia, and anemia. In part 2, infusion-related reactions (IRRs) occurred in 18 patients (56%); most were grade £2 (grade 3, 6.3%). IRRs predominantly occurred during first infusions and were more common during accelerated infusions. In part 2 (median follow-up of 15.6 months), overall response rate was 81%, with 8 stringent complete responses (25%), 3 complete responses (9%), and 9 very good partial responses (28%). Eighteen-month progression-free and overall survival rates were 72% (95% confidence interval, 51.7-85.0) and 90% (95% confidence interval, 73.1-96.8), respectively. Daratumumab plus lenalidomide/dexamethasone resulted in rapid, deep, durable responses. The combination was well tolerated and consistent with the safety profiles observed with lenalidomide/ dexamethasone or daratumumab monotherapy. This trial was registered at www.clinicaltrials.gov as

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

“…17 An ongoing phase 1-2 study of daratumumab in combination with lenalidomide and dexamethasone in patients with relapsed myeloma or relapsed and refractory myeloma has shown high response rates and responses that improved over time. 18 SAR650984, a humanized IgG1 monoclonal antibody, also targets CD38, 19 and clinical responses have been reported in patients with relapsed myeloma or relapsed and refractory myeloma who received the drug as monotherapy 20 or in combination with lenalidomide and dexamethasone, findings that further validate this approach. 21 Elotuzumab, a humanized IgG1 monoclonal antibody that targets the signaling lymphocytic activation molecule F7 (SLAMF7), 22 was associated with stable disease as the best response when it was used as a single agent 23 but has shown clinically relevant activity in combination with lenalidomide and dexamethasone in two studies.…”

A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma

“…34 For the ELO and DARA triplet arms, the data were comparable to those reported in phase 1/2 single-arm studies, which also included patients with predominantly LEN-naive 35 or LENsensitive disease. 36 As discussed, .80% of patients in our study were LEN refractory, for whom the ORR with isatuximab-LEN-Dex was 52%. Only 8 patients included in the isatuximab-LEN-Dex study were less heavily pretreated (1-2 prior lines of therapy), and the ORR in this subgroup was 100%, comparing more favorably to the phase 3 study results discussed above.…”

Hematological approaches to multiple myeloma: trends from a Brazilian subset of hematologists. A cross-sectional study

“…Critical new steps in MM management rely on development of 9 Furthermore, an ability to overdrive genetic mutations, with prolonging of the durable response, has been reported. 10 As described above, most respondents believed that continued exposure to therapy might lead to emergence of resistant clones.…”