Daratumumab plus Lenalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma: Results of the GEN503 Study
Daratumumab is a human anti-CD38 monoclonal antibody that elicits robust cytotoxic effects in myeloma cells, particularly in combination with immunomodulatory agents.1 Clinical studies have since shown antimyeloma activity of daratumumab as a single agent or in combination with lenalidomide/dexamethasone (Len/Dex) in heavily pretreated patients with relapsed and/or refractory multiple myeloma (RRMM).2-4 Updated results of the open-label phase 1/2 GEN303 study, which evaluated the combination of daratumumab plus Len/Dex in patients with RRMM, were presented by Plesner and colleagues following more than 12 months of treatment.5
In the 2-part open-label GEN303 study, part 1 used a 3+3 design for dose escalation (daratumumab 2-16 mg/kg + Len/Dex) and part B consisted of cohort expansion using the recommended phase 2 dose (daratumumab 16 mg/kg + Len/Dex at standard doses). Part 2 included patients with ?1 prior lines of therapy, with 34% refractory to lenalidomide. The most common treatment-emergent adverse events (TEAEs) included neutropenia (84%), muscle spasms (44%), cough (50%), diarrhea (44%), fatigue (34%), and hypertension (28%). The most common grade 3/4 TEAE was neutropenia (78%); only 1 (3%) patient experienced febrile neutropenia (grade 1). Eighteen (56%) patients had an infusion-related reaction (IRR), including cough (25%), allergic rhinitis (9%), nausea (9%), vomiting (9%), dyspnea (6%), and nasal congestion (6%), which were mostly grade 1/2 in severity; 2 (6%) grade 3 IRRs were reported (laryngeal edema and hypertension). Overall, 6 (19%) patients discontinued treatment, which was attributable to disease progression (n = 3), TEAEs (n = 2), and physician decision (n = 1). TEAEs leading to treatment discontinuation were due to gastric adenocarcinoma and laryngeal edema (grade 3 IRR).
The overall response rate was 81%, with 6 (19%) partial responses, 8 (25%) stringent complete responses, 3 (9%) complete responses, and 9 (28%) very good partial responses. The median time to best response was 4.5 months. The median duration of response was not reached. The 18-month progression-free survival and overall survival were 72% and 90%, respectively. Notably, 17 (61%) of 28 responders achieved greater depth of response over time. Based on these results, the authors concluded that the combination of daratumumab plus Len/Dex is a promising and alternate treatment option for heavily pretreated patients with RRMM.
- van der Veer M, et al. Haematologica. 2011;96:284-290.
- Lokhorst HM, et al. ASCO 2014. Abstract 8513.
- Lonial S, et al. ASCO 2014. Abstract LBA8512.
- Plesner T, et al. Blood. 2014;124(21):84.
- Plesner T, et al. ASH 2015. Abstract 507.