Introduction: Patients (pts) with relapsed multiple myeloma (MM) who have high risk cytogenetic features, Stage 2-3 disease, or are refractory respond suboptimally to current therapies representing an unmet medical need in this pt population. In pts who received lenalidomide and dexamethasone in this setting, the objective response rates (ORR) were 39%-43% for those with high risk cytogenetics (Avet-Loiseau et al. Leuk 2010) and 55%-56% for those with β2 microglobulin (β2M) ≥2.5 mg/L at baseline (Weber et al, N Engl J Med 2007; Dimopoulos et al, N Engl J Med 2007). In pts who received prior thalidomide, the ORR was 48% (Madan et al, Blood 2011). Elotuzumab is a humanized monoclonal IgG1 antibody directed against the cell surface glycoprotein CS1, which is highly expressed on tumor cells from >95% of MM pts. The mechanism of action of elotuzumab is primarily natural killer cell-mediated antibody-dependent cellular cytotoxicity against MM cells. In the Phase 2 study of elotuzumab (10 or 20 mg/kg) in combination with lenalidomide and low-dose dexamethasone (len/dex) in relapsed and/or refractory (R/R) MM pts, the ORR was 82% and median progression-free survival (PFS) was not yet reached after a median follow-up of 11.4 months. The combination was generally well tolerated. Elotuzumab-associated adverse events were primarily Grade 1/2 infusion-related reactions, with the incidence and severity mitigated by the defined premedication regimen. Here we report a subset analysis of Phase 2 pts with high risk and/or Stage 2-3 MM and/or refractory to prior treatment.
Methods: In the ongoing Phase 2 study, pts with R/R MM and 1 to 3 prior therapies were randomized to elotuzumab 10 or 20 mg/kg IV (days 1, 8, 15, and 22 every 28 days in the first 2 cycles and days 1 and 15 of subsequent cycles), lenalidomide 25 mg PO (days 1-21) and dexamethasone 40 mg PO weekly or 28 mg PO plus 8 mg IV on elotuzumab dosing days. Pts treated with prior lenalidomide were excluded. All pts received a premedication regimen, which consisted of either methylprednisolone (50 mg IV) or in a later amendment dexamethasone (8 mg IV), diphenhydramine (25-50 mg PO or IV) or equivalent, ranitidine (50 mg IV) or equivalent, and acetaminophen (650-1000 mg PO). Treatment continued until disease progression or unacceptable toxicity. The primary objective was to assess efficacy (ORR; ≥partial response [PR]) according to the International Myeloma Working Group (IMWG) criteria. For the purpose of this subanalysis, patients who received 10 or 20 mg/kg were grouped together. High risk cytogenetics were defined as 13q del, 17p del, t(4,14), or t(14,16) detected by fluorescence in situ hybridization. Refractory to prior therapies was determined based on the IMWG definition.
Results: Among 73 enrolled and treated pts (combined 10 and 20 mg/kg groups), 10 (14%) had known high risk cytogenetics, 17 (23%) were bortezomib-refractory, 14 (19%) were thalidomide-refractory, 24 (33%) were refractory to the last line of MM therapy, and 33/71 (46%) had β2M ≥3.5 mg/L at screening. The ORR for pts with high risk cytogenetics was 80% (8/10); including 30% (3/10) with ≥ very good PR (VGPR) compared with 83% (52/63) ORR and 46% (29/63) ≥VGPR in pts with standard risk. The ORRs for pts refractory to bortezomib, thalidomide, or the last line of therapy were 71% (12/17), 79% (11/14), and 71% (17/24), respectively. The rates of ≥VGPR were 41% (7/17), 29% (4/14), and 38% (9/24). The responses were somewhat higher in pts who were previously not refractory to bortezomib, thalidomide, or the last line of therapy; ORR 86% (48/56), 84% (49/58), and 90% (43/48), and ≥VGPR 45% (25/56), 48% (28/58), and 48% (23/48), respectively. The ORR was not different for pts with β2M ≥3.5 mg/L at screening (82% [27/33]; including 45% [15/33] ≥VGPR) compared with pts with β2M <3.5 mg/L (ORR 82% [31/38] and ≥VGPR 42% [16/38]).
Conclusions: In this retrospective subset analysis, elotuzumab in combination with len/dex showed encouraging activity in cytogenetically high risk, β2M ≥3.5 mg/L, and refractory MM pts. Interestingly, the ORRs were similar between the pts with high or low β2M. These data will be further examined in larger studies. Phase 3 trials of len/dex with or without elotuzumab (10 mg/kg) in R/R MM (ELOQUENT2; CA204-004) and front-line MM (ELOQUENT1; CA204-006) are ongoing. Additional safety data and PFS analysis by subgroup will be presented at the meeting.