Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM

Abstract

Key Points• Elotuzumab, an immunostimulatory antibody, prolongs PFS with no added clinical toxicity when combined with Bd vs Bd alone in RRMM.• Based on results from this phase 2 study, further investigation of elotuzumab with a proteasome inhibitor in RRMM is warranted.In this proof-of-concept, open-label, phase 2 study, patients with relapsed/refractory multiple myeloma (RRMM) received elotuzumab with bortezomib and dexamethasone (EBd) or bortezomib and dexamethasone (Bd) until disease progression/unacceptable toxicity. Primary endpoint was progression-free survival (PFS); secondary/exploratory endpoints included overall response rate (ORR) and overall survival (OS). Two-sided 0.30 significance level was specified (80% power, 103 events) to detect hazard ratio (HR) of 0.69. Efficacy and safety analyses were performed on all randomized patients and all treated patients, respectively. Of 152 randomized patients (77 EBd, 75 Bd), 150 were treated (75 EBd, 75 Bd). PFS was greater with EBd vs Bd (HR, 0.72; 70% confidence interval [CI], 0.59-0.88; stratified log-rank P 5 .09); median PFS was longer with EBd (9.7 months) vs Bd (6.9 months). In an updated analysis, EBd-treated patients homozygous for the high-affinity FcgRIIIa allele had median PFS of 22.3 months vs 9.8 months in EBd-treated patients homozygous for the low-affinity allele. ORR was 66% (EBd) vs 63% (Bd). Very good partial response or better occurred in 36% of patients (EBd) vs 27% (Bd). Early OS results, based on 40 deaths, revealed an HR of 0.61 (70% CI, 0.43-0.85). To date, 60 deaths have occurred (28 EBd, 32 Bd). No additional clinically significant adverse events occurred with EBd vs Bd. Grade 1/2 infusion reaction rate was low (5% EBd) and mitigated with premedication. In patients with RRMM, elotuzumab, an immunostimulatory antibody, appears to provide clinical benefit without added clinically significant toxicity when combined with Bd vs Bd alone. Registered to ClinicalTrials.gov as NCT01478048.

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…158 In both examples, the ability of a specific agent (e.g., oxaliplatin, cyclophosphamide) but not one of its alike (e.g., cisplatin, melphalan) to drive ICD can be explained by the differential activation of ER stress (and hence differential exposure of CALR in the course of RCD). 100,[157][158][159] Well established ICD inducers include commonly employed anticancer chemotherapeutics such as: (1) (6) bortezomib, a proteasomal inhibitor approved for the therapy MM and mantle cell lymphoma (MCL); [171][172][173][174][175][176][177][178][179][180][181] (7) cyclophosphamide, a DNA-alkylating agent approved for use in patients with chronic myeloid leukemia (CML), AML, ALL, chronic lymphocytic leukemia, MM, ovarian carcinoma, breast carcinoma, mycosis fungoides, lymphoma, neuroblastoma, and retinoblastoma; 177,[182][183][184][185][186][187][188][189][190][191] and (8) oxaliplatin, a platinum-derivative licensed for the therapy of advanced colorectal carcinoma in combination with 5-fluorouracil and folinic acid. 156,157,[192][193][194][195][196][197][198] Moreover, there is some evidence that microtubule-targeting agents including taxanes and vinca alkaloids (which are commonly used for the treatment of multiple carcinomas) can stimulate ICD.…”

A phase 2 safety study of accelerated elotuzumab infusion, over less than 1 h, in combination with lenalidomide and dexamethasone, in patients with multiple myeloma

“…If an infusion reaction (IR) did not occur, the infusion rate could be increased to 5 mL/min (duration 1 h) after Cycle 4. 19,20 In study 1703, patients with RRMM receiving elotuzumab plus lenalidomide and dexamethasone demonstrated an overall response rate (ORR) of 84% and a median progression-free survival of 28.6 months. 19 The most common Grade 3/4 adverse events (AEs) were lymphopenia (21%) and neutropenia (19%).…”

“…One IR was reported among the 27 patients who had received the 5 mL/min infusion. 20 The premedication regimen and administration schedule of these medications implemented in studies 1703 and 009 were shown to successfully reduce the number and severity of IRs associated with elotuzumab. 19,22 As a result, this premedication regimen, or an appropriate equivalent, is currently required for all patients prior to infusion of elotuzumab.…”

“…4 Based on previous studies that demonstrated low levels of IRs at 5 mL/min, 18,20 we conducted a study to determine whether infusing this mAb at the rate of 5 mL/min could be achieved safely within the first cycle, rather than after four treatment cycles, thus increasing convenience for patients and reducing resource use during the administration of elotuzumab mAb therapy. This study aimed to assess the safety and tolerability of elotuzumab administered at the rate of 5 mL/min ( 1- The accelerated infusion schedule is detailed in Table 1.…”

Monoclonal antibodies for treating multiple myeloma - a new era, new safety considerations?

“…As single agent in RRMM patients, no objective responses were observed (Table 2) [13], and a potential role in combination with other MM agents was hypothesized. Recently, elotuzumab in combination with bortezomib-dexamethasone (VD; ELO-VD) induced an ORR of 66% and a median PFS approximately 3 months longer than the one reported with VD alone [14]. No additional clinically significant adverse events occurred with ELO-VD versus VD.…”