Adding elotuzumab to induction bortezomib-lenalidomide-dexamethasone (VRD) does not increase the response rate among newly diagnosed, transplant-eligible multiple myeloma patients
During the virtual EHA 2020 meeting, Prof. Goldschmidt presented the results of the German-speaking myeloma multicentre group trial HD6. The first part of this randomised phase III trial assessed the effect of the addition of elotuzumab to bortezomib-lenalidomide-dexamethasone (VRD) induction therapy in newly diagnosed, transplant-eligible multiple myeloma patients. On the bright side, the overall toxicities observed with elotuzumab-VRD (Elo-VRD) were similar to what was seen with VRD. However, the Elo-VRD regimen did not result in an increased rate of very good partial responses (or better) after 4 cycles of induction therapy.
Background
For patients with transplant-eligible newly diagnosed multiple myeloma (NDMM) the current upfront standard of care consists of an intensified treatment regimen with induction therapy, high dose melphalan and subsequent consolidation/maintenance therapy. One of the standard induction regimens in younger patients consists of bortezomib-lenalidomide-dexamethasone (VRD). The German-speaking Myeloma Multicentre Group (GMMG) HD6 trial investigated the role of elotuzumab in combination with VRD as induction/consolidation and lenalidomide maintenance. The GMMG-HD6 trial is a randomised multicentre phase III study including 559 patients with transplant-eligible NDMM in the intention-to-treat (ITT) population and 555 patients in the safety population. Induction therapy consisted of 4 21-day cycles of VRD with or without elotuzumab (VRD, arms A1+A2, N=280 and Elo-VRD, arms B1+B2, N=279). After induction, patients undergo intensifying therapy according to GMMG standard. After intensification a consolidation therapy will be performed with 2 cycles of VRD (A1 and B1) or Elo-VRD (A2 and B2), followed by lenalidomide maintenance therapy with (arm A2 and B2) or without (arm A1 and B1) additional elotuzumab. During EHA 2020, feasibility, response rates and toxicities of VRD versus Elo-VRD induction therapy were analysed and presented by Prof. Goldschmidt. The median age of the patients at trial inclusion was 59 years with Revised International Staging System (R-ISS), ISS stages, adverse cytogenetics and the proportion of patients with renal impairment equally distributed among the VRD and Elo-VRD groups. Nevertheless, there were more patients with bone marrow infiltration with more than 60% plasma cells (51.8% versus 43.0%, p=0.04 and patients with more than one MRI focal lesion in the Elo-VRD arm (48.9% versus 35.5%, p=0.004).
Results
In total, 94.3% and 92.5% of the patients completed at least 4 cycles of their pre-planned VRD or Elo-VRD induction therapy, respectively. Overall, 21 patients in the VRD arm and 25 patients in the Elo-VRD arm left the study during induction therapy or within 40 days after the end of induction therapy because of toxicity, progressive disease, death or withdrawal of consent. The overall response rate (ORR) with a partial response or better (≥PR) after the fourth cycle of induction therapy was reported at 85.6% and 82.4% in the VRD versus Elo-VRD groups, respectively and were not statistically significantly different (p=0.35). Very good partial response rates or better (≥VGPR) were obtained in 54.0% and 58.3% of the patients respectively (p=0.35). Finally, no differences in complete response rates between VRD and Elo-VRD were observed (3.6% versus 2.9%, p=0.81). The rates of progressive disease at any time during induction therapy or within 40 days after the end of induction therapy were low in both arms and did not significantly differ (2.9% versus 2.1%, p=0.79).
At least one (serious) adverse event during induction therapy occurred in 66.5% of the patients in the VRD arm and in 65.4% of the patients in the Elo-VRD arm (p=0.79). The most common adverse events were nervous system disorders (VRD: 24.0% versus Elo-VRD: 23.6%, p=0.92), infections and infestations (22.9% versus 20.0%, p=0.41) and blood and lymphatic system disorders (8.4% versus 14.6%, p=0.02). There were 4 deaths associated with induction therapy in the VRD group and 9 in the Elo-VRD group.
Conclusions
The addition of elotuzumab to VRD in transplant-eligible NDMM patients did not result in an increased rate of VGPR rates or better after 4 cycles of induction therapy. Overall toxicities for VRD as compared to Elo-VRD are comparable. Whether the addition of elotuzumab yields improved response rates at later time points (e.g. after consolidation) or a progression-free and/or overall survival benefit will be revealed in the final analysis of this trial.
