Rationale and design of the German-speaking myeloma multicenter group (GMMG) trial HD6: a randomized phase III trial on the effect of elotuzumab in VRD induction/consolidation and lenalidomide maintenance in patients with newly diagnosed myeloma

Abstract

Background Despite major advances in therapy, multiple myeloma is still an incurable malignancy in the majority of patients. To increase survival, deeper remissions (i.e. CR) translating into longer PFS need to be achieved. Incorporation of new drugs (i.e. bortezomib and lenalidomide) as induction and maintenance treatment in an intensified treatment concept, including high dose melphalan (200 mg/m 2 ), has resulted in increased CR rates, and is considered the standard of care for younger patients. Elotuzumab in combination with lenalidomide and dexamethasone has given better results as lenalidomide and dexamethasone alone in a phase III trial. The GMMG-HD6 trial will be the first phase III trial investigating the role of elotuzumab in combination with bortezomib, lenalidomide and dexamethasone (VRD) induction/consolidation and lenalidomide maintenance within a high dose concept. Methods GMMG-HD6 is a randomized, open, multicenter phase III trial. The planned recruitment number is 564 NDMM patients. All patients will receive 4 VRD cycles as induction and undergo peripheral blood stem cell mobilization and harvesting. Thereafter they will be treated with high dose melphalan therapy plus autologous stem cell transplantation followed by 2 cycles of VRD consolidation and lenalidomide maintenance. Patients in arm B1 + B2 will additionally receive elotuzumab in the induction phase, whereas patients in A2 + B2 will be treated with elotuzumab added to consolidation and maintenance. The primary endpoint of the trial is PFS. Secondary objectives and endpoints are OS, CR rates after induction therapy comparing the two arms VRD (A1 + A2) vs VRD + elotuzumab (B1 + B2), CR rates after consolidation treatment, best response to treatment during the study, time to progression (TTP), duration of response (DOR), toxicity and quality of life. Results Since this is the publication of a study protocol of an ongoing study, no results can be presented. Discussion This phase III trial is designed to evaluate whether the addition of elotuzumab to an intensified treatment concept with high dose melphalan chemotherapy plus autologous stem cell transplantation and induction, consolidation and maintenance treatment with bortezomib and lenalidomide is able to improve PFS compared to the same concept without elotuzumab. Trial registration NCT02495922 on June 24th, 2015.

Treatment Induced Cytotoxic T-Cell Modulation in Multiple Myeloma Patients

“…Most importantly, a similar cytotoxic polarization with reduction of CD4+ cells and increase in CD8+ effector memory cells (resembling the CD3+/CD57+ cells analyzed in our cohort) was observed in patients with long term complete response after ASCT, suggesting a putative immune surveillance effect (18). Of notice, since NK cells are reduced immediately after ASCT, strategies including elotuzumab, whose mechanism of action is fully dependent on NK cells activity, as consolidation after transplantation might be not effective (26). Otherwise, adoptive cell therapy strategies based on NK cells can represent an interesting choice in MM treatment.…”

The Role of Monoclonal Antibodies in Smoldering and Newly Diagnosed Transplant-Eligible Multiple Myeloma

“…A regimen including bortezomib and an IMiD is usually considered the gold standard treatment for patients with NDMM who are fit for high-dose chemotherapy [ 34 ], along with post-transplant maintenance therapy employing lenalidomide [ 35 ]. The GMMGHD6 phase III trial (NCT02495922) is currently investigating the role of Elo in combination with VRd induction/consolidation and lenalidomide maintenance within a high dose concept [ 36 ]. Four treatment strategies are being compared, on the basis of use of Elo in addition to background treatment of VRd induction/consolidation (VRd +/− Elo) as well as lenalidomide maintenance treatment (lenalidomide +/− Elo), regarding PFS as the primary endpoint.…”

Emerging immunotherapies in multiple myeloma

“…More recent studies are now including the monoclonal antibodies daratumumab, elotuzumab, and isatuximab in the upfront setting as part of a quadruplet regimen that includes a monoclonal antibody with standard triplet combinations to improve depth of response and thus outcomes 52138139140141142143144…”