Immunological Subgroups Predicting Efficacy of Elotuzumab in Multiple Myeloma Patients: Insights from the GMMG-HD6 Clinical Trial

Introduction: Elotuzumab, a monoclonal antibody targeting SLAM family member 7 protein (SLAMF7) on multiple myeloma (MM) cells, has shown promise in relapsed/refractory MM when combined with immunomodulatory agents. However, its effectiveness in newly diagnosed patients did not show improved progression-free survival (PFS) nor overall survival. In a previous study we demonstrated that elotuzumab specifically depleted high SLAMF7 expressing regulatory CD8⁺ T cells by macrophage induced antibody dependent phagocytosis. This study aimed to identify immunological predictive factors for elotuzumab efficacy, enabling improved risk stratification and personalized treatment decisions based on the detection and quantification of SLAMF7-positive T cell subsets.

Patients and Methods: This pre-planned accompanying immunological research analyzed samples from the German-Speaking Myeloma Multicenter Group (GMMG) HD6 clinical trial (NCT02495922). The trial investigated elotuzumab in combination with lenalidomide/bortezomib/dexamethasone induction and consolidation, followed by lenalidomide maintenance in transplant-eligible newly diagnosed MM patients and found no progression-free or overall survival advantage with the addition of elotuzumab in any treatment sequence. Peripheral blood samples were collected at three time points: trial inclusion (T1), after induction therapy (T2), and during consolidation or maintenance therapy (T3). Flow cytometry was used to assess T cell subpopulations.

Results: Elotuzumab during induction therapy significantly reduced the percentage of regulatory SLAMF7 high expressing CD8⁺ CD28^- (p < 0.001) and effector CD8⁺ T cells (p < 0.001) in MM patients after induction therapy and during maintenance therapy. A T2 landmark multivariate analysis (after induction therapy) revealed that a higher percentage of effector CD8⁺ T cells at T1 showed a borderline advantageous effect on the progression-free survival (PFS) (HR = 0.98 [CI_95% 0.97; 1.00], p = 0.010) regardless of the study arm. Further, in a multivariate analysis a high regulatory CD8⁺ T cell level at T2 was associated with an adverse PFS in patients receiving elotuzumab in addition to lenalidomide during consolidation and maintenance (PFS from T2 for high vs. low regulatory CD8⁺ T cell levels at T2, HR = 3.64 [CI_95% 1.58; 8.36], p = 0.002 for patients that received elotuzumab during consolidation and maintenance only; regulatory CD8⁺ T cells at T2 [high versus low] HR = 5.93 [CI_95% 2.30; 15.26], p < 0.001 for patients that received elotuzumab during induction, consolidation and maintenance).

Conclusion: The efficacy of elotuzumab in MM patients may be influenced by the frequency of regulatory CD8⁺ T cells after induction therapy. As high levels of regulatory CD8⁺ T cells showed adverse progression-free survival in MM patients, the assessment of the level of regulatory CD8⁺ SLAMF7⁺ T cells could be a prerequisite for MM patients’ response to elotuzumab. This study highlights the importance of T cell level-driven immunological treatment approaches when utilizing elotuzumab.