Immune Profiling Could Optimize T-Cell Therapy in Relapsed Myeloma

Hearn Jay Cho, MD, PhD, chief medical officer of the Multiple Myeloma Research Foundation (MMRF), details how leveraging high-dimensional immune profiling alongside tumor genomics from the CoMMpass dataset (NCT01454297) has unlocked new insights into the bone marrow microenvironment, directly informing novel clinical trial design. By combining genomic data from over 1000 baseline patient specimens with single-cell immune profiling, researchers identified distinct immune microenvironments that correlate with specific tumor genetic subtypes. Notably, a subset of high-risk myeloma patients harboring specific genomic abnormalities exhibited unique T-cell populations, demonstrating that individual tumor-immune profiles require tailored immunotherapeutic strategies.

These translational findings from the Immune Atlas project directly prompted the phase 2 MyCheckpoint trial (NCT04150965). Observation of CoMMpass specimens revealed that patients relapsing after anti-CD38 monoclonal antibody therapy such as daratumumab (Darzalex) or isatuximab (Sarclisa) exhibited upregulation of the second-generation immune checkpoints LAG3 and TIGIT on their T cells. The MyCheckpoint trial proved that administering novel inhibitors targeting LAG3 and TIGIT produced clinical responses in post-daratumumab relapsed patients. By blocking these upregulated checkpoints, the therapies effectively reversed T-cell exhaustion and reinvigorated the immune system to target myeloma cells.

This proof-of-concept carries significant clinical implications as the myeloma paradigm shifts toward T-cell redirection therapies, such as bispecific antibodies and chimeric antigen receptor T-cell treatments, where baseline T-cell fitness is a major determinant of clinical efficacy. Because T-cell exhaustion represents a principal mechanism of relapse following T-cell redirection, these findings provide a blueprint for combinatorial strategies. Cho emphasizes that observations originating from the CoMMpass and Immune Atlas datasets continue to expand therapeutic avenues, offering concrete strategies to overcome immune evasion and enhance T-cell durability in relapsed multiple myeloma.