Discussion
cancer, tumor, MM
TUMOR, PROLIFERATION, CANCER, DISEASE, MYELOMA
This study showed that Atezo alone and in combination with Dara and IMiDs was safe in myeloma patients. There was no safety signal and the observed safety profiles of the combinations were consistent with those of the individual agents. The correlative analysis showed that Atezo had the expected immunologic effects in the T cell compartment even in the absence of clinical activity, and multi-omic SNF analysis of cellular and molecular data from the TME recapitulated the cohorts with high fidelity and revealed novel correlations with clinical outcome.Biomarker data from Cohort A suggest that Atezo promotes T-cell activation as early as C1D15, and all Dara-naïve patients showed an on-treatment increase in T-cell activation and proliferation in blood, although the same effect was not observed in patients with Dara-refractory disease. Evaluation of BMAs and osteoclasts allowed stratification of non-responders and responders, and analysis of baseline osteoclast levels was able to differentiate Dara-naïve patients from those with Dara-refractory disease. This suggests that osteoclasts may contribute to the immunosuppressive TME that inhibits T-cell function as reported previously (Patients in the Dara-containing Cohorts (D1, E1 and F1) demonstrated deep and durable responses, however, patients with Dara-refractory disease did not respond to Dara + Atezo (Cohort D3). Similarly, patients in D2 did not recapitulate the promising responses seen in D1, although differing patient selection criteria may have biased this cohort to older patients and greater frequency of high-risk cytogenetics. Furthermore, baseline CyTOF data revealed that patients in the Dara-refractory cluster had higher numbers of the senescent-type CD57+ T cells, which are known to be unable to inhibit growth of malignant cells and may have negatively affected the immune response to tumor antigens (High-dimensional immune profiling and integrative clustering analysis of baseline and on-treatment samples revealed novel associations with outcome in both Dara-naïve and Dara-refractory R/R MM treated with Atezo+Dara. Pairwise analysis comparing matched treatment samples to baseline identified potential biomarkers, such as NKG2D and T cell activation/exhaustion genes, that were differentially expressed across patient subgroups. Similarly, the one-vs-all comparisons of the hallmark gene sets in the CD138–negative gene expression data layer revealed that cluster 1 is enriched for the T cell gamma delta gene signature and the T effector 6 gene signature. This is in line with previous studies, in which these gene signatures have been associated with response to cancer immunotherapy treatment (Given the complexity of the immune response to cancer and the proliferation of immunotherapeutic strategies in MM, it is critical to identify predictive and prognostic biomarkers to guide treatment. High-dimensional single-cell and whole transcriptomic approaches profiling the tumor and the microenvironment as applied in this study are being more readily applied clinically (