Introduction
tumor, MM, malignancy, authorshipMultiple myeloma, deaths
TUMOR, ADVERSE EVENTS, DISEASE, MULTIPLE MYELOMA (MM), RESIDUAL DISEASE, MYELOMA
Edited by: Arne Östman, Karolinska Institutet (KI), SwedenReviewed by: Patrizia Leone, University of Bari Aldo Moro, Italy; Maximilian Merz, Leipzig University, Germany†These authors share first authorshipMultiple myeloma (MM) remains incurable, and treatment of relapsed/refractory (R/R) disease is challenging. There is an unmet need for more targeted therapies in this setting; deep cellular and molecular phenotyping of the tumor and microenvironment in MM could help guide such therapies. This phase 1b study (NCT02431208) evaluated the safety and efficacy of the anti-programmed death-ligand 1 monoclonal antibody atezolizumab (Atezo) alone or in combination with the standard of care (SoC) treatments lenalidomide (Len) or pomalidomide (Pom) and/or daratumumab (Dara) in patients with R/R MM. Study endpoints included incidence of adverse events (AEs) and overall response rate (ORR). A novel unsupervised integrative multi-omic analysis was performed using RNA sequencing, mass cytometry immunophenotyping, and proteomic profiling of baseline and on-treatment bone marrow samples from patients receiving Atezo monotherapy or Atezo+Dara. A similarity network fusion (SNF) algorithm was applied to preprocessed data. Eighty-five patients were enrolled. Treatment-emergent deaths occurred in 2 patients; both deaths were considered unrelated to study treatment. ORRs ranged from 11.1% (Atezo+Len cohorts, n=18) to 83.3% (Atezo+Dara+Pom cohort, n=6). High-dimensional multi-omic profiling of the tumor microenvironment and integrative SNF analysis revealed novel correlations between cellular and molecular features of the tumor and immune microenvironment, patient selection criteria, and clinical outcome. Atezo monotherapy and SoC combinations were safe in this patient population and demonstrated some evidence of clinical efficacy. Integrative analysis of high dimensional genomics and immune data identified novel clinical correlations that may inform patient selection criteria and outcome assessment in future immunotherapy studies for myeloma.Most patients with multiple myeloma (MM), a bone marrow (BM) malignancy, experience relapse after initial therapy (Programmed death-1 (PD-1) is an inhibitory receptor expressed by regulatory T cells (Treg), B cells and some myeloid cell populations (Daratumumab (Dara) is an anti-CD38 monoclonal antibody with multiple modes of immune activity that is approved as a single agent and in combination with proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) for patients with new and R/R MM (We present data from GO29695 (NCT02431208), an open-label phase 1b study to evaluate the safety and efficacy of Atezo alone or in combination with Len, Dara, Dara and Len, or Dara and Pom in patients with MM who are R/R or post-autologous stem cell transplantation (ASCT) with residual disease (GO29695 