Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster I
Methods: All patients were treated with 16 mg/kg DARA and whole blood samples were collected at baseline and after 8 weeks of treatment. Blood samples were processed for serum and stored frozen until batch analysis. Profiling of 1129 serum proteins was performed using the SOMAscan assay. Patients were classified based on overall best response: responders (stringent and complete responses, very good partial and partial responses), stable disease (stable disease or minimal response) and non-responders (progressive disease). Differential level testing included application of the Wilcoxon rank sum test and Limma for responder versus non-responder analysis, and ANOVA for repeated-measures with post-hoc test validation, Wilcoxon signed rank and Friedman tests for baseline versus on-treatment analysis.
Results: In MMY2002 at baseline, 51 proteins were significantly different between responders and non-responders. Many have known associations with MM or CD38, and interestingly a subset is associated with T-cell biology. We recently observed that DARA induces a multi-factorial T-cell response in patients including CD8+ T-cell expansion and activation, and increased clonality. Proteins differentially expressed between responders/non-responders at baseline included tumor necrosis factor subfamily 8 (TNFSF8/CD30L), TNFSF9/CD137L, macrophage stimulating 1 (MST1), interleukin-1B (IL1B), cadherin 1 (CDH1) and cadherin 3 (CDH3).
Protein profiles were evaluated at baseline and at 8 weeks (Cycle 3 Day 1) to study pharmacodynamic changes. Significant treatment-induced changes were identified in 142 proteins. Of particular interest were the 60 proteins that changed differentially over time in responders vs non-responders. Proteins associated with MM tumor load, such as beta-2-microglobulin [B2M], and immunoglobulins decreased in responders and increased in non-responders. Novel MM therapeutic targets such as signaling lymphocyte activation molecule F7 [SLAMF7] (i.e. CS1) and B-cell maturation antigen [BCMA] decreased in responders and increased in non-responders during DARA treatment. Many proteins associated with immune or T-cell response were also significantly changed by DARA treatment, including TNFRSF1B, CD163, TNFRSF25, TLR2, CCL5, IL5RA, FCGR2A, ICOS, Granzyme B, and programmed cell death ligand 1 [PD-L1] many of which were differential between responders and non-responders.
Differential level testing of GEN501 samples identified a small set of proteins that were significantly altered by DARA treatment over time. Many of these proteins overlapped with those identified in the MMY2002 analysis, increasing confidence in the statistical results.
Conclusions: This exploratory serum proteomic analysis identified proteins that were differentially expressed between responders and non-responders at baseline, including proteins associated with immune response and T-cell biology (TNFSF8/CD30L, TNFSF9/CD137L, IL1B). In addition, significant differential changes in protein expression between responders and non-responders after DARA treatment were seen. Many of these are associated with MM tumor load (BCMA, immunoglobulins, SLAMF7, and B2M) and decreased in responders and increased in non-responders. In addition, proteins related to T-cell activity, immune checkpoints and immune response (TNFRSF1B, CD163, TNFRSF25, TLR2, CCL5, IL5RA, FCGR2A, ICOS, Granzyme B, PD-L1) also showed changes associated with DARA treatment, supporting the recent findings that DARA induces a T-cell response in MM patients that may contribute to clinical response.
Disclosures: Casneuf: Janssen: Employment . Lysaght: Immuneering Corp: Employment , Other: Stockholder . LeFave: Immuneering Corp.: Employment . Bald: Janssen: Employment . Weiss: Janssen and Millennium: Consultancy ; Janssen and Onclave: Research Funding . van de Donk: Janssen Pharmaceuticals: Research Funding ; Amgen: Research Funding ; Celgene: Research Funding . Lokhorst: Amgen: Honoraria ; Janssen: Honoraria , Research Funding ; Genmab: Honoraria , Research Funding . Ahmadi: Janssen: Employment .
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