Investigation of the effects of CXCR1/2 inhibition on the immune microenvironment of patients with multiple myeloma

Summary Multiple Myeloma (MM) is the second most common hematologic malignancy and is considered incurable for most patients. There has been significant improvement in MM patient survival, mainly due to the use of novel treatments including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), monoclonal antibodies (mabs), bispecific antibodies and cellular therapies. However, many of these treatments heavily rely on a healthy patient immune system to fully leverage their efficacy. Unfortunately, prior studies have shown that the phenotype and function of immune cells in the BM tumor microenvironment (TME) in MM is dysregulated. The accumulation of pathological myeloid cells has emerged as a major mechanism by which tumors evade anti- tumor immunity and are a primary obstacle to develop efficient cancer immunotherapies. To characterize the phenotype and transcriptional changes in myeloid cells in tumor, we used single-cell transcriptomics to dissect the differences between the myeloid cell populations in the BM and osteolytic lesions (OL) TME of MM patients (N = 13) and compared them with myeloid ME of BM of healthy controls (HDBM) (N = 3). OL are an aggressive manifestation of MM and can lead to pathologic fractures. We discovered a significant accumulation of CXCR2 positive myeloid cells in BM and OL of MM patients but not HDBM. Using murine preclinical models of MM, we found that targeting CXCR2 positive cells using anti-CXCR2 drugs alone or in combination with standard treatment (bortezomib plus dexamethasone) significantly increased the overall survival in tumor bearing mice. CXCR2 inhibitors are safe, effective, and commercially available (the CXCR1/CXCR2 inhibitor (SX-682) used in this trial is provided by Syntrix Pharmaceuticals). The goal of the clinical trial from which the samples for this correlative study are obtained is to explore safety and tolerability of CXCR2 blockade as a novel, yet practical approach that effectively mitigates myeloid cell dysregulation in MM patients to boost the response to standard treatments in a phase I clinical trial with two specific aims: Aim1) Evaluate the effect of SX-682 on the spatial architecture of the TME in MM on bone marrow samples at baseline and after 6 cycles of treatment. Aim 2) Evaluate the immunomodulatory effect of SX-682 on the BM TME and peripheral blood (PB).