Plasmapheresis facilitates soluble BCMA clearance and contributes to reversing primary resistance to anti-BCMA immunotherapy in multiple myeloma

Abstract Introduction: Despite potent efficacy of bispecific antibodies against the B-cell maturation antigen (BCMA) in multiple myeloma (MM), primary resistance may occur in as many as 40% of patients. Known resistance mechanisms include antigen loss, epigenetic inactivation, T-cell exhaustion, and an immunosuppressive microenvironment. Recent data suggests that elevated plasma levels of soluble BCMA (sBCMA) may additionally hinder antibody binding leading to impaired effector:target (E:T) ratios. Correlative findings from the pivotal MajesTEC-1 trial have led to a proposed baseline threshold for sBCMA of 400 ng/mL to predict responses to BCMA×CD3 bispecific antibodies. Methods and Results: We here report the pilot case of a 67-year-old patient with IgA kappa MM with standard-risk cytogenetics but functional high-risk disease indicated by early relapse ten months after induction and autologous stem cell transplant. The patient received teclistamab as second-line treatment but exhibited no response or cytokine release syndrome (CRS). Baseline sBCMA quantification using a commercially available ELISA revealed markedly elevated levels in peripheral blood (PB, 2267 ng/mL) and bone marrow (BM, 2065 ng/mL). To address hyperviscosity symptoms, a single plasmapheresis session was performed, leading to the removal of 8.5 mg sBCMA from plasma ultrafiltrate. This intervention lowered sBCMA levels by 36.8% in PB and 59.3% in BM, however, both remained above the MajesTEC-1 threshold for clinical response (PB 1433 ng/mL, BM 841 ng/mL), and teclistamab re-exposure immediately after plasmapheresis remained ineffective. Consequently, the patient received debulking chemotherapy (D-P(A)CE), leading to a further drop in PB-sBCMA after 7 (470 ng/mL) and 14 days (176 ng/mL) of therapy. Upon re-exposure to teclistamab, we observed a flare of IL-6, however without overt CRS, and remission deepened over time ultimately resulting in a stringent complete response according to IMWG criteria. Progression occurred after 6.3 months of treatment by paraosseous extramedullary relapse which did not respond to salvage chemotherapy. To recapitulate sBCMA-mediated mechanisms of resistance, we next studied the impact of sBCMA on various anti-BCMA immunotherapies (cilta-cel, in-house BCMA-CAR T, teclistamab, belantamab-mafodotin) using an in vitro firefly luciferase-expressing OPM-2 cell line model. Building on prior data from Lee and colleagues, we demonstrate that stepwise increases in sBCMA (0–1000 nM) in supernatants not only abrogate the cytolytic efficacy of anti-BCMA cellular therapies, but also impair the activity of the T-cell-independent anti-BCMA antibody-drug conjugate belantamab-mafodotin (P < 0.0001). Conclusion: In summary, this data confirms the central role of sBCMA in inducing primary resistance to anti-BCMA immunotherapies in MM. To the best of our knowledge, this is the first report on the feasibility of plasmapheresis as an additional debulking measure to lower sBCMA levels in PB and BM in MM patients with high tumor burden. While chemotherapy may have influenced treatment response in our patient, these findings highlight the importance of personalized sBCMA monitoring and sequential debulking strategies to improve responses in a broader population of MM patients receiving anti-BCMA immunotherapies.