Characterizing and Risk Stratifying Musculoskeletal Toxicities after BCMA CAR-T Therapy for Relapsed/Refractory Multiple Myeloma

Introduction: Chimeric antigen receptor-T (CAR-T) cell therapy has revolutionized the treatment landscape in multiple myeloma (MM). Treatment with commercial CAR-T cells targeting B-cell maturation antigen (BCMA) resulted in drastic improvement in response and progression-free survival. However, CAR-T therapy causes a host of toxicities that pose a challenge for clinicians and patients. While potentially fatal adverse effects like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are frequently reported, the prevalence of lower grade toxicities are often overlooked and underreported. Musculoskeletal (MSK) adverse events such as myalgias, bone pain, and joint complications after CAR-T occur in a significant portion of patients and can cause debility and reduction of quality of life—there are no guidelines on treatment and the prevalence and mechanisms remain unknown.

Methods: We reviewed all relapsed/refractory MM patients who received commercial CAR-T [idecabtagene cicleucel (ide-cel) or Ciltacabtagene cutoleucel (cilta-cel)] in our institute from 12/2022 and were at least 3 months post- CAR-T. MSK events that occurred or significantly worsened after CAR-T infusion were extracted from electronic medical records and graded with CTCAE v5.0. Other variables include disease and patient characteristics, cytogenetics, years from the initial diagnosis to CAR-T, prior MM bone involvement, prior lines of treatment, CRS/ICANS events, and infections occurring post- CAR-T. Inflammatory markers (CRP, ESR and ferritin) and blood cell counts were measured at various time-points. Additionally, for patients who participated in our biobanking study, peripheral blood CD3⁺, CD4⁺, CD8⁺ T cells, B cells, NK cells, myeloid-derived suppressor cells (MDSCs), granulocytic-MDSCs, monocytic-MDSCs, and early stage-MDSCs were quantitated by multicolor flow cytometry at the following times: day 0 before CAR-T infusion, day +7 after CAR-T infusion, and every 3-6 months thereafter. T-cell proliferation in response to CD3 and CD28 stimulation and the expression of T-cell checkpoint inhibitory markers (PD-1, PD-L1, LAG3+, TIGIT and TIM3) were measured.

Results: Of 47 patients (median age: 65 years; median time from diagnosis to CAR-T: 7 years; sex: 24 male, 23 female; race: 32 White, 14 Black, and 1 Hispanic) with relapsed/refractory MM who were three months post-BCMA CAR-T therapy, 16 (34%) developed new or worsening MSK adverse events after CAR-T therapy. The median onset of the MSK complaints was 39 days after CAR-T therapy, lasting a median of 69 days. The symptoms included worsening bone pain, myalgias, and joint stiffness, pain and effusion. Two (12.5%), eight (50%), and six (37.5%) patients had grade 1, grade 2, and grade 3 adverse events by CTCAE v5.0 respectively. Management included topicals, over-the-counter medications (NSAIDs, acetaminophen), prednisone, opioids, and physical therapy.

MSK toxicities occur in both ide-cel and cital-cel products and in all age, gender and race groups. Prior lines of treatment, years from initial diagnosis, and MM disease characteristics did not impact the occurrence of MSK events. Moreover, these events did not correlate with history/presence of myeloma bony disease: MSK symptoms can occur in patients who had no MM bony involvement and do not always correspond to the locations of prior bone lesions. Our analysis did not demonstrate a statistical significance between those with MSK symptoms and those without regarding peripheral blood cell counts, inflammatory markers, immune cell subsets (T-cells, B-cells, NK-cells, MDSCs), T-cell proliferation, T-cell inhibitory checkpoints, or occurrence of CRS. There was a negative correlation between ICANS and MSK events: all 16 patients (100%) with MSK events did not have ICANS compared to 71% of patients without MSK events (p value=0.036), suggesting that the mechanisms underlying the MSK toxicities could be different from those driving the development of CRS or ICANS. We are in the process of measuring and comparing plasma soluble BCMA level, IL-6, IL-12, MIP3, TNF and IFN in patients with and without MSK events.

Conclusion: MSK adverse events are common in MM patients receiving CAR-T cell therapy and can lead to significant debility and poor quality of life. Additional larger studies are needed to understand the mechanisms and management of these toxicities.