Newly Diagnosed High-Risk Multiple Myeloma: Outcomes and Management

No survival improvement in patients with high-risk multiple myeloma harbouring del(17p) and/or t(4;14) over the two past decades.

Outcomes of Autologous Stem Cell Transplantation in Patients with Ultra-High-Risk Multiple Myeloma

CARTITUDE-2: Efficacy and Safety of Ciltacabtagene Autoleucel, a B-Cell Maturation Antigen (BCMA)-Directed Chimeric Antigen Receptor T-Cell Therapy, in Patients with Multiple Myeloma and Early Relapse after Initial Therapy

Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector.

BMS-986393 (CC-95266), a G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D)-Targeted Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from a Phase 1 Study

Advancing CAR T-Cell Care in Relapsed/Refractory Multiple Myeloma: Insights from a Collaborative Quality Improvement Initiative

Infectious Complications during Treatment with Commercial CAR T-Cell Therapy and Bispecific Antibodies for Relapsed/Refractory Multiple Myeloma

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for relapsed or refractory multiple myeloma (RRMM), with high response rates of 80–95%. Serum immunoglobulin changes have been observed throughout conventional multiple myeloma treatment, including after immunomodulatory drugs, proteasome inhibitors, and autologous stem cell transplantation. However, the clinical significance of new abnormal protein bands (APBs) following CAR T-cell therapy is largely unexplored. We retrospectively analyzed consecutive multiple myeloma (MM) patients who received CAR T-cell therapy at the University Hospital Bern between May 2021 and February 2024. Serum paraprotein (M-protein) patterns were assessed using immuno-fixation electrophoresis (IFE) before and after CAR T-cell treatment. Patients were grouped based on serum immunoglobulin changes. Among 46 patients, 9 (19.6%) developed new APBs following CAR T-cell therapy. No significant differences in overall survival (OS) or progression-free survival (PFS) were observed between patients with and without APBs. Immunoglobulin changes occurred in both relapsed and non-relapsed patients, suggesting that the appearance of new APBs does not indicate disease progression. This observation aligns with previous reports of paraprotein changes following conventional MM therapies. This report suggests that new APBs following CAR T-cell therapy are a relatively common finding but do not correlate with inferior clinical outcomes. Our results highlight the need for larger, multi-center studies to further investigate this phenomenon in MM patients undergoing CAR T-cell therapy.

B-cell maturation antigen chimeric antigen receptor T-cell re-expansion in a patient with myeloma following salvage programmed cell death protein 1 inhibitor-based combination therapy.

Predictive role of sustained imaging MRD negativity assessed by diffusion-weighted whole-body MRI in multiple myeloma.

B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy has demonstrated promising therapeutic efficacy in relapsed or refractory (R/R) multiple myeloma. However, distinct CAR T-cell constructs exhibit varying therapeutic outcomes. As the antigen-recognition domain, nanobodies offer a small, stable, single-domain structure with enhanced affinity and specificity compared with conventional single-chain variable fragments. We explored the use of nanobody-based BCMA(S103) CAR T-cell therapy for R/R plasma cell myeloma. The CAR construct incorporates dual-nanobody variable domain of the heavy chain of heavy chain antibody (VHHs) targeting BCMA. A cohort of 27 patients was treated with S103 CAR T-cell therapy, which included 4 patients of plasma cell leukemia, and 1 patient of anaplastic plasma cell myeloma. Eleven patients had multiple extramedullary lesions, and 11 patients exhibited high-risk genetic abnormalities, including 4 with TP53 mutations. One month after CAR T-cell infusion, the overall response rate (ORR) was 96.3% (26/27), with a complete response (CR) + very good partial response (VGPR) rate of 59.2% (16/27). At the 3-month follow-up, the ORR increased to 100% (27/27), with a CR + VGPR rate of 81.5% (22/27). The median duration of remission was 11 months (range, 2-36 months). The 1-year overall survival rate was 61.1%, and progression-free survival was 57.2%. In conclusion, BCMA CAR T-cell therapy, utilizing dual-nanobody VHHs targeting BCMA, demonstrates a high ORR and manageable safety profile in treating patients with R/R plasmacytic myeloma, including those with high-risk features such as extramedullary lesions, high-risk cytogenetic abnormalities, plasma cell leukemia, or anaplastic plasmacytoma. This trial was registered at www.ClinicalTrials.gov as #NCT04447573.

Challenges facing CAR T-cell immunotherapy in multiple myeloma.

Successful Development of an Outpatient Chimeric Antigen Receptor (CAR) T Cell Therapy Program

Extramedullary disease (EMD) in multiple myeloma (MM) represents a distinct clinical entity associated with poor prognosis, therapeutic resistance, and aggressive behavior. EMD can occur at diagnosis or during relapses, either contiguous with bone lesions or as soft tissue plasmacytomas due to hematogenous spread. This review outlines the current understanding of EMD pathophysiology, diagnostic challenges, and therapeutic approaches. The review differentiates between bone-related and non-bone-related EMD, highlighting their prognostic implications. Diagnostic strategies rely on advanced imaging modalities, including PET-CT and MRI, and require histopathological confirmation through biopsy and immunohistochemistry. Management includes local therapies, primarily radiotherapy and, in selected cases, surgery, alongside systemic treatments involving proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. New emerging therapies, such as chimeric antigen receptor T cells (CAR-T) and bispecific antibodies, are under evaluation for the treatment of relapsed/refractory EMD. Autologous stem cell transplantation is recommended for eligible patients, with tandem procedures considered in high-risk cases. The role of minimal residual disease (MRD) monitoring is emphasized, employing next-generation sequencing (NGS), flow cytometry, and imaging, with MRD negativity serving as a surrogate marker for treatment efficacy and survival prediction. Despite therapeutic advances, the prognosis for patients with EMD remains unfavorable. The review underscores the necessity of a multidisciplinary approach for accurate diagnosis, individualized treatment, and consistent monitoring. Recognizing EMD as a high-risk MM variant mandates the integration of novel diagnostics and therapies. Future clinical trials must incorporate EMD-specific endpoints to optimize treatment and improve outcomes.

Safety and Efficacy Outcomes for Patients with High-Risk Multiple Myeloma Receiving Idecabtagene Vicleucel: The MD Anderson Experience