Derman, Benjamin A.

This guideline has been updated. This ASCO Living Guideline is reviewed on an eight-week cycle. Please see the online dynamic version for the latest updates. Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix I and Appendix II). Updates are published regularly and can be found on the ASCO Publications website .

This guideline has been updated. This ASCO Living Guideline is reviewed on an eight-week cycle. Please see the online dynamic version for the latest updates. Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information ( Appendix 1 and Appendix 2 ). Updates are published regularly and can be found on the ASCO Publications website .

Extramedullary presentations of multiple myeloma (MM) involving the central nervous system (CNS) carry a dismal prognosis. Although historically rare, management of extramedullary disease—including CNS manifestations—has become increasingly clinically relevant as advances in systemic therapies have prolonged control of medullary disease. CNS manifestations may occur across a variety of clinical settings and at different time points throughout the disease course. Common symptoms include visual changes, headaches, loss of sensation, confusion, and seizures. MRI identifies leptomeningeal enhancement and/or parenchymal lesions in approximately 90% of cases, and lumbar puncture with cerebrospinal fluid testing for clonal plasma cell populations is confirmatory. Encouragingly, the incorporation of novel therapeutic agents has improved historically poor outcomes in CNS MM. Novel immunotherapeutic approaches using CAR T-cell therapy and bispecific T-cell–engaging antibodies have recently demonstrated significant efficacy in consolidating responses. Multimodality treatment strategies incorporating intrathecal chemotherapy, systemic novel agents, radiation therapy, and immunotherapy hold promise for achieving more durable responses in this devastating manifestation of MM.

Abstract Chimeric antigen receptor (CAR) T-cell therapy enriched for a memory-like phenotype may persist and function longer than a nonenriched product, thereby improving duration of response (DOR). We conducted a phase I study with bb21217 (NCT03274219), an anti–B-cell maturation antigen CAR T-cell therapy manufactured in the presence of the phosphoinositide 3-kinase inhibitor bb007 to enrich for T cells with a memory-like phenotype, in patients with relapsed/refractory multiple myeloma (N = 72). No new safety concerns were raised with bb21217 therapy (three cases each of grade ≥3 cytokine release syndrome and grade ≥3 neurotoxicity were observed). The objective response rate was 69.4% and the median DOR was 23.8 (95% confidence interval, 16.8–34.8) months. Analysis of the drug product established an association between early memory phenotype and robust expansion and depth of response. Examination of baseline characteristics indicated that tumor burden and prior therapies influenced DOR. The data indicate that generation of CAR T cells early in a disease course when tumor burden is lower and source material exhibits a more naïve phenotype may maximize the clinical benefit potential of the drug product.

The treatment landscape for multiple myeloma (MM) is evolving rapidly and includes several new options. The management must be tailored to the individual. The NCCN Guidelines for MM provide a framework to base decisions regarding diagnosis, workup, treatment, and follow-up of both newly diagnosed and previously treated relapsed/refractory MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to newly diagnosed MM (NDMM).

This guideline has been updated. This ASCO Living Guideline is reviewed on an eight-week cycle. Please see the online dynamic version for the latest updates. ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature, and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and Appendix 2 (online only) for more . PURPOSE To provide updated guidance regarding the therapy for multiple myeloma. METHODS ASCO and Ontario Health (Cancer Care Ontario) convened a joint Expert Panel and conducted an updated systematic review of the literature. RESULTS The updated review identified a total of 161 relevant randomized trials. UPDATED RECOMMENDATIONS Daratumumab therapy may be offered to patients with high-risk smoldering myeloma. Quadruplet therapy with daratumumab or isatuximab, combined with bortezomib, lenalidomide, and dexamethasone, should be offered as initial therapy for transplant eligible patients. They should also be offered at least lenalidomide maintenance, with or without daratumumab, carfilzomib, and/or dexamethasone. Quadruplet therapy with daratumumab or isatuximab, combined with bortezomib, lenalidomide, and dexamethasone, should be offered as therapy for suitable transplant-ineligible patients. Patients with relapsed or refractory multiple myeloma should be offered triplet therapy or T-cell redirecting therapies according to a set of recommended principles. Additional information is available at www.asco.org/hematologic-malignancies-guidelines .

The NCCN Guidelines for Multiple Myeloma (MM) provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with MM. These NCCN Guidelines Insights highlight the important updates and changes specific to systemic therapy for patients with newly diagnosed as well as previously treated MM included in Version 1.2025 of the NCCN Guidelines for MM.

Abstract Introduction: The success of CAR-T in multiple myeloma suggests potential in other challenging plasma cell disorders like systemic AL amyloidosis (AL) and plasma cell leukemia (PCL). CAR-T experience in these indications is limited by the rarity of these diseases. Methods: A systematic review examined publications and clinical trials from 2014 to 2024 to gauge clinical outcomes and safety of CAR-T in AL and PCL. Studies of plasma cell-directed CAR-T with safety and efficacy outcomes were included. Results: We identified a total of 21 AL patients from 6 publications and 23 PCL patients from 5 publications. All patients were treated with anti-BCMA CAR-T; 9 different products were administered. Among AL patients, 12 had cardiac amyloidosis, and 6 had at least stage 3. At a median follow-up of 9 months (2.5-26.4), 16 of 21 AL patients (76%) had a response of VGPR or better: 2 had MRD-negative sCR with organ response, 8 CR, 6 VGPR, 1 PR, and 3 not evaluable. From a safety standpoint, CRS occurred in 71%, with 57% experiencing grades 1-2 and 14% grade 3. ICANS occurred in 2 patients (10%): one grade 1, one grade unknown. Of 11 patients treated with HBI0101, 5 patients died of cardiac disease within 1 year of CAR-T (3 PD, 1 VGPR, 1 PR). Hematologic events were common, with neutropenia in 76% (52% grades 3-4), anemia in 38% (19% grade 2-3, 5% grade 1), and thrombocytopenia in 24% (10% grade 2, 5% grade 3, and one grade 4 worsening thrombocytopenia). Infections were also seen, including BK virus hemorrhagic cystitis, SARS-CoV-2 pneumonia, severe respiratory infection, respiratory viral infection, and sepsis, each affecting 5-14%. A review of CAR-T in PCL included 6 patients with primary PCL and 17 with secondary PCL, with a median of 4.5 (range: 0-15) prior lines of therapy. Overall response at a median follow-up of 6.5 (range: 0-15) months was 17/23 (78%): 2 patients with sCR, 2 CR, 7 VGPR, and 7 PR. Adverse events were only described in 20 of the 23 PCL patients. CRS was frequent, with any grade CRS occurring in 18 of 20 (90%); CRS grade was only reported in 10 (4 grade 1, 3 grade 2, 1 grade 3, 2 grade 4, 8 grade unknown). ICANS grade 1 was reported in 4 patients (20%), and infection (any grade) in 8 (40%). Hematologic events of any grade were frequent: neutropenia in 90% of patients (35% grade ≥ 3), anemia in 80% (40% grade ≥ 3), and thrombocytopenia in 70% (40% grade ≥ 3). Three deaths were reported, two due to infection (pneumonia and pulmonary aspergillosis) and one due to GI hemorrhage. Conclusions: BCMA-directed CAR-T has been used in AL and PCL with encouraging responses, though the durability of these responses is unknown. Our review suggests that CAR-T may be safe in AL in patients without significant cardiac disease. Patients with PCL may be at an increased risk of serious adverse events, especially in the setting of active progressive disease. Careful patient selection and potential dose adjustment may be warranted in these orphan indications. Citation Format: Heather T. Morgan, Benjamin Derman, Hong Ma, Shaji K. Kumar. CAR-T in high-risk plasma cell dyscrasias: A systematic review of AL amyloidosis and plasma cell leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3180.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.