Sarcopenia Prevalence and Influence on the Development of Toxicity and Length of Stay in Patients with Relapsed and Refractory Myeloma Treated with Commercial Anti-BCMA CART Cells

Background Sarcopenic muscle loss has well-documented adverse impacts on treatment outcomes and mortality across cancer types and is particularly prevalent in patients with multiple myeloma, reported in 54% of newly diagnosed patients (Nandakumar ASCO 2022). Two chimeric antigen receptor T-cell (CAR-T) constructs have been FDA approved for relapsed/refractory multiple myeloma (RRMM) after exposure to at least 4 prior lines of therapy. MM Treatment combinations frequently incorporate high dose dexamethasone, well known to cause muscle atrophy, and patients may be on therapy for many years prior to becoming eligible for commercial products with associated detrimental effects from cumulative toxicities. We sought to determine the prevalence of sarcopenia in a real-world cohort of patients with RRMM presenting for commercial CAR-T.

Methods We identified all patients presenting to our center treated with commercially approved CAR-T with available restaging imaging performed prior to lymphodepleting chemotherapy (LD-chemo). Cross-sectional area (CSA) of skeletal muscle were measured using Sliceomatic software (v6, Tomovision, 2022), abdominal images obtained from low-dose CT of PET/CT scans, standardized to the midpoint of of the L3 vertebrae. CSA was standardized to the square of patient height to compute skeletal muscle index (SMI, cm2/m2). Patients were categorized as sarcopenic according to international gender-specific consensus cutoffs for SMI, male: < 55.4 cm2/m2 and female: < 38.9 cm2/m2 (Mourtzakis et al, 2008) Patients with the following FISH cytogenetics were considered high risk: t(4;14), t(14;16) and deletion 17p/monosomy 17 whereas the remainder were standard risk. All variables were summarized with descriptive statistics, Mann-Whitney U test, students t-test, chi-squared or Fisher's exact were used where appropriate. Analyses were conducted in Stata (16.1, StataCorp LLC, College Station, TX).

Results The cohort consisted of 61 patients, 55 (90%) received ide-cel and 6 (10%) received cilta-cel. Baseline characteristics are summarized in Table 1. Of these 16 (26%) were ≥70 years at the time of treatment and 36 (59%) had co-morbidity index >2 at the time of therapy (Sorror, Blood 2005). All scans were performed a median of 16 days prior to CAR-T administration (range 2-90). Prior to CAR-T administration 47 (77%) of patients met criteria for sarcopenia based on their pre-LD chemo restaging imaging. Male patients were more likely than women to meet criteria for sarcopenia (89% vs 62%, p=0.01) and 31 (50%) met criteria for sarcopenic overweight or obesity. Sarcopenic patients had poorer baseline performance status ECOG >=2 (23% vs 7%, p=0.17), higher baseline ferritin (p=0.08) and higher baseline tumor burden as defined by >50% marrow involvement (40% vs 14%, p=0.08) when compared to non-sarcopenic patients, although not significant at the P=0.05 level. The majority (63%) of sarcopenic patients did not meet criteria for registration trials. No significant relationship was found between the presence of sarcopenia and the development of cytokine release syndrome, but all patients who developed neurotoxicity (any grade) had underlying sarcopenia (any grade ICANS 12/47, 26% vs 0%, p=0.04). A greater proportion of sarcopenic patients had extended lengths of stay >=9 days 51% vs 21%, p=0.05). In total 24/61 (39%) were recommended for post-discharge rehab/physical therapy, of whom the majority (N=20) had baseline sarcopenia. Similarly, 13/61 (21%) required additional supports at home on discharge, N=10 with baseline sarcopenia.

Conclusion Sarcopenia is highly prevalent, found in 77% of patients attending for BCMA-directed CAR-T therapy in the commercial setting. We have shown that analysis of body habitus is straightforward to perform using images acquired as standard and could inform practice. In the real-world setting, sarcopenic patients appear to be at higher risk of developing neurotoxicity, although this merits further investigation. Although high prevalence of sarcopenia in this sample may preclude statistical detection of its adverse clinical impacts, it is clearly a significant clinical issue for patients undergoing complex immunotherapies for MM and warrants further research and intervention. Pre-habilitation strategies may be beneficial while patients are awaiting apheresis availability, or during cell manufacturing.

Jain:Novartis: Consultancy; MyeloidTx: Consultancy; BMS: Consultancy; Incyte: Research Funding; Kite Pharma: Consultancy, Research Funding. Faramand:Novartis: Research Funding; Kite/Gilead: Research Funding. Grajales-Cruz:sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baz:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; karyopharm: Research Funding; celgene: Consultancy, Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; genentech: Membership on an entity's Board of Directors or advisory committees; Shattuck labs: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria; Merck: Research Funding. Blue:Sanofi: Consultancy, Speakers Bureau; Oncopeptides: Honoraria; Jassen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shain:Bristol Myers Squibb (BMS), Janssen, GlaxoSmithKline (GSK), Adaptive, Sanofi, and Takeda, and Amgen: Honoraria; GSK, Janssen and BMS: Membership on an entity's Board of Directors or advisory committees; GSK, BMS, Sanofi, Karyopharm, Takeda, Janssen, Adaptive and Amgen: Speakers Bureau; AbbVie and Karyopharm: Research Funding; Janssen and BMS: Other: PI of clinical trials. Alsina:BMS: Research Funding; BMS, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Sanofi: Speakers Bureau. Locke:Society for Immunotherapy of Cancer: Other: Education or editorial activity; Imedex: Other: Education or editorial activity; Clinical Care Options Oncology: Other: Education or editorial activity; CAREducation: Other: Education or editorial activity; BioPharm Communications: Other: Education or editorial activity; ASH: Other: Education or editorial activity; Leukemia and Lymphoma Society: Research Funding; Aptitude Health: Other: Education or editorial activity; ), National Cancer Institute: Research Funding; CERo Therapeutics: Research Funding; Takeda: Consultancy; Sana: Consultancy; BMS: Research Funding; Daiichi Sankyo: Consultancy; A2: Consultancy; Celgene: Consultancy; Other: Patents & Royalties: patents, royalties, other intellectual property from several patents held by the institution in my name (unlicensed) in the field of cellular immunotherapy.; Wugen: Consultancy; Umoja: Consultancy; Novartis: Consultancy, Research Funding; Legend Biotech: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy; Iovance: Consultancy; GammaDelta Therapeutics: Consultancy; Emerging Therapy Solutions Gerson Lehrman Group: Consultancy; EcoR1: Consultancy; Cowen: Consultancy; Calibr: Consultancy; Cellular Biomedicine Group: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Bluebird Bio: Consultancy, Research Funding; Allogene: Consultancy, Research Funding; Amgen: Consultancy. Hansen:BMS IMW Ide-Cel Academic Advisory Board: Membership on an entity's Board of Directors or advisory committees; OncLive: Honoraria; Survivorship: Honoraria. Freeman:Janssen: Honoraria, Research Funding; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Sanofi: Honoraria; Amgen: Honoraria.