Outcomes of older adults and frail patients receiving idecabtagene vicleucel: a CIBMTR study

TO THE EDITOR:

Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the care of relapsed/refractory multiple myeloma (MM).¹ Idecabtagene vicleucel (ide-cel), a B-cell maturation agent (BCMA) targeting CAR-T product is approved for MM after ≥2 prior lines of therapy based on the phase 3 KarMMa-3 study.² 

Although the pivotal trials that led to ide-cel approval did not incorporate age-based exclusions, older adults were underrepresented in the trial populations.^1,2 In addition, there are limited real-world data on the outcomes of older and frail patients with relapsed/refractory MM receiving anti-BCMA CAR-T therapy.^3-5 Understanding outcomes in this subgroup is critical because the increased frailty and comorbidities seen in these patients increases the risk of treatment-related toxicity.^4,6 In this study, we aim to bridge this knowledge gap by describing the outcomes of older and frail patients receiving ide-cel using data from the Center for International Blood & Marrow Transplant Research.

This is a retrospective study using data from the Center for International Blood & Marrow Transplant Research for US patients who received ide-cel between May 2021 to June 2023 with at least 100 days of follow-up. Older adults were defined as those aged ≥70 years, and frailty was assessed using an adapted version of the simplified frailty index (SFI).⁷ Patients with an adapted SFI score of ≥2 were classified as frail. Details on definitions and statistical methods are included in the supplemental Appendix.

This study was approved by the institutional review board of the National Marrow Donor Program.

Of 821 patients, 251 patients (30.6%) were aged ≥70 years. The median follow-up for the overall population was 11.6 months (range, 1.1-26.7). Baseline characteristics, including performance status, comorbidities, and high-risk disease features, were balanced between the 2 age groups (Table 1).

Cytokine release syndrome (CRS) rates (any grade or grade ≥2) were similar across age groups (supplemental Appendix). However, in a multivariable model studying the impact of age (≥70 years and 60-69 years vs <60 years), age ≥70 years was associated with an increased risk of CRS grade ≥2 (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.12-2.50; P = .0127). Immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade was reported more frequently in patients aged ≥70 years (37.1% vs 24.2%; P < .01), with multivariable analysis showing an increased risk for ICANS in this age group (HR, 2.25; 95% CI, 1.55-3.24; P < .0001). Prolonged cytopenia or clinically significant infections of any grade did not differ by age group.

There were no differences in rates of response (overall response or complete response) at 6 months by age group. Disease relapse at 6 months was 26.6% (95% CI, 21%, 32.7%) and 36.9% (95% CI, 32.8%, 41.1%; P < 0.01) in the ≥70 years and <70 years, respectively (Figure 1A). Treatment-related mortality (TRM) at 6 months was 5.1% (95% CI, 2.6-8.5) vs 2.7% (95% CI, 1.5-4.2; P = .07) (Figure 1B). Progression-free survival (PFS) at 6 months was higher in patients aged ≥70 years (68.3% [95% CI, 61.9-74.3] vs 60.4% [95% CI, 56.2-64.6]; P = .02; see the supplemental Appendix) (Figure 1C). In a multivariable model, age ≥70 years was associated with improved PFS (HR, 0.62; 95% CI, 0.48-0.82; P = .0007). The overall survival (OS) at 6 months was comparable between the age groups, (85.5% [95% CI, 80.5-89.9] vs 82.6% [95% CI, 79.2-85.7], respectively; P = .18) (Figure 1D). Multivariable analysis suggested improved OS in patients aged ≥70 years (HR, 0.63; 95% CI, 0.44-0.89; P = .0095). TRM at 3 months was 2.5% (95% CI, 0.9-4.8) vs 1.6% (95% CI, 0.7-2.8) and at 6 months was 5.1% (95% CI, 2.6-8.5) vs 2.7% (95% CI, 1.5-4.2; P = .07). The most common causes of death are listed in the supplemental Appendix. A multivariable regression analysis to assess factors associated with efficacy outcomes within the age ≥70 years cohort (n = 251) are listed in the supplemental Appendix.

Frailty score could be calculated in 766 patients (93.3%), and 343 patients (44.8%) were identified as frail (supplemental Appendix). Among patients aged ≥80 years, frailty was not attributed due to age alone, with Eastern Cooperative Oncology Group performance score and HCT-CI contributing to the scores. There were no significant differences in rates of CRS (any grade or grade ≥3) between frail and nonfrail patients. Frail patients had increased rates of ICANS (any grade, 37% vs 21.5%; P < .01) and clinically significant infections (49.6% vs 40.9%; P = .02). There were no differences in response (overall or complete response), PFS, or OS at 6 months between the 2 groups. The TRM at 6 months was 5.3% (95% CI, 3.0-8.1) vs 1.9% (95% CI, 0.7- 3.5) in frail vs nonfrail patients, respectively (P = .40). Overall, there were 98 deaths in the frail group and 113 deaths in the nonfrail group. In the frail group, CRS and ICANS contributed to death in 3% and 1% of patients, respectively. Among nonfrail patients, CRS contributed to 1 death (0.9%), and no deaths were attributed to ICANS. In both frail and nonfrail patients, disease progression was the most common cause of death.

In summary, these findings provide clinically actionable information that can guide the management and counselling of older and frail patients planned to receive ide-cel in a real-world setting. In the pivotal KarMMa study, there were only 20 patients aged >70 years.⁸ In a subgroup analysis, these patients had comparable efficacy and numerically higher rates of ICANS (30%) than the overall population (18%).⁸ Comparable with these results, we found higher rates of ICANS (any grade) in patients aged ≥70 years (37%) and noted that age (≥70 years) was associated with an increased risk of CRS grade ≥2 and ICANS (any grade) in a multivariable model. Previous studies examining the association of age with immune-mediated toxicities in patients receiving CAR-T therapy for MM have demonstrated mixed results, with a meta-analysis of studies involving anti-BCMA CAR-T therapy demonstrating a higher rate of ICANS in older patients.^3,9 The exact etiology for this increased risk is unclear, and we were unable to identify risk factors for increased grade ≥2 CRS or ICANS among older patients.

In this study, we noted decreased relapse and improved survival in the older adult subgroup. Although these findings might represent an unmeasured selection bias, the effect of age was independent of known disease risk factors. The possibility that there is an underlying immune-mediated mechanism for these improved outcomes in older patients cannot be excluded. We did not find significantly increased risk for TRM in older patients, highlighting that chronological age should not be the sole criterion to determine eligibility for ide-cel therapy.

Although these findings are reassuring, it is important to recognize that older adults are heterogenous in frailty and comorbidity burden.^10-12 Validated frailty assessment tools such as the SFI integrate assessments of multiple geriatric domains to identify frail patients.^13-15 We found increased rates of ICANS and infections in frail patients, but there were no significant differences in CRS, PFS, or OS. In fact, to our knowledge, for the first time, patients identified as frail using the SFI were found to have outcomes comparable to their nonfrail counterparts.^14,16 It is important to highlight that although TRM was not significantly different, more frail patients died from CRS/ICANS (n = 4) than nonfrail patients (n = 1).

There are several limitations to this study. Data on prior therapy including bridging strategies were incomplete for some patients. Similarly, response assessments and other outcomes were not available for all patients. In addition, frailty assessments were based on physician assessment of performance status, which is subject to bias.

Despite these limitations, this study fills a critical knowledge gap. To the best of our knowledge, this is the largest reported data set of older adults treated with anti-BCMA CAR-T, and these findings provide reassurance that older adults treated with ide-cel, including frail patients, experience efficacy comparable to younger patients. Although higher rates of ICANS were observed, there was no increase in TRM. Disease progression remains the most common cause of death in all patient subgroups.

Acknowledgments: Center for International Blood & Marrow Transplant Research is supported primarily by the Public Health Service (U24CA076518) from the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute, and the National Institute of Allergy and Infectious Diseases; Cellular Immunotherapy Data Resource (CIDR-NCI, U24CA233032); 75R60222C00011 from the Health Resources and Services Administration; and N00014-23-1-2057 and N00014-24-1-2057 from the Office of Naval Research. Support is also provided by the Medical College of Wisconsin, National Marrow Donor Program, Gateway for Cancer Research, Pediatric Transplantation and Cellular Therapy Consortium, and from the following commercial entities: AbbVie; Actinium Pharmaceuticals; Adaptive Biotechnologies Corporation; ADC Therapeutics; Adienne SA; Alexion; AlloVir, Inc; Amgen; Astellas Pharma US; AstraZeneca; Atara Biotherapeutics; BeiGene; BioLineRx; Blue Spark Technologies; bluebird bio; Blueprint Medicines; Bristol Myers Squibb; CareDx; CSL Behring; CytoSen Therapeutics; DKMS; Elevance Health; Eurofins Viracor, DBA Eurofins Transplant Diagnostics; Gamida-Cell, Ltd; Gift of Life Biologics; Gift of Life Marrow Registry; GlaxoSmithKline; HistoGenetics; Incyte Corporation; Iovance; Janssen Research & Development, LLC; Janssen/Johnson & Johnson; Jasper Therapeutics; Jazz Pharmaceuticals, Inc; Karius; Kashi Clinical Laboratories; Kiadis Pharma; Kite, a Gilead company; Kyowa Kirin; LAB; Legend Biotech; Mallinckrodt Pharmaceuticals; Med Learning Group; medac GmbH; Merck & Co; Mesoblast; Millennium, Takeda Oncology Co; Miller Pharmacal Group, Inc; Miltenyi Biotec.; MorphoSys; MSA-EDITLife; Neovii Pharmaceuticals AG; Novartis Pharmaceuticals Corporation; Omeros Corporation; Optum Health; Orca Biosystems, Inc; OriGen BioMedical; Ossium Health, Inc; Pfizer; Pharmacyclics, LLC, an AbbVie company; PPD Development, LP; REGiMMUNE; Registry Partners; Rigel Pharmaceuticals; Sanofi; Sarah Cannon; Seagen Inc; Sobi; Stemcell Technologies; Stemline Technologies; STEMSOFT; Takeda Pharmaceuticals; Talaris Therapeutics; Vertex Pharmaceuticals; Vor Biopharma Inc; and Xenikos BV.

This study was funded by Bristol Myers Squibb.

Contribution: O.S.A., C.L.F., and M.C.P. designed the study; T.O., R.B., and M.B. analyzed the data; O.S.A., C.L.F., and M.C.P. wrote the first draft of the manuscript; and all authors reviewed the manuscript and provided feedback.

Conflict-of-interest disclosure: O.S.A. reports an advisory board role with Sanofi. A.A. reports research funding from AbbVie, Adaptive Biotech, and K36 Therapeutics, and advisory roles with Karyopharm, Bristol Myers Squibb, Sanofi, and Janssen. H.H. reports consulting/advisory board activity with Janssen, Amgen, GlaxoSmithKline, and Karyopharm. S.S. reports research funding from Bristol Myers Squibb, Allogene, Janssen, and Novartis, and consultancy fees from Bristol Myers Squibb, Janssen, Sanofi, Oncopeptides, Takeda, Regeneron, AbbVie, Pfizer, BioLineRx, and Legend. N.A. reports consultancy and institutional research funding from Kite/Gilead, and advisory board fees from Bristol Myers Squibb, Legend Biotech, Kite/Gilead, and Janssen. D.H. reports research funding from Bristol Myers Squibb, Karyopharm, and Adaptive Biotech, and consulting or advisory role for Bristol Myers Squibb, Janssen, Legend Biotech, Pfizer, and Karyopharm. C.F. reports consulting/advisory board activity with Janssen and stock ownership of Affimed. D.D. reports employment with Bristol Myers Squibb, along with stock/equity ownership. M.H. reports employment with Bristol Myers Squibb, along with stock/equity ownership. A.K. reports holding Bristol Myers Squibb stock. A.-S.M. reports consulting or advisory role for Bristol Myers Squibb. P.P. reports employment with Bristol Myers Squibb, along with stock/equity ownership. M.Q. reports research funding from Johnson & Johnson, Angiocrine, and Sanofi, and advisory board fees from Sanofi. K.P. reports consulting/advisory board activity with Bristol Myers Squibb, Janssen, Legend Biotech, Kite, Oricel, Novartis, Caribou Sciences, Pfizer, AbbVie, Genentech, Sanofi, AstraZeneca, and Takeda. T.N. reports clinical trial support from Novartis to the institution and clinical trial support (drug only supply) by Karyopharm to the institution. S.G. reports ad board fees from Bristol Myers Squibb, Sanofi Genzyme, Kite Pharma, and AstraZeneca. L.D.A. Jr reports consulting/advisory board activity with Janssen, Celgene, Bristol Myers Squibb, Amgen, GlaxoSmithKline, AbbVie, BeiGene, Cellectar, Sanofi, and Prothena, and research funding from Bristol Myers Squibb, Janssen, GlaxoSmithKline, and AbbVie. S.U. reports research funding from Amgen, Array BioPharma, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDx, and Takeda, and consulting fees from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Edo Pharma, Genentech, Gilead, GlaxoSmithKline, Janssen, Oncopeptides, Sanofi, Seattle Genetics, SecuraBio, SkylineDx, Takeda, and TeneoBio. C.L.F. reports honoraria/consulting fees from Bristol Myers Squibb, Seattle Genetics, Celgene, AbbVie, Sanofi, Incyte, Amgen, ONK Therapeutics, and Janssen, and research funding from Bristol Myers Squibb, Janssen, and Roche/Genentech. The remaining authors declare no competing financial interests.

Correspondence: Marcelo C. Pasquini, Medical College of Wisconsin, Center for International Blood & Marrow Transplant Research, 9200 West Wisconsin Ave, Suite C5500, Milwaukee, WI 53226; email: mpasquini@mcw.edu.