Editor’s Note: From April 14 to 17, 2024, the 50th European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting was grandly held in Glasgow, UK, a city renowned for its historical significance. This year marks the 50th anniversary of EBMT, and the event gathered leading figures in the field of hematopoietic stem cell transplantation and over 6,000 hematology experts from around the world. The attendees reviewed the remarkable achievements in the fields of hematology and bone marrow transplantation over the past 50 years and explored forward-looking patient management strategies. At the conference, chimeric antigen receptor T-cell (CAR-T) therapy, a highlight of this meeting, showcased a series of breakthroughs in the treatment of multiple myeloma and lymphoma, attracting significant attention. This issue features a special invitation to Professor Jun Ma from the Harbin Institute of Hematological Oncology to provide an insightful interpretation of five major research studies in the field of CAR-T cell therapy. Here, we present a compilation of these insights for our readers.
Study Background
CAR-T cell therapy has revolutionized the treatment strategy for relapsed/refractory (r/r) large B-cell lymphoma (LBCL) and multiple myeloma. Key clinical trials and real-world data have shown significant heterogeneity in the toxicity and efficacy of CAR-T cell products. To account for these differences, researchers developed a new composite endpoint of no toxicity and no progression survival, including no severe (≥grade 3) cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hematologic toxicity, no disease progression/stable disease (PD/SD), and no relapse death within 3 months for multiple myeloma (TPFS3) and 6 months for LBCL (TPFS6).
Study Methods
Researchers analyzed 282 r/r LBCL patients treated with axi-cel, tisa-cel, and liso-cel, and 133 r/r multiple myeloma patients treated with ide-cel and cilta-cel. CRS and ICANS were graded according to ASTCT criteria. Hematologic toxicity in multiple myeloma patients was graded according to CTCAE v5.0 and defined as single-lineage or multilineage cytopenias at two (or more) time points, including any ≥grade 2 cytopenias on day 30 post-CAR-T treatment progressing to at least grade 3 by day 60 and/or day 90.
Study Results
Baseline characteristics of the LBCL and multiple myeloma cohorts were summarized, and patients were grouped into those with or without TPFS. In the LBCL cohort, 37% achieved TPFS6 (95% CI: 31%-43%), with no statistical differences among the axi-cel, tisa-cel, or liso-cel treatment groups. Differences between TPFS6 patients and others included gender (male, 51% vs. 65.7%, P=0.014), large mass (8.7% vs. 17.4%, P=0.045), or extranodal involvement (≥2 sites, 30.8% vs. 46.6%, P=0.009), ECOG score (≥2, 7.7% vs. 20.8%, P=0.004), prior autologous transplant (25% vs. 13.5%, P=0.015), C-reactive protein (CRP) (>4 mg/dL, 10.6% vs. 35.4%, P<0.001), ferritin (≥400 ng/mL, 37.5% vs. 62.4%, P<0.001), and lactate dehydrogenase (LDH) at lymphodepletion (LD) (≥225 U/L, 51% vs. 76.4%, P<0.001). In a landmark Cox multivariable analysis of overall survival (OS), adjusting for age (HR=1.24 per 10-year increase, P=0.077), male gender (HR=1.92, P=0.013), ECOG≥2 (HR=2.34, P=0.004), high LDH at LD (HR=2.63, P<0.001), and CAR-T product (tisa-cel vs. axi-cel HR=1.67, P=0.079), TPFS6 was closely associated with a 5.2-fold difference in OS (P<0.001).
In the multiple myeloma cohort, 48% achieved TPFS3 (95% CI: 38%-55%). TPFS3 patients showed lower bone marrow burden at LD (P=0.025), R-ISS stage (revised International Staging System) (I/II vs. III; P=0.015), CRP levels (P=0.019), and ferritin levels (P=0.002) compared to others. There was no significant correlation between treatment with ide-cel (n=109) or cilta-cel (n=24) and TPFS3 (P=0.119). In a 3-month landmark Cox survival analysis, after adjusting for potential confounders (age, gender, CRP, CAR-T product, bone marrow burden, R-ISS stage, extramedullary disease; all P>0.1), TPFS3 was associated with a 6.54-fold better OS (HR=0.15, 95% CI: 0.05-0.52, P=0.003).
Study Conclusion
In this study, the sustained survival rates for patients treated with CAR-T for LBCL and multiple myeloma were 37% and 48%, respectively, without experiencing TPFS-defined events. The analysis indicates that achieving TPFS6 for LBCL patients and TPFS3 for multiple myeloma patients suggests a favorable long-term overall survival (OS). Therefore, disease-specific TPFS may serve as an ideal composite endpoint that balances efficacy and safety in future CAR-T clinical trials aimed at enhancing effectiveness and reducing toxicity.
Expert Commentary
This study established a new composite endpoint of no toxicity and no progression survival, including TPFS3 for multiple myeloma within three months and TPFS6 for LBCL within six months. The study compared significant heterogeneity in the toxicity and efficacy of CAR-T products and analyzed multiple parameters. The LBCL cohort analysis included factors such as gender, large mass or extranodal involvement, ECOG score, prior autologous transplantation, C-reactive protein, ferritin, and lactate dehydrogenase at the time of lymphodepletion. The multiple myeloma cohort analysis included lower bone marrow burden at lymphodepletion, revised International Staging System (R-ISS) stage, C-reactive protein, and ferritin levels. It was concluded that LBCL patients achieving TPFS6 and multiple myeloma patients reaching TPFS3 are indicative of favorable long-term OS. This provides a new composite endpoint for CAR-T clinical trials that consider both safety and efficacy.
