Efficacy and safety of chimeric antigen receptor T-cell therapy for plasma cell leukemia

Plasma cell leukemia (PCL) can be primary or secondary, the latter arising from leukemia transformation of plasma cell myeloma.¹ Chimeric antigen receptor (CAR) T-cell therapy is effective in plasma cell myeloma.^2-4 Because PCL shares the same origin as plasma cell myeloma, we determined whether CAR T-cell therapy might also be effective in PCL. This study complied with the Declaration of Helsinki and Good Clinical Practice guidelines. It was approved by the Institutional Review Board/Ethics Committee, and all patients provided written informed consent.

Subjects were 18-70 years with PCL, according to International Myeloma Working Group (IMWG) criteria, had a Karnofsky performance score (KPS) ≥50, life expectancy >12 weeks and no contraindications to the proposed treatment.⁵ The trial is registered at chictr.org.cn with numbers ChiCTR2100048888 and ChiCTR-OIC-17011272.

Lymphocytes were isolated using a blood cell separator and CD3⁺ T cells were sorted and activated using anti-CD3/ CD28 immunomagnetic beads (CTS™ Dynabeads™ CD3/D28, Gibco, Grand Island, NY, USA). The anti-B-cell maturation antigen (BCMA) and G protein-coupled receptor, class C group 5 member D (GPRC5D)-targeted CAR constructs, consisting of a scFv, CD8α hinge/transmembrane, 4-1BB, and CD3ζ domains, were cloned into lentiviral vectors. While the GPRC5D scFv originated from a phage display library, the BCMA scFv was humanized and linked to an EGFRt reporter via a T2A sequence. For manufacturing, patient-derived CD3⁺ T cells were transduced with the respective lentivirus, and expanded in vitro for subsequent use. Subjects received cyclophosphamide, 750 mg/m² on day -5; fludarabine 30 mg/m²/day on days -5 to -3 and the CAR T-cell infusion on day 0.

Efficacy evaluations included overall response rate, stringent complete response, complete response, very good partial response and partial response based on the IMWG criteria.⁵ Progression-free survival was defined as the interval from CAR T-cell infusion to progression or death from any cause. Survival was defined as the interval from CAR T-cell infusion to death from any cause. Duration of response was defined as the interval from best response to progression or death from any cause. Bone marrow aspirates were analyzed for measurable residual disease using the EuroFlow standardized protocol (sensitivity threshold: 10^-5).⁶

Table 1.Baseline characteristics of the patients (N=11) with plasma cell leukemia.

Adverse events including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded using American Society for Transplantation and Cellular Therapy (ASTCT) criteria and severity scored using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.^7,8

The data cutoff date was March 2025. Eleven subjects were enrolled between June 2020 and March 2025. Four had primary PCL and seven had secondary PCL. There were seven men and the median age was 54 years (interquartile range [IQR], 44-61 years). The subjects had stage II or III disease according to the Revised International Staging System. The median number of prior therapies was 4 (IQR, 2-5). Seven subjects had had a prior autologous hematopoietic cell transplant and one, an allotransplant. None of the enrolled patients had previously received any BCMA-or GPRC5D-targeted therapies, including bispecific T-cell engagers (e.g., bispecific antibodies) or antibody-drug conjugates. Four subjects had soft tissue involvement and five had complex cytogenetic abnormalities defined as ≥3 clonal abnormalities^9,10 (Table 1).

All subjects had CRS, including eight (73%) who had grade 1 and three (27%) who had grade 2 CRS (Table 2). The median duration of CRS was 5 days (IQR, 4-5 days). Management included tocilizumab and corticosteroids. All subjects had transient increases in serum interleukin-6 and ferritin. One subject had grade 2 ICANS. All subjects had grade >2 hematologic adverse events and late immune effector cell-associated hematotoxicity, predominantly grades 1 and 2.¹¹

All subjects responded to the CAR T-cell therapy (Online Supplementary Table S1). The best responses were stringent complete response (N=3), complete response (N=4), very good partial response (N=1) and partial response (N=3) (Figure 1A). Of the five patients with a complex karyotype, four obtained a very good partial response or better. Only one of four patients with soft tissue involvement achieved a complete response. Two of three subjects with a partial response had soft tissue involvement. All subjects had a bone marrow negative measurable residual disease test by day 28. The failure to attain a stringent complete response despite achieving measurable residual disease negativity might be linked to extramedullary disease or specific genetic profiles (Online Supplementary Figure S1). The median progression-free survival was 290 days (95% confidence interval [95% CI]: 90 days - not reached, but must exceed 420 days) (Figure 1B). The median survival was 320 days (95% CI: 120 days - not reached, but must exceed 690 days) (Figure 1C). Four patients remained progression-free after CAR T-cell therapy, and seven patients experienced recurrence during the follow-up period. Five of seven subjects who progressed received a second CAR T-cell infusion and all of these achieved a partial response or better, of whom three patients survived over 600 days. (Online Supplementary Table S1).

Our study advances beyond comparative analyses of anti-BCMA CAR T-cell therapy by prospectively evaluating a salvage regimen incorporating both anti-BCMA and anti-GPRC5D CAR T-cell products.¹² Furthermore, it provides pioneering clinical data demonstrating the feasibility and efficacy of this strategy, which involves intentional target switching upon relapse after prior CAR T-cell therapy. Seven subjects died, due to disease progression (N=5), graft-versus-host disease after an allotransplant (N=1), and hemorrhage (N=1; patient 6 died from massive hemoptysis [pulmonary hemorrhage] secondary to severe, grade 4 thrombocytopenia 4 months after the infusion).

Here, we report on a cohort of 11 subjects with advanced primary or secondary PCL who were treated with CAR T-cell therapy targeting either BCMA or GPRC5D. All patients exhibited a clinical response to treatment, with seven individuals achieving a complete response, underscoring the substantial antitumor activity of CAR T cells in this aggressive hematologic malignancy. Notably, among those patients who experienced disease relapse, five responded favorably to a second CAR T-cell infusion, suggesting that repeated administration may recapture clinical benefit and extend disease control in selected cases. These findings position CAR T-cell therapy as a promising and potentially transformative therapeutic option for PCL, a condition historically associated with limited treatment alternatives and poor outcomes.

This study included patients with both primary PCL and secondary PCL. Despite the limitation of a small sample size, subgroup analysis suggested divergent survival outcomes following CAR T-cell therapy. Patients with primary PCL achieved a median progression-free survival of 345 days, compared to 120 days for those with secondary PCL. Similarly, the median survival was 375 days for patients with primary PCL and 300 days for those with secondary PCL (Online Supplementary Figure S2). These trends are concordant with the established biological heterogeneity and differential clinical prognosis between the two disease subtypes. Although the differences did not reach statistical significance in this limited cohort, they emphasize the necessity of evaluating primary PCL and secondary PCL as distinct entities in future, larger-scale studies to delineate treatment efficacy and prognostic determinants more precisely.

Our data suggest that CAR T cells are a potential therapy for PCL. To our knowledge, only a limited number of similar clinical experiences have been documented in the literature, as referenced in prior reports,^13-15 highlighting the novelty and importance of the present analysis. Nevertheless, our study has several limitations that warrant consideration. First, the small sample size may limit the generalizability of the conclusions and preclude robust subgroup analyses. Second, heterogeneity in patients’ characteristics, and prior treatment histories introduces potential confounding factors. Third, the relatively brief follow-up period restricts the ability to assess long-term efficacy. Therefore, while our results are encouraging, further validation is essential through larger, prospective, and ideally multicenter clinical trials designed to evaluate CAR T-cell therapy in homogeneous PCL populations, with longer follow-up and comprehensive correlative studies to identify predictive biomarkers and optimize treatment strategies.

Table 2.Adverse events.

Figure 1.Clinical outcomes of patients with plasma cell leukemia treated with chimeric antigen receptor T-cell therapy. (A) Response durations following the first chimeric antigen receptor T-cell therapy. Each bar represents one subject in this study. (B, C) Kaplan–Meier estimates of progression-free survival (B) and survival (C). The shaded area indicates the 95% confidence interval. PR: partial response; SD: stable disease; PD: progressive disease; sCR: stringent complete response; CR: complete response; VGPR: very good partial response; CAR: chimeric antigen receptor; PFS: progression-free survival.

Footnotes

• Received January 3, 2026
• Accepted March 11, 2026

Correspondence

*CH, NQ and WW contributed equally as first authors

W. CHEN - feihu0808@163.com

K. ZHAO - kainyzhao@163.com

Disclosures

RPG is a consultant to Antengene Biotech LLC and Shenzen TargetRx; is Medical Director of FFF Enterprises Inc.; is a speaker for Janssen Pharma, BeiGene and Hengrui Pharma; sits on the Board of Directors of the Russian Foundation for Cancer Research Support and is a member of a scientific advisory board for StemRad Ltd. The other authors have no conflicts of interest to disclose.

Contributions

Funding

This study was supported, in part, by Jiangsu Province High-Level Hospital Construction Project (SHJDBF2024210, LCZX202512, GSPJS202417, GSPJS202420, GSPJS202414), the National Natural Science Foundation of China (grant number 82341203), and the National Key Clinical Specialty Construction Program, Medical Research Foundation of Jiangsu Provincial Health Commission (M2024059). RPG receives support from the UK National Institute of Health Research (NIHR).