Anti-FcRL5 CAR-T exhibits anti-MM activity against EMM after progression of anti-BCMA and anti-GPRC5D CAR-T: a case report

TO THE EDITOR:

The prognosis for patients with relapsed and refractory multiple myeloma (RRMM) with extramedullary MM (EMM) is dismal.¹ In a phase 1 trial on idecabtagene vicleucel, the overall response rate (ORR) was 75.8%; median progression-free survival and overall survival were 8.8 and 34.2 months, respectively.² In a phase 2 study on ciltacabtagene autoleucel in China, the ORR was 89.6%; median progression-free survival and overall survival were not reached.³ Previous studies have demonstrated the impressive safety and efficacy of anti–B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapies for patients with RRMM with EMM, with the ORR ranging from 57% to 100%.^4-8 Although effective, most patients are likely to have an eventual relapse. Recently, CAR-T–targeting G protein–coupled receptor class C group 5 member D (GPRC5D) have shown promising efficacy in RRMM, including those who have relapsed from prior anti-BCMA therapies.⁹ Fc receptor-like 5 (FcRL5), also known as FcRH5 or CD307, is specifically expressed on the surface of B-cell lineage.¹⁰ Additionally, FcRL5 is upregulated on malignant plasma cells. At present, FcRL5-directed CAR-Ts have shown anti-MM activity in vitro and in animal studies, but data about its efficacy in the clinical settings are not yet available. Here, we present, to our knowledge, a first-in-human case to show that FcRL5-directed CAR-Ts may exhibit antitumor activity against EMM after progression of both BCMA- and GPRC5D-targeted CAR-T therapies, suggesting that FcRL5-targeted CAR-T might potentially rescue patients experiencing a relapse after prior CAR-T treatment.

The patient is a 66-year-old woman with immunoglobulin G κ MM diagnosed in June 2019, with karyotype of 52,XX,del(1)(p21),+2,+3,+7,+12,-18,+19[1]/46,XX,-11,+mar[1]/46,XX[18] and a gain of 1q21. She was treated in June 2022 on a phase 1 trial of BCMA-targeted CAR-Ts (murine scFv/4-1BB/CD3ζ domains). At enrollment, she had been heavily pretreated with 7 prior lines of therapy and was refractory to proteasome inhibitors (bortezomib and carfilzomib), immunomodulatory drugs (lenalidomide and pomalidomide), and daratumumab. Baseline bone marrow aspirate and biopsy demonstrated no clonal plasma cells, but positron emission tomography–computed tomography scan showed a soft mass in the left neck (Figure 1A-B). Baseline serum M-spike was 2.89 g/L (Figure 1A). In June 2022, she received 2.0 × 10⁶/kg BCMA-targeted CAR-Ts after fludarabine and cyclophosphamide (FC) conditioning and achieved a partial response with the lesion having disappeared on a computed tomography scan performed at another hospital (Figure 1B) and a decrease of M-spike to 1.21 g/L at month 2 after anti-BCMA CAR-T infusion. She underwent a grade 2 cytokine release syndrome (CRS) with fever and hypoxemia on day 6 after CAR-T infusion, which was well controlled by methylprednisolone, 2 doses of tocilizumab, and supportive care. A previous study has reported that combination therapy of CAR-Ts and an anti–PD-1/PD-L1 antibody is commonly used to rescue CAR-T effector functions in clinical trials.¹¹ Afterward, she received maintenance treatment with 2 doses of PD-1 antibody.

However, by month 7, she progressed with a new lesion behind the left ear, with a recurrence of serum M-spike to 1.70 g/L (Figure 1A-B). The bone marrow aspirate was still negative. She received the third dose of PD-1 antibody with a combination of ixazomib to control the EMM, but it failed. Afterward, she was administrated with venetoclax and selinexor. Unfortunately, the lesion was progressively enlarged with M-spike up to 5.22 g/L by month 8. She subsequently enrolled in a clinical trial to receive anti-GPRC5D CAR-T treatment (humanized scFv/4-1BB/CD3ζ domains) in March 2023. She received 3.0 × 10⁶/kg GPRC5D-targeted CAR-Ts after FC conditioning and again achieved a partial response, with the lesion shrinking (Figure 1A-B). She had a grade 1 CRS with fever only and was controlled by nonsteroidal antipyretic. She did not receive any subsequent treatment until October 2023.

She was readmitted to our hospital because of a new lesion in her left temporal region, detected by cranial magnetic resonance imaging (Figure 1B), whereas the lesion behind the left ear disappeared. Serum M-spike was increased to 3.60 g/L (Figure 1A). No clonal plasma cells were observed in the bone marrow aspirate (Figure 1A). Given her multiple recurrences, resistance may occur even when BCMA and GPRC5D are expressed. Therefore, we considered a new target, FcRL5. The structure of FcRL5 is shown in Figure 1C, and the expression of FcRL5 in the extramedullary lesion was confirmed by immunofluorescence (Figure 1D). Afterward, she enrolled in the clinical trial to receive FcRL5-targeted CAR-Ts in October 2023. She received 2.0 × 10⁶/kg FcRL5-targeted CAR-Ts after FC conditioning. She experienced a grade 1 CRS with fever on day 5, and her condition was improved by nonsteroidal antipyretic. In view of her multiple recurrences and the decrease in the CAR-T numbers at day 17, she received a dose of PD-1 antibody to enhance the expansion of CAR-Ts (Figure 1E). By month 4 after FcRL5-targeted CAR-Ts, she achieved a complete response, with the lesion having disappeared and an undetected serum M-spike (Figure 1A-B). She did not receive any subsequent treatment. As of 15 April 2024, serum M-spike was still undetectable, and no other new extramedullary lesions were observed. The results of the blood biochemical examination, as well as the absolute counts of leukocyte and lymphocyte, which may be related to the adverse events of anti-FcRL5 CAR-T, are shown in Figure 1F and supplemental Table 1. Overall, short-term adverse effects associated with anti-FcRL5 CAR-T therapy may be manageable. However, unfortunately, she died of COVID-19 pneumonia 6 months after anti-FcRL5 CAR-T treatment.

This trial was registered at www.chictr.org.cn as ChiCTR2000041025. It was conducted in compliance with the Declaration of Helsinki and with the approval of the ethics committee of Tianjin First Central Hospital. Written informed consent was obtained from the patient and her families for the publication of any potentially identifiable images or data included in this article. Inclusion criteria and exclusion criteria are included in supplemental Table 2. Immunofluorescence assessment for FcRL5 (antibody clone: 509f6) expression was performed as described.¹⁰ 

EMM is an independent prognostic risk factor for patients with RRMM.^12,13 There is no consensus on standardized treatment regimens for EMM. CAR-T therapies have demonstrated efficacy in patients with RRMM with EMM. As of 15 April 2024, we searched the published data on PubMed using the terms “multiple myeloma,” “chimeric antigen receptor,” and “BCMA” or “GPRC5D” or “FcRL5/FcRH5” for clinical studies and summarized the 3 targets including patients with EMM in Table 1.

Previous studies have reported that the ORR of anti-BCMA CAR-T therapy in patients with RRMM with EMM ranged from 57% to 100%.^16-19 However, relapse is common in patients with EMM after anti-BCMA CAR-T infusion.^14,15,20,24 Several studies have shown an exciting efficacy of GPRC5D-targeted CAR-Ts in patients with RRMM, regardless of prior BCMA-targeted immunotherapy.^21-23 For those who progressed from both anti-BCMA and anti-GPRC5D CAR-T therapies, what should be the next step? Clinical data from the first-in-human phase 1 study (GO39775) suggest that cevostamab monotherapy is highly active in heavily pretreated patients with RRMM, with an ORR of 54.5% at the 160-mg dose level.²⁵ FCRL5-targeted antibody-drug conjugates have been proven to be effective in treating MM(10). Yu et al reported that FcRL5-directed CAR-Ts could exhibit anti-MM activity in a preclinical study.¹⁰ However, there are no published data about the anti-MM efficacy of FcRL5-directed CAR-Ts in patients with MM.

To our knowledge, this is the first reported patient who progressed after prior BCMA-targeted and GPRC5D-targeted CAR-T therapies and who subsequently benefited from FcRL5-targeted CAR-T treatment. This case may demonstrate that FcRL5-targeted CAR-Ts could effectively eradicate EMM, and it is possible for short-term adverse effects associated with anti-FcRL5 CAR-T therapy may be manageable. The patient died of COVID-19 pneumonia 6 months after anti-FcRL5 CAR-T therapy while in complete remission. Given the single-patient experience, we are not sure that anti-FcRL5 CAR-T therapy may have contributed to the fatal COVID-19 infection. More patients with EMM should be included in clinical trials of FcRL5-targeted CAR-Ts to evaluate its efficacy and safety, including its impact on conditions such as COVID-19 and any other infection in the future. The use of IV immunoglobulin, vaccines, or antimicrobial prophylaxis may be considered as future directions to minimize the risk of infections.

Acknowledgments: The authors thank diagnostic radiology specialist Yujiao Zhao for her valuable advice in comparing images on the same level as much as possible.

This work is sponsored by Tianjin Health Research Project grant TJWJ2024QN040, Tianjin Natural Science Foundation grant 22JCQNJC00820, and Tianjin Key Medical Discipline (Specialty) Construction Project grant TJYXZDXK-056B.

Contribution: M.Z. designed the research; X.H., X.X., H.L., J.M., X.B., and Y.J. performed the research; X.H., X.Z., Z.Y., and Y.Z. collected and analyzed the data; X.H. wrote the manuscript; M.Z. revised the manuscript; and all authors approved the final version of the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Mingfeng Zhao, Department of Hematology, Tianjin First Central Hospital, No. 2 Baoshan West Rd, Xiqing District, Tianjin, 300384 China; email: mingfengzhao@sina.com; and Xia Xiao, Department of Hematology, Tianjin First Central Hospital, No. 2 Baoshan West Rd, Xiqing District, Tianjin, 300384 China; email: xxiiaao@126.com.