From March 2nd to 3rd, 2024, the “7th Beijing Thrombosis and Hemostasis Conference and the 5th Beijing Hematologic Malignancies and Immunity Summit Forum,” hosted by the National Clinical Research Center for Blood Diseases at Peking University Institute of Hematology and Chinese Academy of Medical Sciences Peking Union Medical College Hospital, was successfully held in Beijing. Numerous domestic and international hematology experts shared the latest advances in the treatment of leukemia, coagulation diseases, and malignant hematologic disorders through keynote reports, paper discussions, case presentations, and expert symposiums. At the conference, Professor Chengcheng Fu from The First Affiliated Hospital of Soochow University gave an excellent presentation on the topic of “The Current Status and Future Trends of CAR-T Therapy for Multiple Myeloma.” The content was compiled by “Oncology Watch – Hematology News” for the reference of readers.
The Current Status of BCMA CAR-T in the Later-Line Treatment of MM
Chimeric antigen receptor T cells (CAR-T) have become a revolutionary therapy for the treatment of hematologic malignancies, marking a milestone event. B-cell maturation antigen (BCMA) is theoretically expressed in all patients with newly diagnosed (NDMM) or relapsed/refractory multiple myeloma (RRMM) and is a key target in the treatment of MM.
Compared to acute lymphoblastic leukemia (ALL) and non-Hodgkin’s lymphoma (NHL), CAR-T research in MM started relatively late. In March 2021, the U.S. FDA approved Bristol Myers Squibb’s Abecma (idecabtagene vicleucel, Ide-cel) for the treatment of adult patients with RRMM who have received at least four prior therapies. This was the first FDA-approved CAR-T therapy for the treatment of multiple myeloma. Following this, in 2022, the FDA approved JnJ/Legend’s CARVYKTI (ciltacabtagene autoleucel, Cilta-cel) for the treatment of RRMM, with the same indications as Ide-cel. Subsequently, in 2023~2024, two BCMA CAR-T therapies, Equecabtagene Autoleucel and Zevorcabtagene Autoleucel, were approved in China, indicated for adult patients with RRMM after at least three lines of therapy.
So, how effective and safe are the four BCMA CAR-T products that have been approved for the later-line treatment of RRMM? There are relatively clear and objective results in the KarMMa, CARTITUDE-1, LUMMICAR-1 (Phase I/II), and FUMANBA-1 (Phase I/II) studies.
KarMMa Study (idecabtagene vicleucel)
The approval and marketing of Idecabtagene vicleucel was based on the favorable results obtained from the KarMMa study, which is a Phase II, single-arm, multi-center clinical trial. It enrolled 140 patients with RRMM, of which 128 received ide-cel treatment. The median age was 61 years, with 39% having extramedullary disease, 16% in R-ISS stage III, and 35% with high-risk cytogenetics.
With a median follow-up of 13.3 months, the results showed: (1) According to IRC assessment, 94 patients achieved remission after ide-cel treatment, with an objective response rate (ORR) of 73% (95% CI: 66-81%; P < 0.001), including 42 (33%) who achieved complete remission/stringent complete remission (CR/sCR), and 67 (52%) achieved very good partial remission (VGPR) or better. Among the 42 patients who reached CR/sCR, 33 (79%) achieved MRD negativity at the 10-5 level. (2) The overall median progression-free survival (mPFS) was 8.8 months, with the 450×10^6 group having an mPFS of 12.1 months. (3) Adverse events (AEs) associated with ide-cel treatment mainly included neutropenia (91%), anemia (70%), and thrombocytopenia (63%), with 84% experiencing cytokine release syndrome (CRS), 5% at grade 3 or above, 18% experiencing neurotoxicity, and 3% at grade 3, with no events above grade 3.
CARTITUDE-1 Study (Ciltacabtagene Autoleucel)
At the 2023 EHA Congress, Professor Nikhil Munshi and colleagues updated the final follow-up results of the CARTITUDE-1 study, a single-arm, multi-center Phase Ib/II clinical trial that enrolled 97 patients with RRMM who had received at least three prior lines of therapy and were treated with Ciltacabtagene Autoleucel (Cilta-cel). The median age was 61 years, with a median of 6 prior lines of therapy, 19.6% had extramedullary plasmacytomas, and 25% had high-risk cytogenetics, with 88% being triple-class refractory. With a median follow-up of 33.4 months, the results demonstrated: (1) The best response ORR assessed by IRC was 97.9%, with a CR rate of 82.5% and VGPR or better at 94.9%. The median duration of response (DOR) was 33.9 months, median progression-free survival (PFS) was 34.9 months, and median overall survival (OS) has not yet been reached.
LUMMICAR-1 Study (Zevorcabtagene Autoleucel)
The Phase I part of the LUMMICAR-1 study enrolled 14 patients with RRMM (who had received at least one prior treatment with IMiDs and PIs and had progressed after their last treatment) and treated them with Zevorcabtagene Autoleucel cell infusion. The median age was 54 years, with a median of 6 prior treatment regimens, 50% had high-risk cytogenetics, 14.3% had extramedullary disease, and 14.3% were in ISS stage III. With a median follow-up of 37.7 months, the results showed: ORR was 100%, with sCR achieved in 71.4% and ≥CR rate at 78.6%; all patients achieving ≥CR were MRD negative. The overall median PFS was 25 months, with a median PFS of 26.9 months for patients in sCR/CR; the median DOR was 24.1 months; and the median OS had not been reached.
LUMMICAR-1 Phase II Study (Zevorcabtagene Autoleucel)
The Phase II part of the LUMMICAR-1 study enrolled 102 patients with RRMM who had received ≥3 prior lines of therapy (at least one IMiDs and PIs, with disease progression after the last treatment) and were treated with a 1.5×10^8 infusion of Zevorcabtagene Autoleucel. The median age was 59.5 years, with a median of 4 prior lines of therapy, 38.2% in ISS-III, 45.1% with high-risk cytogenetics, 10.8% with extramedullary lesions, 89.2% double-refractory, and 22.5% triple-refractory.
With a median follow-up of 12.6 months, the results indicated: (1) An ORR of 91.7% was evaluated by IRC; the CR/sCR rate was 56.7%; ≥VGPR was 88.3%; both median PFS and DOR have not been reached. (2) Out of the 51 patients who achieved VGPR or better, 92.2% reached MRD negativity, and all 34 patients who achieved a CR or better were MRD negative (10^-5).
FUMANBA-1 Phase I/II Study (Equecabtagene Autoleucel)
In the FUMANBA-1 study, 103 patients with RRMM received Equecabtagene Autoleucel cell infusion. The median age was 58 years, with a median of 4 prior lines of therapy, 18.4% had previous CD38 monoclonal antibody treatment, 48.5% with high-risk cytogenetics, and 9.7% with extramedullary disease. In the Phase II trial of 62 patients with a median follow-up of 8.7 months, the IRC evaluated results showed: the 6-month best response rate was 90.3%, the CR rate was 58.1%, and VGPR or better was 87.1%; median PFS and DOR have not been reached, and median OS has not been reached. 57 patients achieved MRD negativity (91.9%), and all 34 patients who achieved CR or better were MRD negative (10^-5).
Current Status of Early-Line Studies of BCMA CAR-T in MM Treatment
CAR-T has shown encouraging therapeutic activity in RRMM, but relapse remains common, especially in patients with rapidly progressing or advanced MM. Existing data indicates that patients with RRMM who progress after previous BCMA-targeted therapy have a poor prognosis with subsequent CAR-T therapy, making the sequencing of CAR-T with other treatments challenging.
The early-line application of BCMA CAR-T in MM patients is one of the current hot research topics. When applied early, T cells may be healthier, and the invasiveness of myeloma may be lower. There are currently two main clinical trials focusing on early-line research for BCMA CAR-T: the KarMMa-3 study (2-4 lines) and CARTITUDE-4 study (1-3 lines).
KarMMa-3 Study (Early-line application of Idecabtagene Vicleucel)
KarMMa-3 is a Phase III study that enrolled 386 patients with RRMM who had an average of 2-4 prior lines of therapy (including IMiDs, PIs, and daratumumab), and then were randomized in a 2:1 ratio to receive Ide-cel (n=225) or standard therapy (including DPd, DVd, IRd, Kd, and EPd regimens, n=126), with allowance for cross-over between groups. Baseline patient characteristics: median age 63 years, median time since first diagnosis about 4 years, approximately 85% had prior autologous stem cell transplant (ASCT). About 12% were R-ISS III stage, extramedullary disease accounted for 24%, and high-risk cytogenetics around 65%. Updated follow-up results at the 2023 ASH conference showed:
In terms of efficacy: (1) Ide-cel significantly improved median PFS in the ITT population compared to the standard therapy group (13.8 months vs. 4.4 months, p<0.0001), reducing the risk of disease progression and death by 51% compared to the standard group. (2) In the standard group, 56% of patients crossed over to the Ide-cel treatment group, and the median OS for both groups has not been reached, but still, Ide-cel group OS showed improvement (HR=0.83). (3) ITT population: The ORR for the Ide-cel group was 71.3% (CR of 43.7%), compared to 42.4% for the standard group (CR of 5.3%).
Regarding safety: (1) For Ide-cel versus standard therapy, severe adverse events (SAEs) were 47% and 41%, respectively. Deaths due to disease progression were 25% for Ide-cel and 28% for standard therapy. Any grade cytokine release syndrome (CRS) occurred in 88% of the Ide-cel group, with grade 3 or higher CRS at 4%; neurotoxicity occurred in 15%, with grade 3 or higher at 3%; infections were reported in 56%, with grade 3 or higher infections at 22%. (2) In the Ide-cel group, there were two deaths related to secondary malignancies, and no T cell-related secondary malignancies occurred.
CARTITUDE-4 Study (Early-line application of Ciltacabtagene Autoleucel)
At the 2023 ASCO and ASH conferences, Professors Binod Dhakal and M Hasib Sidiqi reported follow-up results of the CARTITUDE-4 study, which compared the efficacy and safety of early-line treatment with Cilta-cel (1-3 lines) versus standard therapy (PVd or DPd regimens) in patients with lenalidomide-refractory MM. At the ASCO conference, with a median follow-up of 15.9 months, the results showed:
In terms of efficacy: (1) Cilta-cel significantly improved median PFS in the ITT population compared to standard therapy (not reached vs. 11.8 months, P<0.0001), reducing the risk of disease progression and death by 74% compared to the standard group. (2) In the ITT population, the ORR for Cilta-cel was 84.6% (CR at 73.1%), compared to 67.3% for the standard group (CR at 21.8%). The MRD negativity rate for the Cilta-cel group was 60.6% in the ITT population, compared to 15.6% for the standard therapy group.
Regarding safety aspects of the CARTITUDE-4 study (Early-line application of Ciltacabtagene Autoleucel), the results presented at the ASH conference demonstrated similar outcomes to those at ASCO, emphasizing common hematologic toxicities and long-term concerns about secondary tumors. The most common CAR-T cell-related toxicity was CRS (any grade 76.1%, grade 3 at 1.1%), with CAR-T cell neurotoxicity occurring in 20.5% of cases (grades 3/4 at 2.8%). The incidence of ICANS was 4.5% (none at grades 3/4); 17% of patients experienced other neurotoxicities (grades 3/4 at 2%), including cranial nerve paralysis in 9.1% (grades 3/4 at 1.1%), peripheral neuropathy in 2.8% (grades 3/4 at 0.6%), and one case of grade 1 MNT.
Development Status of GPRC5D CAR-T
GPRC5D, a member of the GPCRs and an orphan receptor, is expressed only in the immunologically privileged areas of hair follicles under normal conditions but is highly expressed on the surface of multiple myeloma (MM) cells. Recently, targeting GPRC5D with CAR-T has become a hot topic in MM treatment. It’s crucial to establish that GPRC5D expression is independent of BCMA, especially since BCMA-targeted therapies have already been approved and established as a target in MM treatment. Memorial Sloan Kettering Cancer Center conducted immunohistochemical analysis on bone marrow samples from 83 patients with MM, comparing the expression levels of GPRC5D and BCMA in each sample and concluding that GPRC5D expression is independent of BCMA expression.
CC-95266-MM-001 Study (BMS-986393)
The CC-95266-MM-001 study is the first human Phase I clinical trial targeting GPRC5D with CAR-T, enrolling 84 patients with RRMM who had progressed within 12 months after receiving three prior treatment regimens. The dose-escalation phase enrolled 36 patients, while the dose-expansion phase enrolled 48 patients. The Phase II recommended dose of 150×10^6 CAR-T cells enrolled 26 patients, with a median age of 63 years, a median of 5 prior lines of therapy, 40.5% with high-risk cytogenetics, 44% with extramedullary involvement, 73.8% triple-refractory, and 32.6% refractory to five drugs; 20.2% were refractory to BCMA-targeted therapies.
Results indicated: (1) An ORR of 88% for all dose groups that received infusions (CR: 45%), with the RP2D dose group (150×10^6 CAR-T cells) achieving an ORR of 91% (CR: 48%). (2) Among 23 patients in the RP2D dose group, those who had not previously received BCMA-targeted treatment had a response rate of 87%, while those who had previously received BCMA-targeted treatment had a response rate of 100%. The median follow-up was 9 months, with a median DOR of 13 months, and 67% of responding patients maintained response status. 86% of patients evaluable for MRD who achieved CR or better reached MRD negativity. (3) Grade 3 or higher neutropenia occurred in 61.9% of patients, anemia in 29.8%, and thrombocytopenia in 26.2%; the median recovery time for grade 3 or higher hematologic reductions was 46 days. Any grade CRS occurred in 76.2%, with grade 3 or higher at 3.6%, CRS typically onset on day 3, and lasted a median of 4 days; no grade 3 or higher CRS or HLH occurred in the RP2D dose group. Grade 3 or higher ICANS occurred in 2.4% of cases, with no grade 3 or higher ICANS in the RP2D group.
The MCARH109 study is a Phase I clinical trial targeting GPRC5D. It enrolled 17 patients with relapsed/refractory multiple myeloma (RRMM) who had progressed after treatment with three classes of drugs and at least three lines of therapy. The patients were assigned to CAR-T cell doses of 25×10^6, 50×10^6, 150×10^6, and 450×10^6.
Of these patients, the median age was 60 years, the median number of prior lines of therapy was 6, and 77% had high-risk cytogenetics. Extramedullary disease was present in 41% of the patients, and 94% were refractory to three classes of drugs. Fifty-nine percent had previously received BCMA-targeted therapies, and 47% had undergone prior CAR-T therapy.
Cytokine release syndrome (CRS) occurred in 88% of patients, with 6% experiencing grade 3 or higher CRS. One patient (6%) developed ICANS, and 12% had grade 3 or higher infections. Nail changes occurred in 65% of patients, but none were grade 3 or higher. One hundred percent of patients experienced grade 3 or higher neutropenia, and 65% had grade 3 or higher thrombocytopenia.
Future Trends in MM CAR-T Therapy
The future trends in CAR-T therapy for multiple myeloma (MM) can be summarized in the following points:
- Multi-target CAR-T: Currently, BCMA CAR-T is the most established in the MM field. However, as research progresses, other new target CAR-T therapies are emerging, such as dual-target CAR-T therapies targeting both BCMA and CD19, and modular CAR-Ts are beginning to appear in clinical trials.
- Universal CAR-T Entering Clinical Research: Allogene’s universal CAR-T product, ALLO-715, which knocks out the TCR and CD52 genes, has achieved an ORR (Overall Response Rate) of 71% and a CR (Complete Response) of 25% in MM treatments. Additionally, Cellectis’s universal CAR-T product, UCARTCS1A, which knocks out TCR and CS1, has shown an ORR of 40% in treating MM.
- Development of In Vivo CAR-T: In the future, patients may only need an injection with a virus that infects T cells to integrate the genes targeting cancer cells into the T cell genome, thus transforming them in vivo to produce CAR-T cells. Preclinical studies have shown that in vivo CAR-T cells can eliminate B cells in monkeys, and human trials are set to begin.
- Position: Associate Director of Hematology, First Affiliated Hospital of Soochow University; Chief Physician; Associate Professor; Doctoral Supervisor.
- Roles: Vice Chair of the Plasma Cell Group of the Hematology Branch of the Chinese Medical Association, Member of the Multiple Myeloma Expert Committee of the Chinese Medical Doctor Association, Member of the Hematologic Oncology Branch of the Chinese Anti-Cancer Association.
- Additional roles include Committee Member of the Targeted Therapy Committee and Vice Chair and Member of the Plasma Cell Disease Group of the Female Physicians Association.
- Vice Chair of the Plasma Cell Disease Group of the Jiangsu Anti-Cancer Association, Jiangsu Medical Association Hematology Branch, Jiangsu Research Hospitals Association.
- Executive Member of the Hematology Committee of the China Medical Education Association.
- Member of the Asia Pacific Myeloma Network, the International Myeloma Society, and an International Member of ASH (American Society of Hematology).
- Awards: Recipient of the Fifth People’s Famous Doctor Excellence Model, has led projects that won funding from the Jiangsu Health Department, the National Natural Science Foundation of China, and the Jiangsu Natural Science Foundation. Awards include the Second Prize of Chinese Medical Science and Technology, the Second Prize for Scientific and Technological Progress by the Ministry of Education and the Ministry of Science and Technology, the First Prize of Jiangsu Province Science and Technology, and the New Technology Introduction Award.
