Dual attack on multiple myeloma: targeting BCMA and CD19

Multiple myeloma (MM) is a malignant disorder of plasma cells which comprises 10% of hematological malignancies and 1.8% of all new malignancy diagnoses (1). Approximately 30,000 new cases of myeloma will be diagnosed, and 13,000 deaths will occur every year in the United States (US). The 5-year survival rate for US patients with MM diagnosed from 2010 to 2016 was 53.9% (2). MM is characterized by expansion of neoplastic clones of plasma cells. These plasma cells proliferate within the bone marrow compartment, disrupting hematopoiesis (3). The malignant cells cause destructive lesions throughout the skeleton resulting in fractures and often debilitating pain (3). The goal of initial therapy in MM (also known as induction therapy) is to elicit a swift reduction in tumor burden, stall end-organ damage and preserve organ function, and to achieve deep control of disease. The new standard of care for both transplant-eligible and -ineligible fit patients is a four-drug regimen comprised of a CD38 monoclonal antibody (mAb), proteasome inhibitor (PI), immunomodulatory drug (IMiD), and steroid (4,5). After induction, consolidation with high dose melphalan and autologous hematopoietic cell transplant (AHCT) can be considered for transplant-eligible patients (6,7). Maintenance therapy is offered to all patients to prolong remission and prolong overall survival (OS) (8). However, despite the significant advances made in treatment of MM, patients invariably relapse. This risk is more pronounced for those with high-risk disease (9). This is further compounded by the lack of standardized risk models for defining high-risk disease (10,11).

Chimeric antigen receptors (CARs) are genetically engineered receptors designed towards altering T cell function by enabling specificity to a specific cancer antigen (12). Autologous T cells are obtained from the patient and transduced using inactivated viral vectors. B cell maturation antigen (BMCA) is part of the tumor necrosis factor receptor (TNFR) superfamily. This receptor is expressed predominantly by mature B lymphocytes. BCMA has minimal expression in hematopoietic stem cells or non-hematopoietic cells (13). It is essential for the survival of bone marrow plasma cells (13,14). The two seminal trials that led to the US Food and Drug Administration (FDA) approval of CAR-T cell therapy in MM after four prior lines of therapy were the CARTITUDE-1 (15) and the KarMMA-1 studies (16). Recent phase 3 trials have led to the approval of these therapies in earlier lines with more promising results (17,18). We have summarized salient features of these trials in Table 1.

CD19 antigen is part of the type-I transmembrane glycoprotein of the IgG immunoglobulin superfamily. While MM cells do not express CD19 at high levels, it is expressed on the minor multiple myeloma stem cell (MMSC) subset which is capable of self-renewal and drug resistance (19). Initial study of CD19-targeted CAR-T therapy (CTL019) infusion following AHCT was shown to be effective in RRMM (20). In spite of the impressive responses seen with CAR-T therapy, relapse continues to be a problem in over 50% of the patients (21). Though the exact mechanisms of relapse post CAR-T cell therapy are not clearly known, low persistence of CAR-T cells, antigen escape and tumor microenvironment suppression are some of the factors that could shorten disease response (22). One of the strategies to overcome treatment resistance is to target multiple tumor-associated antigens that could help overcome antigen escape and provide longer immunosurveillance. Several dual and triple CAR-T products are being developed combining BCMA with other antigens such as signaling lymphocytic activation molecule family 7 (SLAMF7), CD38, CD138 and CD56, and currently undergoing investigation.

GC012F is a BCMA/CD19 dual targeting CAR-T manufactured on the Gracell FasTCAR platform. The GC012F CAR consists of the anti-CD19/BCMA FasT CAR-T which was constructed using an FMC63 single-chain variable fragment (scFv) and a BCMA scFv with a loop configuration. The CAR-T includes a CD8 hinge and transmembrane domain, 4-1BB costimulatory domain, and a CD3ζ activation domain. The CARs were transduced to primary T cells using a lentiviral vector. This product was studied in patients with newly diagnosed MM (NDMM) and relapsed/refractory non-Hodgkin’s lymphoma with promising results (20,21,23).

The study by Qiang et al. (24) describes the efficacy and tolerability of GC012F in patients with NDMM. In this phase 1 open-label, single-arm study, the authors enrolled patients with high-risk MM, as defined by several risk factors such as Revised International Staging System (R-ISS) stage II or III at diagnosis, specific high-risk chromosomal abnormalities, elevated serum lactate dehydrogenase (LDH), presence of plasmacytomas, immunoglobulin D (IgD) or immunoglobulin E (IgE) MM and high-risk disease per mSMART stratification 3.0 (25). The median age of the participants was 59 years and 63% of them were male. Of these, 26% had a high tumor burden defined as having 60% or more plasma cells in the bone marrow. Plasmacytomas were present in 63% of the patients and of these, 16% were extra-medullary. High-risk chromosomal abnormalities were seen in nearly half the patients with 37% having amp(1q21), 11% del(17p), 5% t(4;14) and 2 or more high-risk cytogenetics in 5% of the patients enrolled. All patients received at least one cycle of bortezomib, lenalidomide and dexamethasone (VRd) as part of prior therapy. Very good partial response (VGPR) or better was seen in 79% of the patients prior to GC012F and 22% achieved complete response (CR) or better with half of those achieving minimal residual disease (MRD) negativity. The patients then received lymphodepleting chemotherapy with fludarabine and cyclophosphamide, followed by a single infusion of GC012F. There were three different cell doses at 1×10⁵, 2×10⁵ and 3×10⁵ cells.

The primary end points of this study were overall response rate (ORR), progression-free survival (PFS), duration of response (DOR), adverse events (AEs), CR rate and rate of MRD negativity. Key secondary events included OS, time to first response, time to best response and pharmacokinetic biomarkers. This was in keeping with other phase 1 trials conducted in cell therapy and/or MM.

The investigators enrolled 26 patients out of which 22 received GC012F infusion and were included in the safety analysis. The authors noted that 3 patients died during induction therapy, and 1 withdrew consent. At a median follow up of 16 months, 19 patients were evaluable for the efficacy analysis.

The most common adverse events were hematological in nature. Leukopenia was the most common hematological AE (86%) which was grade 3–4 in half the cases. Similarly, 77% developed neutropenia with 41% being grade 3–4 in severity. Anemia and thrombocytopenia were less frequent, observed in 36% and 27% of patients, respectively. The most common non-hematologic AE were hypocalcemia (41%), hypoalbuminemia (41%) and elevated LDH (41%). CRS was observed in 27% of patients with all events being grade 1–2 in severity. The median time to onset of CRS was 7 days and the median duration was 1 day. There was no reported instance of ICANS, though long-term follow-up data for late neurological complications was not reported. B cell aplasia was seen in 100% of patients and 23% had hypogammaglobulinemia with IgG level less than 400 mg/dL in the first 3 months following CAR-T therapy. Lung infections were seen in 26% of patients with the majority of these diagnosed within 3 months of receiving CAR-T. Nearly 60% of patients developed COVID-19 infection, all of which were 3 months after infusion.

In terms of efficacy, all patients responded irrespective of the cell dose level. All 19 patients achieved stringent CR (sCR) with median time to first sCR of 84 days. MRD negativity rate (at 10⁻⁶ sensitivity) of 100% was seen at first assessment. MRD negativity was sustained in 12 out of these 19 patients at 12 months. While the numbers were small, there was no significant difference in MRD negativity at 12 months based on HR features with 2/4 with 2 HR features, 4/8 with 3 HR features, 6 out of 6 with 4 HR features maintaining MRD negativity at 12 months. The presence of paraskeletal plasmacytomas and extramedullary disease was not associated with difference in the rate of MRD negativity. According to the authors, the median PFS, OS and DOR were not reached.

In recent years, there have been significant advances in outcomes for patients with MM. However, treatment of high-risk MM remains challenging with poor outcomes due to refractory disease and early relapse. There is a need for novel therapies with deep and durable responses in this subgroup of patients. The early results of this study investigating the safety and efficacy of GC012F, that targets both BCMA and CD19, in NDMM with high-risk disease features are promising. GC012F presents an exciting alternative to currently approved CAR-T cell options (idecabtagene vicleucel and ciltacabtagene autoleucel) as for patients with high-risk MM. Long-term follow-up is needed to demonstrate the durability of response and occurrence of any late complications. This study provides an interesting precedent for further investigation of GC012F in trials involving MM with larger sample size.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-275/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-275/coif). N.B. has served on the speaker bureau of Sanofi and participated in the advisory board of Janssen. S.D. has participated in the advisory board of Janssen. A.K. reports research support from Secura Bio, Sanofi, and BMS; travel support from BMS; and serving on the speaker bureau of Sanofi and Amgen. The authors have no other conflicts of interest to declare.

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