Multiple myeloma (MM) is a malignant hematologic disorder characterized by abnormal proliferation of plasma cells. It is the second most common hematologic malignancy after non-Hodgkin's lymphoma, accounting for approximately 10% of hematologic malignancies. MM has a higher incidence in the middle-aged and elderly population, with a median age of 66 years at the time of diagnosis.

In recent years, significant progress has been made in the treatment of MM, with the approval of several standard regimens, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), corticosteroids, monoclonal antibodies (mAb), CAR-T, etc. Among them, targeted therapeutics have become a trend in research and development. Currently, CD38, BCMA, CD138, CD47, GPRC5D and other targets have become popular targets for MM research.

Figure 1. Pathobiological function of validated MM target antigens commonly used in current MM immunotherapies. [1]

CD38 Targeted Treatment for MM

CD38-targeted agents are currently one of the principal treatments for MM, and two targeted agents have been approved for marketing, including daratumumab (Darzalex) and isatuximab (Sarclisa). Besides, there are many other drugs targeting CD38 for treating MM in the clinic, including mAb, bispecific antibodies, ADCs, and CAR-T cell therapies (Table 1).

Table 1. A selection of CD38 Targeted Treatments for MM

CD38 Targeted mAbs: Daratumumab (Darzalex) & Isatuximab (Sarclisa)

Daratumumab, the world's first humanized anti-CD38 mAb developed by Johnson & Johnson approved by the FDA in November 2015 for the fourth-line treatment of MM patients. Since its launch, daratumumab has continued to expand from fourth-line to front-line due to its efficacy and is now among the first-line treatments for MM.

Daratumumab generated net sales of $6.023 billion in 2021, growing to $7.977 billion in 2022, an increase of 32.4% year-on-year. In the first half of 2023, daratumumab has achieved sales of $4.695 billion, an increase of 22.2% year-on-year, and is on track to exceed $10 billion for the full year.

Sanofi-developed isatuximab (Sarclisa), a CD38-directed cytolytic antibody, was approved by the FDA in March 2020 for third-line treatment of multiple myeloma in combination with pomalidomide and dexamethasone. The trial showed a median progression-free survival (PFS) of 11.53 months for the therapy, significantly better than the 6.47 months in the pomalidomide/dexamethasone group.

Subsequently, on March 31, 2021, the FDA approved isatuximab in combination with carfilzomib and dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy. The approval was based on results from a Phase 3 IKEMA clinical trial (NCT03275285) that randomized 302 patients (3:2) to receive isatuximab in combination with carfilzomib and dexamethasone (Isa-Kd) or carfilzomib and dexamethasone (Kd). Results showed that median progression-free survival (PFS) was not achieved in the Isa-Kd group and was 20.27 months in the Kd group, and patients treated with Isa-Kd had a 45% lower risk of disease progression or death compared to the Kd group [2].

CD38 Targeted Bispecific Antibodies: ISB-1442

ISB 1442 represents an innovative biparatopic bispecific antibody, incorporating two proprietary anti-CD38 binding arms, each with distinct CD38 target regions, and an antagonistic anti-CD47 arm, making it equivalent to a tri-specific antibody. It is the first product based on Ichnos’ BEAT® 2.0, a proprietary protein engineering platform designed for maximal adaptability and manufacturability of full-length multispecific antibodies for clinical applications. ISB 1442 has showcased impressive potency and anti-tumor activity in numerous in vitro and in vivo models. Furthermore, its unique capability to simultaneously bind to CD38 and block CD47, and enhance signaling through FcR (fragment crystallizable receptors) on immune cells distinguishes it from monospecific anti-CD38 therapeutics. [3]

BCMA Targeted Treatment for MM

B-cell maturation antigen (BCMA), also referred to as TNFRSF17 or CD269, is a member of the tumor necrosis factor receptor (TNFR) superfamily. BCMA is widely expressed on the surface of MM cells with increasing expression as MM progresses, but is lowly expressed on normal cells and not expressed on CD34+ hematopoietic cells. Therefore, BCMA is an ideal target for MM therapies, including mAb, bispecific antibodies, ADCs, and CAR-T cell therapies (table 2).

Table 2. A selection of BCMA Targeted Treatments for MM

BCMA Targeted Bispecific Antibodies: Teclistamab-cqyv (Tecvayli) &  Elranatamab-bcmm (Elrexfio)

There are 2 bispecific antibodies approved by FDA for treatment of R/R MM, teclistamab-cqyv (Tecvayli) and elranatamab-bcmm (Elrexfio).

Teclistamab (Tecvayli), a bispecific antibody targeting BCMA/CD3 constructed using Genmab DuoBody's bispecific antibody platform, was conditionally approved for marketing by the European Medicines Agency (EMA) on August 25, 2022 for the treatment of RRMM.

Subsequently in October 2022, Teclistamab was approved for marketing by the FDA. This approval was based on results from the MajesTEC-1 (NCT03145181; NCT04557098). The trial included 110 patients who had received at least three prior therapies, including PIs, IMiDs, and anti-CD38 mAbs, and had not received prior BCMA-targeted therapy.

The results showed that patients had an objective response rate (ORR) of 61.8%, a median follow-up of 7.4 months, and an estimated duration of response (DOR) of 90.6% at 6 months and 66.5% at 9 months [4].

Elranatamab (Elrexfio), a humanized CD3/BCMA bispecific antibody, received accelerated approval from the FDA on August 14, 2023 for the treatment of R/R MM.This approval was based on positive data from Cohort A of the MagnetisMM-3 (NCT04649359) study. Results showed a 58% objective response rate (ORR) in patients treated with elranatamab as their first BCMA-targeted therapy, with duration of response (DOR) of 82.3% at 9 months. [5]

BCMA Targeted CAR-T Cell Therapies: Idecabtagene vicleucel (Abercma) & Ciltacabtagene autoleucel (Carvykti)

Two BCMA-directed CAR-T cell therapies Idecabtagene vicleucel (Abercma，ide-cel) and Ciltacabtagene autoleucel (Carvykti, cilta-cel) are approved by FDA for MM.

On March 26, 2021, the FDA granted regular approval to idecabtagene vicleucel, co-developed by Bristol-Myers Squibb Co. and Bluebird Bio Inc., for the treatment of adult patients with RRMM after four or more prior lines of therapy, This is the first FDA-approved CAR-T therapy for multiple myeloma.

Ciltacabtagene autoleucel, approved by the FDA in February 2022, is the second approved anti-BCMA CAR T-cell product after idecabtagene vicleucel (ide-cel) to treat myeloma patients. The approval was based primarily on the results of the pivotal clinical Phase 1b/2 CARTITUDE-1 study. The results showed that patients received ciltacabtagene autoleucel in the range of 0.5-1.0 x 106 CAR-positive live T-cells per kilogram, with an overall response rate of 97.9% for patients. Among the 95 responding patients, the median duration of response was 21.8 months, with a median follow-up of 18 months.

BCMA Targeted ADC: Belantamab Mafodotin (Blenrep)

There are also a number of ADC drugs targeting BCMA for the treatment of MM, with Belantamab mafodotin (Blenrep), developed by GSK, being the first BCMA ADC drug approved for the treatment of MM. However, as Blenrep failed to show significant PFS (progression-free survival) benefit in the Phase 3 DREAMM-3 (DRiving Excellence in Approaches to Multiple Myeloma-3) validation study, the product was withdrawn from the U.S. market late 2022 at the request of the FDA.

GPRC5D Targeted Treatment for MM

G-protein-coupled receptor, class C, group 5, member D (GPRC5D), an orphan receptor of unknown physiological function,  is expressed on malignant and normal plasma cells at least 500-fold higher in bone marrow than that in peripheral plasma cells, and normal tissue expression is restricted to the hair follicle.

It was found that overexpression of GPRC5D was associated with poor prognosis and tumor load in multiple myeloma (MM). Moreover, GPRC5D was independently expressed with BCMA.

Currently, there is only one drug targeting GPRC5D for the treatment of MM approved by FDA- Talquetamab. Besides, there are many other GPRC5D-targeted therapies in the pipeline, involving bispecific antibodies, CAR-T therapies, and ADCs, etc.

Table 3. A selection of GPRC5D Targeted Treatments for MM

GPRC5D Targeted Bispecific Antibody - Talquetamab-tgvs (Talvey)

On August 9, 2023, the FDA granted accelerated approval to talquetamab-tgvs (Talvey), a GPRC5D/CD3 bispecific antibodies, for adults with RRMM who have received at least four prior lines of therapy.

The approval was based on results from a trial of MMY1001 (MonumenTAL-1) (NCT03399799, NCT4634552), which included 187 patients who had received at least four prior systemic therapies. The results showed that 100 patients treated with 0.4 mg/kg weekly had an ORR of 73% and a median DOR of 9.5 months. The ORR for the 87 patients who received 0.8 mg/kg every two weeks was 73.6%, and the median DOR could not be estimated. It was estimated that 85% of responders maintained response for at least 9 months [6].

SLAMF7 Targeted Treatment for MM

Signaling Lymphocyte Activation Molecule Family Member 7 (SLAMF7), a member of the immunoglobulin superfamily, has a relative molecular weight of 66 kDa. SLAMF7 is expressed predominantly on immune cells and tumor cells, including natural killer cells (NK cells), plasma cells, etc. Under normal conditions, SLAMF7 is expressed at low levels on a variety of human immune cells. However, SLAMF7 expression levels are significantly upregulated in patients with multiple myeloma, and the SLAMF7 gene is frequently amplified in progressive multiple myeloma.

SLAMF7 Targeted mAb - Elotuzumab (Empliciti)

Elotuzumab (Empliciti), an immunostimulatory, humanized, IgG1 monoclonal antibody developed by BMS in collaboration with AbbVie, binds to the cell surface SLAMF7 receptor and was approved for marketing by the FDA in 2015 for the treatment of patients with relapsed or refractory multiple myeloma in combination with lenalidomide and dexamethasone.

Conclusion

Currently, the therapeutic drugs for MM have gradually entered the era of large molecule therapy from small molecule drugs. Among them, CD38 antibody has been among the first-line treatments and its sales are rapidly rising, and BCMA-targeted drugs are also on the rise. GPRC5D, as a potential therapeutic target for MM, is expected to bring new hope to R/R MM patients in the future.

References:
​[1] Cho, S.-F.; Xing, L.; Anderson, K.C.; Tai, Y.-T. Promising Antigens for the New Frontier of Targeted Immunotherapy in Multiple Myeloma. Cancers 2021, 13, 6136. https://doi.org/10.3390/cancers13236136
[2] https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-isatuximab-irfc-multiple-myeloma
[3] https://ichnos.com/ichnos-sciences-announces-initiation-of-first-in-human-study-for-isb-1442/
[4] https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma
[5] https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-elranatamab-bcmm-multiple-myeloma
[6] https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-talquetamab-tgvs-relapsed-or-refractory-multiple-myeloma
 
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