Emerging Myeloma Treatments and Their Targets: Beyond BCMA

I remember my specialist telling me in early 2014, “One of our objectives is to buy you time. There are many promising products in the development queue that will give us different treatment options in the future.” 

A decade ago, treatment options were limited. Since that time, the arrival of numerous new therapies has offered more hope in our myeloma journey. 

The approval of monoclonal antibodies like daratumumab really started to change the myeloma treatment game. Then came the breakthroughs of BCMA-directed therapies, like CAR-T and bispecific antibody (bsAb) therapies, which have transformed myeloma treatment and are expected to be used earlier in treatment. 

But what options remain at relapse after CAR-T or bispecific antibodies, and what targets lie beyond BCMA? 

A recent article in Blood Advances by the American Society for Hematology addresses these questions. The article itself is quite an “easy read,” and I recommend that you read it as it includes some tables and charts that provide a wealth of added understanding and information that simply cannot be provided in this summary of this excellent survey. 

Understanding Myeloma Treatment Targets and Therapies 

In the sections below, you will find an overview of various targets currently used or under exploration in multiple myeloma treatments, along with the therapies designed to target these mechanisms and eliminate myeloma cells.

CD38 

This was one of the first novel targets in myeloma treatment. Monoclonal antibodies have served as a great treatment option in combination with standard therapies for newly diagnosed myeloma patients. 

There are two FDA-approved myeloma therapies, monoclonal antibodies, that target CD38. 

They are: 

• Daratumamab (Darzalex, Johnson&Johnson)
• Isatuximab (Sarclisa, Sanofi) 

Research is ongoing for CAR-T and T-Cell engagers targeting CD38, but challenges remain due to its expression on healthy cells.

BCMA

As mentioned above, therapies targeting the BCMA protein on the surface of myeloma cells drastically changed the landscape due to the high levels of response elicited in patients receiving these therapies. 

Below are myeloma treatments that target BCMA.

Antibody Drug Conjugate 

• Belantamab mafadotin (BLENREP, GSK)
• Note: belantamab mafodotin- BLENREP- is included in this list even though its FDA approval has been withdrawn. The innovator, however, is expected to re-submit their regulatory dossier with updated clinical data.

CAR T-cell Therapy 

• Idecabtagene vicleucel (Abecma, Bristol Myers Squibb)
• Ciltacabtagene autoleucel (Carvykti, Johnson&Johnson)

Bispecific Antibody Therapy 

• Teclistamab (Tecvayli, Johnson&Johnson)
• Elranatamab (Elrexfio, Pfizer) 

GPRC5D

GPRC5D is a protein highly expressed on the surface of myeloma (MM) cells. GPRC5D therapies show efficacy even in patients who relapse after BCMA therapies. They have manageable side effects, mostly involving skin, nails, and oral issues.

“Importantly,” the Blood Advances article shares, “GPRC5D-directed therapies result in reduced risk of infections compared with BCMA-directed therapies…GPRC5D-targeted therapies will assume a key role in [myeloma] treatment.”

As of Fall 2024, the only FDA-approved myeloma therapy is a bispecific antibody, Talquetamab (Talvey, Johnson&Johnson). It is designated for myeloma patients on or after their fourth line of therapy.

There are other therapies currently being tested in clinical trials that target GPRC5D on myeloma cells. While this is not a comprehensive list, some of those include: 

• MCARH109: This is the first GPRC5D-targeted CAR-T therapy. In the Phase I clinical trial, the overall response rate (ORR) was 71%, with no severe side effects.
• BMS-986393 (CC-95266): This is also a CAR-T therapy. Phase I clinical trial results showed an 86% ORR, with CRS (cytokine release syndrome, a serious side effect of immunotherapies) in 84% of patients, though a few experienced severe CRS.
• OriCAR-017: Another CAR-T therapy with promising results (ORR 100%) in early trials. However, 100% of patients experienced neutropenia and other low blood counts. 
• Forimtamig (RG6234): This is a bispecific antibody therapy that can be administered either via IV or injection. The ORR was 71.4% (with IV) and 60.4% (injection), with common CRS and skin-related side effects.

SLAM7

SLAM instigates myeloma cell growth, so the therapies targeting SLAM7 are designed to reduce and eliminate this growth.  

As of Fall 2024, the only FDA-approved myeloma therapy targeting SLAM7 is a monoclonal antibody called elotuzumab (Empliciti, Bristol Myers Squibb).

A SLAMF7-CAR-T trial in Germany shows potential but formal, peer-reviewed, and published results are not yet available.

FcRH5 

While limited data is available about this target, it is known that normal plasma cells express FcRH5. Malignant plasma cells (such as myeloma cells) have an increased expression of this protein on their surface, especially those with amplification or gain of chromosome 1q.

No myeloma therapies currently are approved with this target. However, cevostamab, a bispecific antibody, showed a dose-dependent ORR of 54.4%. 

Other Targets

• CD138: Therapies with this target currently being tested include an antibody-drug conjugate and a CAR T-cell therapy, but data is still limited. 
• CD229, Integrin β7, ILT3, SEMA4A, CCR10, MUC1, CD46, CD56, CD74: These are various targets in early trials that show potential but require more data.

Future Directions in Myeloma Treatment 

• Multitargeted and combination therapies are being developed to address myeloma’s heterogeneity, such as dual-targeted CAR-T constructs.
• Optimization of immune effector cells, like CAR-NK cells, aims to reduce treatment risks like CRS.
• Treatment sequencing will play a critical role in overcoming resistance and optimizing patient outcomes.

While this article contains much information, the main message is that this ongoing research provides hope for longer survival and better quality of life for myeloma patients.

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Sources: 

• Beyond BCMA: newer immune targets in myeloma | Blood Advances | American Society of Hematology