Multiple Myeloma Awareness Month: Advancing The Understanding of Targeted Therapies Role

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Multiple Myeloma expert Santhosh K Sadavish MD, discusses the importance of targeted therapies for these patients and how CAR T-cell therapy has changed the outcomes of patients who relapse after multiple lines of therapy.

The understanding for patients with multiple myeloma is that they will most likely experience a relapse of their disease, but with the expansion of new targeted therapies for these patients outcomes are becoming better.

Driving the field has been the approval of CAR T-cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel, 2 B-cell maturation antigen (BCMA) targeting CAR T-cell therapies that can impact the outcomes of patients who have had up to 4 lines or more of prior therapy.1,2

For Multiple Myeloma Awareness Month, Targeted OncologyTM interviewed Santhosh Sadashiv, MD, a hematologist with Allegheny General Hospital, to discuss the targeted therapies that are changing the landscape for patients and clinicians alike, as well as emphasizing current treatments that are still crucial to a patient’s regimen.

Multiple myeloma, CAR-T cell, therapy, BCMA

Santhosh K. Sadashiv, MD

What have been some of the bigger changes for in the space of treating patients with multiple myeloma?

What has been exciting over the last few years is that there are multiple new treatment options that have come out, [and more on the horizon], that has made treatment of [patients with] myeloma much safer and the outcomes have been much more superior than what it has been in the past.

Now, chemotherapy is almost non-existent [in this space] as there are now many [new treatments like] targeted treatments, immunomodulatory agents, and monoclonal antibodies. All of these have kind of changed the treatment landscape of myeloma over the course of the last few years. In addition to newer treatments, we now can assess for deeper and deeper responses which might eventually help us in understanding patients who can achieve cure.

How has the role of MRD negativity changed in this field?

[We can observe] what we call MRD negativity, [which means] the minimal residual disease. This is beyond just looking at their bone marrow and blood work and saying that [the patient is] in complete remission. These are looking deeper into the genetic level and can tell you whether there is cancer at level of 1 in 10,000 cells or even 1 in a million cells based on the technology. One can get into those kinds of deep responses with the addition of the monoclonal antibody and other combination treatments.

What is the current standard of care for multiple myeloma and do you see that changing?

The autologous transplant still remains as the standard of care. For patients to benefit from an autologous transplant one has to achieve at least a partial response or more, which would then deem them chemo sensitive and can proceed with autologous transplant. The two studies that investigated it, the IFM [trial] from France and DETERMINATION trial [NCT01208662] from the United States, established the beneficial role of autologous transplant as the standard of care in the upfront setting.3

Previously 3 drug regimen was considered standard, but more recently 4 drug regimen are being used to improve response. With improved response, more people are becoming eligible to undergo an autologous transplant. The mortality risk from the transplant is quite low, it's a 1% to 2% even in patients who are older than 70 years. So, when you add all these together, a good initial treatment regimen plan, low mortality risk for patients able to undergo transplant and post-transplant maintenance strategy has overall greatly improved the survival of myeloma compared to just a decade ago.

There are some trials, such as the MASTER trial [NCT03224507], looking at incorporating MRD testing as an indicator to guide treatment. In this trial if a patient at any point of time during treatment course achieves 2 MRD negative tests, they could discontinue treatment and be monitored.4 This is an exciting idea, where one could define a duration of treatment, otherwise todays standard is a patient diagnosed with multiple myeloma in the United States need to remain on some maintenance treatment until disease progression.

How has the field of treating patients who relapse on their disease change?

Despite having all these new treatment options, patients with multiple myeloma, unfortunately, will have relapses. There are many factors that influence relapse [in a patient] and we are slowly beginning to understand the various clones in myeloma and how they evolve or develop resistance over time that leads to relapse and refractoriness of this disease.

The introduction of anti-BCMA treatments and other drugs targeting proteins that are expressed on the surface of myeloma are quickly changing the treatment options in the relapse setting. There are monoclonal antibodies, bispecific agents, and CAR-T directed toward blocking the survival signal coming from these surface proteins on myeloma cells.

What role does targeted therapy play in the relapsed treatment setting?

There is a lot more development in that sphere [with] targeted treatments in this setting. Of course, there are now 3 approved agents in that particular space. The first two are [CAR T therapies], which is the chimeric antigen receptor T cell therapy where they harness the T cells from the patients and engineer them to target certain agents and then add a stimulatory signal to this T cell so that they can simulate whenever the [agent] binds to this target.

The one that is studied the most is a cell surface protein called BCMA. These are proteins that are present on myeloma cells and specifically, they are present in more abundance on these neoplastic myeloma cells, and signals coming from these proteins confer a certain survival advantage to the myeloma cells.

Once you block these proteins, you can stop the signals from being transmitted to the cell nucleus, thereby causing cell death, which is the theory behind this targeted therapy targeting BCMA and other proteins such as GPRC5D and FcRH5. The two anti-BCMA CAR T [therapies] approved in this sphere are called idecabtagene vicleucel and ciltacabtagene, [which were approved] in the last year.

Both have a very good response rate, about 70% to 90%, depending upon the type of CAR T that you've used, and the median progression-free survival is between 1 to 2 years, depending again, on the type of CAR T therapy. So that has been exciting for patients who have reached multiple lines of treatment, up to 5 to 9 treatments previously before going to this treatment. These patients have been heavily pretreated, going through multiple lines, and having this kind of response was previously unseen.

Another drug called teclistamab is a bispecific agent binding BCMA to innate T cells causing activation T cells, which can then lead to myeloma cell death was recently approved.5 It came with an impressive overall response rate of 63% with a median duration of response of 18 months. There are many other such classes of drugs being developed targeting surface proteins, as noted above. All these newer treatments are making a significant impact on improving the lives of those diagnosed with multiple myeloma.

References

1. FDA approves idecabtagene vicleucel for multiple myeloma. FDA news. March 29, 2021. Accessed: March 8, 2023. https://bit.ly/3FcZsBr

2. Carvykti Approval Marks Second CAR T-Cell Therapy for Multiple Myeloma. National Cancer Institute. March 30, 2022. Accessed: March 8, 2023. https://bit.ly/3FebPgC

3. Richardson PG, Jacobus SJ, Weller EA, et al; DETERMINATION Investigators. Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma. N Engl J Med. 2022 Jul 14;387(2):132-147. doi: 10.1056/NEJMoa2204925

4. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma. J Clin Oncol. 2022 Sep 1;40(25):2901-2912. doi: 10.1200/JCO.21.01935

5. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. FDA. October 25, 2022. Accessed: March 13, 2023. https://bit.ly/3YLE659

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