Key Innovations and Ongoing Challenges in Multiple Myeloma Treatment

Amrita Krishnan, MD

Significant advancements have transformed multiple myeloma treatment, including the development of T-cell engagers like chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies targeting multiple antigens.

While these innovations and more have improved response rates for patients with advanced disease, managing toxicities and infection risks remains a challenge in this patient population.

In an interview with Targeted Oncology^TM, Amrita Krishnan, MD, director of the Judy and Bernard Briskin Center for Multiple Myeloma Research at City of Hope and executive medical director of hematology at City of Hope Irvine, discussed several key advancements and challenges in the field of multiple myeloma.

Targeted Oncology: What have been some of the most exciting advancements in multiple myeloma research and treatment?

Krishnan: The advent of T-cell engagers, and that can be T –cell-directed therapy like CAR T-cell therapy, has been around a couple years now. We are looking for potential approvals of both BCMA-directed CAR T cells in earlier lines of therapy. I think that will be a huge step forward. Second is the role of bispecific antibodies with multiple targets. We have both BCMA-directed and GPRC5D-directed [bispecific antibodies]. [We are] excited in regard to options patients have for prior lines of therapy in advanced myeloma which is showing across the board [that] over 50% of patients are responding. Many of these patients are triple-class refractory, so to have options that are off-the-shelf for such advanced myeloma has been a tremendous game changer for many patients.

How have such advancements impacted patient outcomes?

There are a lot of real-world comparisons with standard-of-care options. One could surmise that outcomes are better because you have agents now that [have] response rates more than double. Some of the challenges have been mitigating toxicities, especially infection risk that could potentially impact overall survival outcomes. As we get more experience, we will learn how to best use these drugs in terms of schedule and duration of therapy, which will also help mitigate infection risk.

Multiple Myeloma multiplex leukemia cancer 3d color render illustration closeup: © LASZLO - stock.adobe.com

Are there any specific patient populations or risk factors that community oncologists should be particularly vigilant about?

The biggest challenges for us are 2 groups of patients. The first are patients who present with renal failure. I think knowing those often present to the community, starting therapy quickly and being extremely aggressive about that therapy that you start is important to be able to try and salvage kidney function. Second is, in regard to both in the upfront setting and even more in the relapse setting, patients with extramedullary disease tend to be extremely challenging in terms of responses to therapies and durability of those responses, so be aware of those patients.

What factors do you consider most important when making treatment decisions for your patients?

I think biological factors, such as cytogenetics, and clinical factors like what we call functionally high-risk patients, patients who relapse early after autologous transplant, patients who have extramedullary disease, and patients who have renal insufficiency. All those things together also become important factors when we decide on subsequent therapies.

When treating an individual patient, how do you weigh their needs and preferences against clinical guidelines?

Especially when we talk about T-cell-directed therapies, that is a huge part of it with the burden of care needed. For example, for CAR T cells, having to have a dedicated caregiver stay near the center for X period of time. It is very much a patient and physician mutual decision about trying to select the best option.

How is precision medicine evolving in multiple myeloma? Are there any specific tests or therapies to be aware of?

I think the biggest need right now is for patients with relapsed disease. As we speak more about sequencing therapy, because we have targeted therapies against BCMA, against GPRC5D, the question is, once you relapse after 1 of those targeted therapies, why did they progress up to that therapy? Is it mutations in the target? Is it immune fitness or T-cell health? It helps us then sequence the next therapy. That is a huge part of where precision medicine can help us. It is trying to understand mechanisms of resistance, for example, in specific patients.

What other challenges remain in this space?

[The central nervous system (CNS)] in myeloma remains an extremely challenging area when patients relapse with either leptomeningeal disease or CNS disease. One of the biggest unmet needs right now are for patients with plasma cell leukemia, and they remain a challenging group of patients to treat. These are patients who have aggressive, rapidly proliferative disease, and because CAR T cells, for example, take a while to manufacture, those patients may progress before you can even give them CAR T cells. Better bridging strategies for patients before CAR T cells is another unmet need.

Moving forward in this field, what are you excited to see research tackle next?

I think we still want to see therapies for patients with 11;14 translocation, so more targeted therapies for those groups of patients. There are different BCL-2 inhibitors under study. We are looking at precision medicine and using genomics to help us better define sequences of therapies with relapsed disease, and we are looking for [minimal residual disease (MRD)]-directed therapies from some several large trials to help us decide if we can actually abrogate therapies in patients with sustained, deep responses.

How can community oncologists stay informed about the potentially relevant clinical trials that there are for multiple myeloma treatment?

Obviously ClinicalTrials.gov is fairly broad and hard to narrow down, but I think going to the center's website per institution. For example, we have our trials, we have our investigators, and those are options. Certainly, there are many different myeloma patient-directed organizations as well that also can serve as resources.

I think [it is important] just to understand that we are partners, and we understand myeloma is a very confusing disease. There are so many different drugs, and it is challenging to know how to optimally use them and in what sequence. We are happy to see patients and work with them as partners to best navigate that.