Hamza Hashmi, MD, Memorial Sloan Kettering Cancer Center, shares insights on recent advancements in myeloma treatment and gives a preview of his session on managing myeloma at the 2024 Community Oncology Conference. 

Transcript: 

Hamza Hashmi, MD: My name is Hamza Hashmi, and I'm a physician at Memorial Sloan Kettering. Here I focus on plasma cell disorders with myeloma and amyloidosis, and I also am a part of a cell therapy team here at Memorial Sloan.

Can you outline the most significant recent advancements in the treatment of myeloma, and how these developments differ from previous standards of care?

Dr Hashmi: I think there have been several developments in the last one year that have really changed how we are treating myeloma not only in the newly diagnosed setting, but as well as in relapsed/refractory disease states. One of the most exciting development that we have seen is a clinical trial that actually compared four drug regimen versus three drug regimen for patients with newly diagnosed myeloma.

The name of the trial was PERSEUS Trial, compared daratumumab in combination with len, bortezomib, and dexamethasone versus len, bortezomib, and dexamethasone. And at the ASH meeting, we had a four-year follow-up showing at least a 20% improvement in progression-free survival for the patients who received the quadruplet daratumumab-based therapy.

I think that really has changed as a confirmatory study to the GRIFFIN trial previously, the standard of care in US where all patients with newly diagnosed, transplant-eligible myeloma are now getting quadruplet C38-based induction chemotherapy. Also in this trial we learned that that patients who receive daratumumab in combination with len maintenance for two-year duration do end up achieving MRD negativity, 10 to the power of 6, at the end of two years, then are able to come off of daratumumab and continue len maintenance without any detrimental impact on their remission.

Another exciting area that I think has recently been investigated with several abstracts of publications coming out simultaneously is the role of CAR-T in early lines of therapy. KarMMa-3 was a trial that looked at ide-cel in combination with standard of care chemoimmunotherapy for relapsed/refractory myeloma. Essentially looked at three prior lines of therapy in relapsed myeloma, heavily daratumumab-exposed in refractory and showed an improvement in PFS, nearly 14 months versus only four months for standard of care chemotherapy. There is an expected approval hopefully coming of ide-cel in the earlier lines of therapy based on the results of this KarMMa-3 study. And then more exciting was perhaps the CARTITUDE-4 study that again looked at use of CAR-T cell therapy in earlier lines of therapy in patients who have had at least two prior lines of therapy and were len-exposed and refractory.

And in those particular patient population, again, we saw a significant improvement in progression-free survival. So again, there is an expected approval for a cilta-cel in earlier lines of therapy, perhaps only one prior line of therapy in patients who are len-refractory in the coming weeks to months. So I think these are some of the very exciting developments that have taken place in the last few months to a year.

Some of the areas that have seen some exciting developments also include use of small molecules known as CELMoDs or cereblon E3 ligase modulators with the name of iberdomide and mezigdomide that have shown very potent activity and tolerable side effect profile for patients with relapsed myeloma. 

How do these updates influence the selection of treatment modalities for patients with different stages of myeloma? 

Dr Hashmi: Having PERSEUS Trial, a phase three randomized controlled trial with many more patients, many more centers, and much longer follow-up available, I think we have a confirmation of the phase two GRIFFIN trial and the new standard of care in US for transplant-eligible myeloma is CD38 antibody daratumumab in combination with RVD triplet. I also believe that CARTITUDE IV trial has shown very promising outcomes of using cilta-cel in earlier lines of therapy, after perhaps one line of therapy with patients who are progressing on len-based maintenance, is likely going to be approved in the coming months and will be available for earlier use in the patient's myeloma journey. And finally, there's also a possibility that ide-cel will also have an approval for earlier lines of therapy as an option for patients with triple-class refractory myeloma.

With the emergence of new therapeutic options, how do you anticipate these updates will impact the overall survival rates and the quality of life for patients with myeloma? 

Dr Hashmi: So I think for a disease like myeloma, where median overall survival in 2024 is expected to be somewhere between 10 to 15 years, it's hard to look at overall survival as an outcome in a trial. Hence, we have been using surrogates in the form of progression-free survival and MRD negativity for long-term overall survival benefit.

And all of these studies have actually clearly shown that there is an improvement in progression-free survival when compared to the standard of care regimens. Whether you look at PERSEUS trial, you look at KarMMa-3 or CARTITUDE IV. And we believe that with improvement in progression-free survival, there is going to eventually be an improvement in the overall survival as well. It may take a bit longer for us to actually show that with trial data, but using PFS as a surrogate, we do believe survival will be improved. 

What's more important when it comes to quality of life is two things, two aspects, I believe, when a patient is really diagnosed, it's important to control the disease, the symptoms, the organ damage, with more potent therapies, with deep early responses. We are seeing more better disease control and hence a better quality of life. And once patients have had disease control, I think it becomes important to tailor therapy where we can mitigate some of the treatment-related side effects.

And in that regard, I think we have seen some of the clinical trials evaluating discontinuing one or both therapies based on an MRD negative status. and perhaps that will also eventually lead to an improvement in quality of life as patients are either deescalating their therapy or they're discontinuing all treatment in favor of observation once they have achieved deep levels of transmission. 

Are there any promising avenues for further research or potential breakthroughs on the horizon? 

Dr Hashmi: I think there are several areas that are being very robustly investigated. Some of the therapies that have already been approved in late-line relapsed/refractory myeloma are currently being explored in earlier lines of therapy in combination with other therapies and then finally they have been also pitched against stem cell transplants.

To give you some examples, bispecific antibodies, including teclistamab, elranatamab, and talquetamab, they're all being explored in earlier lines of therapy, where they've been compared to standard of care, daratumumab-based triplet regimens. There are combinations of bispecifics, like teclistamab and talquetamab, being looked at high-risk myeloma patients with extramedullary disease and poor outcomes, typically seen with those patients.

And then finally, there are trials that are ongoing, including KarMMa-9 and CARTITUDE-6, that are actually exploring the role of CAR-T, cilta-cel and ide-cel, all the way in the upfront settings, either comparing it with a transplant or following up with transplant as limited-duration maintenance strategy. These trials will probably be conducted in the coming years, and will have results available and very likely to change the standard of care, especially when it comes to the use of cell immunotherapy with bispecifics and CAR-T in earlier lines of treatment.

What are you the most excited to share with attendees from your presentation at COA 2024? 

Dr Hashmi: There are several areas that I'm excited about. In the newly diagnosed setting, I think now we have a very clear winner when it comes to induction regimen for transplant-eligible newly diagnosed myeloma.

What would be more important is how to be administered, daratumumab, len, bortezomib, and dexamethasone in real-world practice so that patients can tolerate it. Important will be to also discuss duration of maintenance chemoimmunotherapy and what to do at the end of two year mark. For relapsed myeloma setting, I'm very excited about to present some of the data that has come out looking at some of the bispecific antibodies in late line relapse and some of the clinical trials that actually evaluate them in earlier lines and in combination with the other chemoimmunotherapy options.

And finally, I think CAR-T has really made a big splash as it's going to be moving in the earlier lines of treatment, as early as first relapse after transplant. And all of these trial studies data, they're sooner or later going to impact our real-world practice. And I will be very excited to share some of these developments with the audience.