Updated Data from the MAIA Trial in Transplant-Ineligible MM


Expert perspectives on updated data from the MAIA trial in newly diagnosed transplant-ineligible multiple myeloma and how this can be applied to clinical practice.

Rafael Fonseca, MD:
At the 2021 American Society of Hematology Annual Meeting, I did an oral presentation regarding a simulation that compared the outcomes of patients based on the following scenarios. The scenario could be a patient is treated first with the combination of daratumumab, lenalidomide, and dexamethasone. For that first relapse, we would recommend treating the patient with carfilzomib or pomalidomide. In contrast, you can have a patient who was first treated with something like RVd [lenalidomide, bortezomib, dexamethasone] or even Rd [lenalidomide, dexamethasone], for whom the first relapse would be treated with a daratumumab based combination.

To create the simulation, we used real-world data from the Flatiron database and baseline data from the MAIA clinical trial. We created a simulation that included the process of attrition. Our group and others have published on the importance of attrition among the various lines of therapy. With every passage from 1 line to the next, there’s a significant fraction of patients who are lost and cannot complete the subsequent line of therapy. In our publication, that was 50% of patients, which is consistent with what others have reported. Lastly, we use real-world data to estimate the duration of therapy on that first relapse—the second line—and that came from the Flatiron database.

We didn’t use the clinical trials for relapsed/refractory multiple myeloma, which would be a natural question. Because those are different patient populations, those patients are about a decade younger, and about 60% of them have received a prior stem cell transplant. During the simulation, we estimated the projected median survival for these patients, and we realized that the only way to completely address the question is with a frontline randomized phase 3 study. Luckily, we have 1 going on through SWOG.

In the meantime, given that both regimens are approved by both guidelines, and they have category 1 information, how can we make those choices? What we reported was that if you start with something like the MAIA regimens—daratumumab, lenalidomide, and dexamethasone, followed by carfilzomib or pomalidomide for that first relapse—you’d have an expected median overall survival of approximately 9.1 years, which is remarkable for this patient population. That’s 2½ years more than if you start with RVd [lenalidomide, bortezomib, dexamethasone] and use daratumumab to move up for the first relapse, and 3½ years more than if you start with Rd [lenalidomide, dexamethasone] and use daratumumab for the first relapse.

This is simply to ask the question, “What makes more sense for the first-line therapy?” We presented in this particular study that it would make more sense to start with the daratumumab combinations, such as in the MAIA regimen, and that you’d reserve drugs such as carfilzomib and pomalidomide for that first relapse. In contrast, it doesn’t make sense to reserve daratumumab for later. Keep in mind that if you start with something like a MAIA regimen, you essentially have no risk or minimal risk for peripheral neuropathy, which is not the case when we use a bortezomib-based combination. When we take all this together, our studies suggest the best choice for frontline therapy is the MAIA regimen.

The MAIA study has proven and has been published in peer-reviewed literature to be a regimen that provides superiority when it comes to response rate, progression-free survival, and overall survival. We have overall survival that clearly exceeds 5 years and, in our previous simulation, it could be 9 or 10 years for patients who have a good response to initial therapy. Fortunately, for patients in the nontransplant category, we see a slightly lower prevalence of some of those high-risk markers. Patients in the noneligible population tend to be enriched for patients with standard-risk multiple myeloma, in particular with the hyperdiploid version of multiple myeloma.

Nevertheless, a question that remains is whether one has to consider high-risk markers doing the treatment selection. We still have the prevailing notion that patients who have high-risk markers would benefit from the addition of proteasome inhibitors [PIs]. Many studies showed that proteasome inhibitors would improve outcomes for high-risk patients. However, they showed that PIs were almost always compared with IMiDs [immunomodulatory imide drugs] in combination with dexamethasone.

Several studies have shown that novel therapeutics have beneficial effects for patients with high-risk markers. In fact, daratumumab is 1 of them. Daratumumab was shown, in a meta-analysis published in 2020 in JAMA Oncology by Dr [Smith] Giri, to have a significant impact on patients with high-risk disease.

There’s an emerging conversation with regard to isatuximab, and we have that data for the addition of selinexor to the combination of bortezomib and dexamethasone. The question is: are PIs truly beneficial for patients who have high-risk markers, or was it just that IMiDs alone or in combination with dexamethasone is insufficient for this patient population? That’s important because what we’re going to see is that, as we get more follow-up and more curation of the data, and we have this subsequent analysis for high-risk markers, we can still recommend the combination of daratumumab, lenalidomide, and dexamethasone for patients across the board who are transplant eligible.

Transcript edited for clarity.

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