A New Wave of Progress in The Treatment of Multiple Myeloma: Translating Evidence to Clinical Practice - Episode 6
An overview of the frontline treatment armamentarium for patients with transplant-ineligible multiple myeloma and review of the MAIA and SWOG-S0777 trials.
Ajai Chari, MD: Let’s move to the transplant-ineligible. We don’t want to shortchange this population, which is a huge percentage of the patients being treated, especially in the community. Historically, in the United States, we’ve used Rd [lenalidomide, dexamethasone]-based backbones, and some use bortezomib. [There are] interesting data about [daratumumab], some data about ixazomib, and of course, across the Atlantic, there’s a lot of VMP [bortezomib, melphalan, prednisone] being used out there with or without the [daratumumab] added. With that, Rafael, maybe you could start us with the MAIA study [NCT02252172] and why that’s important to you.
Rafael Fonseca, MD: The MAIA study, as our audience knows, is a combination of 3 drugs—daratumumab, Rd vs Rd randomized—a phase 3 study with 737 patients, and the results are nothing short of remarkable. We see a prolongation of progression-free survival [PFS] and clear evidence of an improvement in overall survival. We’ve [also] seen updates—I think Sharif Aicon has published this already in Lancet Oncology and is going to be presented again in a few days at ICA, but we’re seeing overall survival that gets into the 66% plus at 5 years, which, for this patient population, is something we had not seen. As you stated, the 2 preferred regimens supported by the [National Comprehensive Cancer Network] are VRd [bortezomib, lenalidomide, dexamethasone], which was essentially based on the SWOG-S0777 study [NCT00644228], and the MAIA. They both come with category 1 evidence because they both are with PFS with overall survival. Those are the 2 regimens to consider in the United States. There might even be room for a doublet still, but even within MAIA, there [are] some data that those patients that are frail. If you can get the 3 drugs, they do better than if they’re treated with a doublet. There are a lot of things being challenged right now. One of the things that dawned on me yesterday is [that] we can’t conclude but we always compare. But if you look at the PFS of MAIA’s experimental arm, it’s not that different from the DETERMINATION trial [NCT01208662].
Cristina Gasparetto, MD: I agree. [That is] what I was saying, adding the antibody—I didn’t know we were going to make a difference.
Ajai Chari, MD: This is a perfect segue…. Omar, we’re not supposed to do cross-study, but please compare MAIA [with] SWOG-S0777.
Omar Nadeem, MD: As Rafael pointed out, 2 of our most commonly used regimens. There are some important differences, though, between the studies. You clearly see what seems to be much longer PFS with the antibody lenalidomide combination with daratumumab compared [with] the SWOG-S0777 trial, which was [approximately] 43 months in terms of PFS. The difference is that the bortezomib was fixed duration. So the question remains: If you’re doing fixed-duration therapy with bortezomib for 8 cycles and going on [lenalidomide] maintenance, is that enough? We’ve talked a lot about combination maintenance strategies already in the transplant-eligible population. So in this case, it really is a fixed duration. Part of the problem there is that it was given twice weekly in the traditional schedule. So in this older population, you had a higher incidence of peripheral neuropathy. That is its limitations in the real world. How can we get bortezomib? That’s why the RVD-lite [lenalidomide, bortezomib, and dexamethasone] platform came out in the transplant-ineligible population, showing you can give it weekly and still get the same responses and durability. In practice, that’s become the comparator. I think it’s a little unfair to bortezomib to compare it head-to-head [with] MAIA because it wasn’t really given until progression. But I will say, in practice, the Dara-Len-dex regimen is amazing. You see absolutely amazing tolerability, it’s so convenient, you give it monthly in maintenance, and not subcutaneous. So advantages seem to be trending in that direction.
Ajai Chari, MD: You alluded to the neuropathy, the tolerability, which is important, even within these older patients. There’s obviously heterogeneity. The frailty index is becoming increasingly important and recognized across all of oncology; it’s not your age but your geriatric fitness. There was a subgroup analysis presented by Dr Hugh Falco and published in Leukemia that showed even frail patients in the MAIA have the same benefit. This was done retrospectively using Charlson comorbidity performance status, but even the frail patients have the same benefit. This is nice to see because that’s something we can talk more about with the SWOG-S0777 [trial]. But I’m curious—we’ve talked about frailty, but the other concern would be high-risk. How are you treating high-risk older patients?
Krina Patel, MD: There’s this belief that we really need PIs for high-risk patients. We have lots of smaller subsets of patients, [in which] we’ve all come to that [realization]. I tried to do GRIFFIN [NCT02874742]. I tried to do [quadruplet therapy] in my frail patients that have high-risk disease, because I think [daratumumab] adds a lot. But my true high-risk patients with 17p deletion, or my ultra–highrisk older patients—if I can get away with weekly bortezomib and the [daratumumab] and [lenalidomide] at a lower dose, 10 to 15mg, and even a lower dose of steroids—I tend to feel like that’s going to help them get better responses and hopefully deeper responses.
Ajai Chari, MD: I think you hit the nail on the head, which is an important point. It’s not always the number of drugs; it’s the dose intensity of what you’re giving. One could argue that [lenalidomide plus dexamethasone] at full dose in a petite elderly [woman] might be much more poorly tolerated than an added CD38 or even bortezomib, right?
Krina Patel, MD: Right.
Ajai Chari, MD: Your advice about dose attenuating is essential. I’m curious, Christina, what about you? How do you pick between these choices?
Cristina Gasparetto, MD: I try to individualize, as well. And I agree with Krina, the problem is that if you look at the overall survival projected of the younger patients, it is much longer compared [with] the older population and not because there is anything different in the biology of the disease. It’s just because we are unable to deliver the same therapy. I also try to treat [those who are] high risk a little more aggressively. Of course, you have to make dose adjustments or dose modifications, but the CD38 antibody has changed the treatment algorithm because they are well tolerated. In fact, in MAIA, several patients end up discontinuing lenalidomide, but they continue the single-agent [daratumumab]. That is also one of the reasons why the PFS—and probably the overall survival—were superior because they were able to stay on therapy longer.
Ajai Chari, MD: That’s a great segue for Omar. You heard about discontinuation, so how long do you have to continue these drugs? What’s your end point? Does everybody need everything forever?
Omar Nadeem, MD: It’s a little different in the transplant-ineligible population. We talked about transplant-eligible patients trying to get the deepest response as quickly as possible and get them through all the steps of transplant, etc. With the older patient population, it’s more about the continuation of therapy and trying to limit toxicity to have good quality of life. So dose attenuations and continuation of therapy until progression—MAIA is a perfect example of that, [which] makes such a huge difference for these patients. It gives us a lot more flexibility. If you’re not so dependent on 1 particular agent in a combination, then these patients are able to tolerate it. We have patients on 2.5 mg of lenalidomide, sometimes in combinations with daratumumab, and that’s OK [if] they’re in a response. It could be many years into their therapy, and that’s good enough. Then we have so many salvage strategies now that are tolerated in the older patient population. It’s more about maximizing the benefit and therapy is continuing until a progression, but I don’t necessarily make too many changes to the therapy to try to get a deeper response.
Ajai Chari, MD: Both of your points about the dose attenuation are shown in a well-done prospective study by Larocca, which was published, that a planned dose attenuation of [daratumumab] and elimination of [dexamethasone] led to less [adverse] events, [which is] a reminder that we need to think about our patients.
Cristina Gasparetto, MD: Very important study. Absolutely.
Transcript edited for clarity.