Combinations For Transplant-Ineligible NDMM Need Careful Monitoring
During a live event, Taewoong Choi, MD, discussed the potential use of quadruplet in transplant-ineligible multiple myeloma and the need for monitoring for neuropathy with bortezomib.
Taewoong Choi, MD
Transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM) have a wider range of treatment regimens including agents that pose tolerability challenges in older patients with greater frailty. With recent data supporting triplet and quadruplet regimens, oncologists must consider how to respond to adverse events such as neuropathy and the toxicities of maintenance regimens. In a recent in-person Case-Based Roundtable meeting in Durham, North Carolina, Taewoong Choi, MD, assistant professor of medicine and member of the Duke Cancer Institute in Durham, discussed the importance of closely managing short- and long-term toxicities with these agents and looked at the trials establishing the role of quadruplet therapy in patients not receiving autologous stem cell transplant.
This article is part 2 of a 2-part series from a Case-Based Roundtable event.
Targeted OncologyTM: Do the updated data from the phase 3 MAIA trial (NCT02252172) change your opinion toward use of this regimen?1
Taewoong Choi, MD: It depends on whether you're already using the MAIA regimen in your practice for transplant-ineligible patients or not. At our practice, we were using the MAIA regimen for transplant-ineligible patients for a long time, and then most recently, we started including a bit of bortezomib [Velcade] based on the recent data [supporting quadruplet therapy]. In transplant-ineligible and frail patients, especially when they have high-risk features, we try to include some bortezomib upfront, but there will be a limitation, because it can cause pretty debilitating neuropathy, and we have to be careful. But there is a clear benefit when you give bortezomib, especially for high risk.
How do you decide between VRd (bortezomib, lenalidomide [Revlimid], and dexamethasone] and Dara-Rd (daratumumab [Darzalex], lenalidomide, and dexamethasone) for patients who are transplant ineligible?
In my practice, based on the data, the easier way of giving it, and…that the result of the VRd in frail patients was inferior to the patients who got just Rd in a non-frail population, I would choose Dara-Rd.2
How do you determine which therapies to use in the maintenance setting? How long do patients remain on maintenance?
If you started Dara-Rd, in the MAIA study, [daratumumab and lenalidomide] was supposed to be continued until disease progression and response was getting deeper as you continued therapy. I think you're supposed to continue that. After a while it is once-a-month [daratumumab], essentially a maintenance regimen.
Depending on the MRD [minimal residual disease] assessment, you may consolidate into lenalidomide-only maintenance. In my practice, for standard risk, if they have sustained MRD negativity, you would consider stopping. I usually continue both because when the disease comes back, I think you need to treat it with the full induction, and we can sustain good response for a longer period by continuing both.
Monitoring IgG [immunoglobulin G] and infectious complications is going to be important. If you continue daratumumab and lenalidomide together for maintenance, the IgG level can be borderline, so you still monitor for it.
How does dosing convenience factor into your treatment choice?
The efficacy of both CD38 antibodies, daratumumab and isatuximab [Sarclisa], is pretty much the same. There's no head-to-head comparison. There's no way of knowing without that kind of comparison. Because daratumumab is subcutaneous, and then down the road, it’s once a month, that's what most patients would accept as convenient therapy. Isatuximab is still intravenous, and it is given every 2 weeks. I think there's a little bit of inconvenience, but I don't think it's a deal breaker.
How can early and aggressive management of neuropathy benefit patients receiving bortezomib?
Once there is debilitating neuropathy, we know how long it takes to get better, or it may not actually get better after 2 or 3 years. It’s affecting their quality of life. So whenever you see neuropathy developing and getting worse, [you should be] either lowering the dose of bortezomib, changing the dosing frequency, or eventually discontinuing. If you use more drugs in combination, then it’s easier to just drop 1 drug.
What if a patient has neuropathy at baseline, for example due to poorly controlled diabetes?
In that case, if they're high risk, I would still consider using bortezomib at the lower dose, like 0.7 mg/m2, and I would start at once a week. If they complain about worsening neuropathy, I may consider changing to every 2 weeks. But in that case, if they are high risk, carfilzomib [Kyprolis] is a good option, because it may be even more potent than bortezomib and it doesn't cause much neuropathy. But carfilzomib has its own risks, so it's not an easy choice.
Could you describe the trials that investigated quadruplet therapy for transplant-ineligible patients?
The first one is the phase 3 CEPHEUS study [NCT03652064], and this is Dara-VRd [daratumumab plus VRd] vs VRd in transplant-deferred patients. This is for transplant deferred, not exactly transplant ineligible. Some of them simply just decided not to pursue transplant, and they were included this study. If you compare CEPHEUS and IMROZ [NCT03319667], there was a slight difference in the study population; you probably have more voluntarily deciding not to pursue transplant in this study.
The primary end points were progression-free survival [PFS] and MRD negativity.3 The benefit was clear with the 4-drug combination [as well as] the complete response or better rate being better with Dara-VRd. There was a detailed analysis about the peripheral neuropathy, and that matters because in that transplant-deferred population, they used bortezomib in the regimen. Any grade is [55.8% vs 61.0%, respectively], grade 3 or higher [8.1% vs 8.2%]. I think this is a significant percentage that we are seeing. That means when you apply these trial data to your practice, you have to be careful about using bortezomib.
IMROZ is a phase 3 study, essentially the same kind of comparison, but using isatuximab, but the data are very impressive, and…NCCN guidelines already include this regimen for transplant-ineligible patients.4 It was Isa-VRd [isatuximab plus VRd] vs VRd comparison, but the regimen is a little bit complicated. During the induction phase, 1 cycle was 6 weeks, and then during the maintenance and continuous treatment, it was a 4-week cycle.
I want to emphasize that the bortezomib was still [given on] days 1, 4, 8, and 11, twice a week, which is not the ideal regimen. For PFS, there was a very clear benefit with the Isa-VRd.5 They analyzed all the treatment-related adverse events, including what we worry about. But in real-world practice, when you want to give some bortezomib in the transplant ineligible population, you are monitoring for peripheral neuropathy, and then you may need to modify the regimen. You may not be able to complete the course as defined in the study. You want to start something close to the study regimen, and once you start noticing neuropathy is getting worse, you need to deescalate early because that debilitating neuropathy can be bad.
DISCLOSURES: Choi had no known relevant disclosures.
