Evolving Treatments in Newly Diagnosed Multiple Myeloma (NDMM)

In this Precision Medicine Perspectives series, “Evaluating Treatment Outcomes in Newly Diagnosed Multiple Myeloma,” Peter Voorhees, MD, at the Levine Cancer Institute in Charlotte, NC, outlines the therapeutic landscape of newly diagnosed multiple myeloma and explores how recent data will shape treatment paradigms.

Targeted Oncology™: Regarding treatment selection in newly diagnosed multiple myeloma, what factors guide your selection for induction maintenance and consolidation therapy?

Dr Voorhees: The most important factor in treatment selection for newly diagnosed patients at this point is whether I consider them transplant eligible or not. And transplant eligibility and frailty kind of go hand in hand. If you’re a frail patient, it’s likely that you’re not going to be transplant eligible. So, for those patients who are relatively fit and deemed transplant eligible, I will typically treat that patient with a quadruplet-based induction therapy based on the results of the GRIFFIN trial [NCT02874742] and more recently the PERSEUS trial [NCT03710603], as previously discussed. If the patient is deemed not to be a candidate for autologous stem cell transplantation, [then I would] lean toward a triplet-based therapy for that group. And...based on the available data, the combination of daratumumab, lenalidomide, and dexamethasone is my preferred triplet in that patient population. As a general rule of thumb, I have not made treatment decisions about induction therapy for newly diagnosed patients based off of standard versus high-risk cytogenetic abnormalities. I think as we get more data, it [will be] clear that the addition of the CD38 antibodies to backbone therapy for multiple myeloma affords benefit both for those with standard-risk as well as those with high-risk disease. So, I wouldn’t let cytogenetic risk influence which way I’m going to go. There is a lot of interesting data with the use of carfilzomib, lenalidomide, and dexamethasone [KRd] with or without a CD38 antibody for patients with high-risk cytogenetic disease. And there are a number of us in the myeloma community who gravitate towards KRd-based therapy for those with high-risk cytogenetics. But we currently don’t have any randomized data demonstrating that the use of carfilzomib over bortezomib in that specific patient population is superior.

Targeted Oncology: In transplant eligible newly diagnosed multiple myeloma patients, could you please discuss the latest data from the MASTER trial, as well, your publication with the use of RVd and the GRIFFIN trial?

Dr Voorhees: So, the MASTER trial [NCT03224507] was a very interesting study that looked at the combination of daratumumab, carfilzomib, lenalidomide, and dexamethasone [Dara-KRd] in transplant eligible patients with newly diagnosed multiple myeloma. And the way that this study was designed is that patients would receive 4 cycles of induction therapy followed by MRD [minimal residual disease] testing. They would then go on to autologous stem cell transplantation, followed by MRD testing, and they could potentially receive up to 8 cycles of consolidation therapy with MRD testing done after 4 and after 8 cycles of that consolidation, followed by lenalidomide maintenance therapy. What was really interesting and unique about this particular trial is that if you were MRD negative by at 10-5 level of sensitivity over 2 consecutive readouts, the way the protocol was designed is that you could actually stop therapy at that point. So, for example, if you had a patient who was MRD negative after their 4 cycles of induction dara-KRd, and again, MRD negative after their transplant, they could stop therapy and be off all drugs at that point. So, this study demonstrated unprecedented MRD negativity, not just at 10-5 level of sensitivity, but at 10-6 level of sensitivity as well, results that we haven’t seen in other regimens to date, which was really exciting. And with longer follow-up and what was recently published in Lancet Hematology, progression-free survival is looking very good in this particular trial, despite the fact that they de-escalated therapy based off of MRD results. And I would say that the progression-free survival data looked very similar to that of [the] GRIFFIN [study], which is really quite remarkable given the fact that, again, the MASTER trial had a de-escalation component to the regimen built into it. We’re comparing across studies here, so we have to take this with a grain of salt, but it is interesting that their PFS [progression-free survival] curves are very similar to what we saw in GRIFFIN, even with the de-escalation. So, it’s hypothesis generating, and it certainly supports the idea that we should start exploring this de-escalation strategy in randomized studies more rigorously.

Targeted Oncology: In patients with high-risk cytogenetic abnormalities, could you comment on some of the data from GRIFFIN and MASTER as it pertains to that specific patient population?

Dr Voorhees: So, we did a combined analysis of the GRIFFIN and MASTER studies based off of cytogenetic risk. And what was interesting in this analysis and was very consistent between the 2 studies is that if you had no high-risk cytogenetic abnormalities or just one, you did equally well from a progression-free survival perspective with the quadruplet therapy. If you had 2 or more high-risk cytogenetic abnormalities, you did not do as well from a progression-free survival perspective. Now, a number of people have taken that inferior progression-free survival in the MASTER trial with 2 or more high-risk cytogenic abnormalities as evidence that you should not de-escalate in that patient population like they did in that study. And while that may be true, I would argue that the PFS curves in that group were very similar to what we saw in the GRIFFIN trial, which applied continuous therapy in that group of patients. So, I think what that speaks to is the fact that for those patients who have ultra–high-risk disease, and 1 way we define that is by the presence of 2 or more high-risk cytogenetic abnormalities, I think that’s a patient population where we really, truly need a completely different approach to treatment.

Targeted Oncology: What does the latest data suggest about the use of triplet regimens for patients with transplant eligible newly diagnosed multiple myeloma?

Dr Voorhees: So, as far as triplet therapy in transplant eligible patients with newly diagnosed myeloma, again, the triplet of lenalidomide, bortezomib, and dexamethasone [RVd] is well established in this patient population. The really pivotal study of triplet regimens in transplant eligible patients was actually a study that was run many years ago, which looked at thalidomide and dexamethasone with or without bortezomib as part of induction therapy in post-transplant therapy for newly diagnosed patients with transplant eligible disease. And what they found in that study was that there was an improvement in progression-free survival with the addition of the proteasome inhibitor into the IMiD/dex backbone, and with longer follow-up, they showed an overall survival advantage as well. Now, lenalidomide, bortezomib, and dexamethasone has never been compared in a randomized study to len/dex or bortezomib/dex in transplant eligible patients with newly diagnosed myeloma. But given the previous results as well as the excellent results with RVd followed by transplant, both in the IFM 2009 [NCT01191060] and DETERMINATION [NCT01208662] trials, that’s become a standard of care for that group of patients. Now, again, as I mentioned before, there’s a lot of interest in carfilzomib, lenalidomide, and dexamethasone triplets in this patient population. There was a study called the ENDURANCE trial [NCT01863550] that was conducted by ECOG [Eastern Cooperative Oncology Group] led by Dr. Shaji Kumar at Mayo Clinic. And this was a study that looked at RVd versus KRd for newly diagnosed patients. Now, the important thing here is that these patients were either deemed not to be eligible for transplant, or they had elected not to pursue transplant as part of frontline therapy. The other important caveat to this study is that it really focused on patients with standard-risk cytogenetics. There were a couple of groups that were allowed participation in the ENDURANCE trial. So, for example, those with gain 1q21 were eligible for the study as well as those with 4;14 translocations. But those caveats aside, there was really no clear difference in progression-free or overall survival with bortezomib versus carfilzomib in that patient population. Nonetheless, there still remains a lot of interest in the use of carfilzomib instead of bortezomib for those with high-risk disease. There was a presentation at our 2023 ASH annual meeting from the Memorial Sloan Kettering and Emory Groups looking at their institutional experience with KRd-based therapy in transplant eligible patients with newly diagnosed myeloma and their median progression-free survival is really quite remarkable, whether you had zero, 1 or 2 high-risk cytogenetic abnormalities. Now, given these are myeloma centers of excellence, you have to take these results with a grain of salt, as the patient population could be highly selected in other ways; but it really does support the potential use of KRd-based therapy in this group of patients. I’ll also point out that there was a study called the CONCEPT trial [NCT03104842] which was a single-arm phase II study that was conducted in Europe, which looked at the CD38 antibody isatuximab with the KRd backbone for newly diagnosed myeloma patients. This study took on both those who were transplant eligible as well as those who were not transplant eligible, although the majority of patients [who] participated were transplant eligible. And the MRD-negative rates in this particular trial were absolutely phenomenal, and early progression-free survival data looked quite promising in a very rigorously selected, clearly high-risk group of patients. So, I think that there’s still a lot of interest in KRd-based therapy in the transplant eligible patients, but to date, we don’t have a randomized study suggesting that KRd-based therapy is superior to RVd-based therapy in that group of patients.

Targeted Oncology: In newly diagnosed multiple myeloma, how does data from the MAIA and SWOG S0777 trials impact your treatment selection for patients who are transplant ineligible?

Dr Voorhees: As we discussed earlier in the program, for our patients who are transplant ineligible with newly diagnosed myeloma, the NCCN [National Comprehensive Cancer Network] currently recommends 1 of 2 triplets; lenalidomide, bortezomib, and dexamethasone, or daratumumab, lenalidomide, and dexamethasone. These [regimens] are both level 1 recommendations based on randomized phase III studies that have shown that the addition of bortezomib and daratumumab to the len/dex backbone in this group of patients not only improves progression-free survival but improves overall survival as well. Currently, we do not have any head-to-head comparisons of RVd versus daratumumab-Rd in transplant ineligible patients with newly diagnosed multiple myeloma. So, at the ASCO [American Society of Clinical Oncology] meeting in 2023, Dr Brian Durie and colleagues conducted an analysis looking at patients who had been treated in the MAIA trial [NCT02252172], [which] was len/dex with or without daratumumab, and those [who] had been treated in the SWOG S0777 trial [NCT00644228], which was lenalidomide/dexamethasone with or without bortezomib. They focused on those patients who are 65 years of age and older, and they matched off of age, off of gender, off of performance status, off of cytogenetic risk and ISS [International Staging System] stage. Interestingly, they showed a PFS advantage to dara/len/dex over len/bortezomib/dex in that particular analysis. In fact, the hazard ratio for PFS in favor of dara/len/dex was 0.6, translating into a 40% reduction in the risk of disease progression or death with the use of daratumumab in combination with len/dex as opposed to bortezomib with len/dex. Now again, there may be biases that were unaccounted for, [for example] confounding factors that were unaccounted for in this particular comparison, but [it] is certainly provocative. I will point out that there is an ongoing study that’s being led by the SWOG Cooperative Group, which is actually comparing these regimens head-to-head in transplant ineligible patients with newly diagnosed myeloma. And that study will more definitively answer whether one is better than the other. Just from a practical perspective, I find that daratumumab, lenalidomide, and dexamethasone is easier to give. I find that the neuropathy caused by bortezomib can potentially impact quality of life to a greater extent. So, I have gravitated toward the daratumumab/len/dex approach in this patient population over time.

Targeted Oncology: What unmet needs or challenges still exist in NDMM? From ASH 2023, were there any emerging combination regimens or ongoing trials that were significant to you and that may address those unmet needs/challenges?

Dr Voorhees: I think there are 2 particular unmet needs in newly diagnosed multiple myeloma. We talked earlier about the fact that patients with ultra–high-risk myeloma, defined as 2 high-risk cytogenetic abnormalities or more,...still has a suboptimal progression-free and overall survival in spite of the addition of CD38 antibodies into the RVd and KRd backbones. So, I think that’s a group of patients where we really, truly need a new approach; I think as a myeloma community, we need to do more studies specifically selecting new therapies for the patients [with the highest risk]. Another area that I think has been understudied are our patients who are frail and have newly diagnosed multiple myeloma. There are a number of analyses that have been done based off frailty status in clinical trials that have been conducted to date. There’s a group of frailer patients in the real world that many of us see all the time, who are not approached about participating in clinical trials simply because they’re not eligible. What is the best treatment option for that group of patients? I don’t think that we really know the answer to that question. As far as emerging agents or combination regimens or ongoing studies in the pipeline that are of interest, I think one of the most interesting [current] studies is the EMN28 or CARTITUDE-6 trial [NCT05257083]. This is a phase III randomized study that’s taking place in Europe and the United States in which patients are assigned to daratumumab RVd induction therapy, and then they’re randomly assigned to either autologous stem cell transplant consolidation or cilta-cel [ciltacabtagene autoleucel] CAR T-cell consolidation therapy, followed by 2 years of lenalidomide maintenance. So this is a study comparing transplant to CART-cell therapy [in a] head-to-head [comparison], and it’ll be very interesting to see if we see an improvement in longitudinal outcomes with the use of cilta-cel as opposed to high-dose melphalan for transplant eligible newly diagnosed myeloma patients. There was an interesting study that was presented at the plenary session at the 2023 ASH meeting, a study that looked at adding the CD38 antibody isatuximab to the KRd backbone for transplant eligible patients with newly diagnosed multiple myeloma. This [study] was presented by Dr Francesca Gay, and what she showed is that the addition of the CD38 antibody significantly improved achievement of MRD negativity compared to [patients who] got the triplet. [That was,] perhaps, not surprising. I suspect with longer follow-up we will see an improvement in progression-free survival with that quadruplet over the triplet. So [that’s] very interesting. Another study that I think we have to pay attention to going forward is the GMMG-HD7 trial [NCT03617731]. This was the randomized, phase III study that looked at the addition of isatuximab to the RVd backbone in transplant eligible newly diagnosed myeloma patients. [Researchers] previously have published that the addition of isatuximab to RVd improves achievement of MRD negativity as part of induction therapy. And that’s why it’s listed as one of the potential regimens in the updated NCCN guidelines. But importantly, there’s a second randomization in this trial after transplant where patients are assigned to either lenalidomide maintenance or isatuximab-lenalidomide maintenance. And this study is going to help us better understand for those patients [who] get CD38 antibody quadruplets upfront before transplant, is there value to adding the CD38 antibody into the maintenance therapy in that group of patients? [It’s] an area that’s somewhat controversial at this point, but I think that particular study is best positioned to answer that open question.