Among a Myriad of Treatment Options, Questions Remain in Newly Diagnosed Myeloma

Shambavi Richard, MD

Despite an ever-growing armamentarium, questions remain regarding the optimization of up-front treatment, use of novel combination regimens, implementation of maintenance therapy, and role of transplant eligibility status in newly diagnosed multiple myeloma, said Shambavi Richard, MD.

“A lot of interesting things are happening in the myeloma field, and we are fortunate to have so many approved agents with different mechanisms of action,” Richard said. “[However,] important, debatable questions [remain] in the up-front management of newly diagnosed multiple myeloma. What is the best induction treatment? Is quadruplet therapy better than triplet therapy? Are we ready to replace bortezomib (Velcade) with carfilzomib (Kyprolis)? What about high-risk patients? What about transplant ineligible patients?”

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on Multiple Myeloma, Richard, an assistant professor of medicine, hematology, and medical oncology in the Center of Excellence for Multiple Myeloma at Mount Sinai Hospital, discussed pivotal data in the myeloma paradigm, as well as remaining questions that future research efforts should aim to address.

OncLive^®: What does the up-front treatment of patients with multiple myeloma consist of, and how does it compare with historical standards?

Richard: We are entering a very exciting new era in the management of patients with multiple myeloma. Our philosophy is starting to change, and we are no longer content with suboptimal responses while we wait for our patients to relapse. Now, we are looking for deep, sustained remissions. Minimal residual disease (MRD) response assessment is becoming an important end point in several clinical trials, even as a primary end point in some. It is also starting to sneak into clinical practice.

With the approval of many new drugs with many new mechanisms of action, it is becoming more of a reality that we can start to [approach] the goal of cure in the not-too-distant future. That is exciting, not to mention the explosion of T-cell redirection maneuvers. Bringing [these approaches] earlier into our treatment plans is something that is very exciting to look forward to.

What role does transplant play in multiple myeloma, and what factors do you consider when deciding whether a patient is transplant eligible or ineligible?

The division between transplant eligible and transplant ineligible is somewhat of an artificial construct. Perhaps it started off with certain medications such as melphalan that we did not want to use up front for transplant-eligible patients. However, these are regimens that we can use today for transplant-eligible as well as transplant-ineligible patients. When you divide patients, it implies that the goals of care are different. The regimens that were used [for transplant-eligible and transplant-ineligible patients] were different, but I am not sure that is the case anymore. We may have to do certain dose modifications for frail patients with comorbidities, but overall, I am not sure we want to continue to think of patients in non-overlapping categories.

Patients are living longer and longer. The lifespan of our patient population is increasing as is the efficacy of our treatments. We are looking for treatments that are sustainable for the long term to produce great remissions without negatively impacting quality of life.

Could you shed light on the MAIA trial and the significance of these data in patients with untreated multiple myeloma?

In the MAIA trial, we are applying the same concept that we tried in a couple of other scenarios, which is basically adding daratumumab (Darzalex) to an established standard of care regimen. We did that with the transplant-eligible group. It has been proven in phase 3 randomized trials in the relapsed/refractory space that adding daratumumab to standard of care regimens increases response rates and depth of remissions and prolongs remission durations.

The MAIA trial just applies the same concept to the transplant-ineligible group using the standard of care lenalidomide (Revlimid) and dexamethasone (Rd) as established by the FIRST trial. The [MAIA] study uses Rd as the control arm, and the experimental arm adds daratumumab to that. Not surprisingly, the study is showing [similar findings] with better response duration, response rate, and depth of response. This is a concept that we are continuing to experiment with in various treatment groups.

Could you expand on the FORTE trial? What were the key takeaways from the study?

The FORTE trial teaches us a couple of things, or perhaps confirms a couple of things that we had a sense of. One is that a proteasome inhibitor-based triplet, an immunomodulatory agent (IMiD) in combination with a proteasome inhibitor is better than cyclophosphamide plus a proteasome inhibitor. We’ve seen this already in the Intergroupe Francophone de Myelome trial where we saw that [lenalidomide, bortezomib, and dexamethasone (VRd), plus transplant] was better than [VRd alone]. It is not surprising, but it is interesting to note that even when they put in carfilzomib, this seemed to hold true. It also seemed to remain true in spite of adding transplant to the cyclophosphamide triplet, wherein we still not did not get to the equivalency of an IMiD plus a proteasome inhibitor-based triplet. That is one thing that we have learned.

The other thing we see is that transplant [still plays a role in the current paradigm]. Now, we are perhaps looking at transplant more for high-risk patients to reduce the risk of early relapse because transplant still appears to be superior to non-transplant [alternatives] such as prolonged induction therapy. We have to continue to understand where transplant fits into [the paradigm]. [Should transplant be] reserved for a subspecialized high-risk group?

What are the clinical implications of the GRIFFIN and CASSIOPEIA studies for patients with transplant-eligible disease?

These are the 2 big trials [that we think of] when we consider up-front induction regimens for the transplant-eligible group. The GRIFFIN trial is the United States counterpart to the CASSIOPEIA trial, which was a European study. CASSIOPEIA is a bit ahead of the game compared with the GRIFFIN trial, but they both prove the same concept that adding daratumumab to a standard of care regimen seems to improve [outcomes]. The response rates, depth of responses, and remission durations are getting better. When you combine this in an induction regimen and consolidation with transplant, we’re seeing unprecedented rates of stringent complete response and MRD negativity compared with transplant and cytotoxic chemotherapy. That is very exciting.

As I said, the CASSIOPEIA trial is a bit ahead of the game where we now have 18-month progression-free survival data that shows a hazard ratio of 0.47. I expect to see similar results from the GRIFFIN trial. This is the first time we are seeing the clinical benefit of adding daratumumab to standard of care treatment in transplant-eligible patients with newly diagnosed multiple myeloma.

Could you speak to the initial findings from the Washington University School of Medicine phase 2 study evaluating maintenance ixazomib (Ninlaro)?

The question of maintenance therapy has been debated. There have been a lot of different studies on maintenance therapy, but the best data we have is for lenalidomide maintenance. The phase 2 study [enrolled patients] following autologous stem cell transplant. Patients received ixazomib, lenalidomide, and daratumumab consolidation and were then randomized to maintenance with ixazomib or lenalidomide for 3 years.

The interim analysis [revealed] that the ixazomib arm showed an inferior remission duration. Patients are being given the option and are actually being encouraged to switch to lenalidomide. I think ixazomib will still be an option; we shouldn’t write it off. It is an oral proteasome inhibitor, so it may be worthwhile for patients who can’t tolerate lenalidomide. Certainly, we have to see the results of the TOURMALINE trial that is showing benefit with ixazomib. However, it does seem like this is one of the few trials where we see lenalidomide performing better in a head-to-head fashion.

What is your take-home message regarding the future treatment of patients with newly diagnosed multiple myeloma?

There is a lot of exciting data coming up. As we treat patients, we observe that patient attrition and diminishing returns are important concepts to keep in mind. Not everybody gets onto the ninth or tenth line of therapy, and even when they do, the response with the initial lines of therapy is so much better compared with later in treatment.

It is important to use our best regimens in the beginning when patients are in better health and are better able to tolerate these regimens. We have to try to get rid of these clones early so that they don’t have a chance to persist and mutate over time. Improving up-front regimens is the big thing that we should be focused on now. The quadruplet regimens that are being tested now are an important part of this goal.