Raje Relays Recent Developments in Multiple Myeloma

Noopur S. Raje, MD

The multiple myeloma pipeline continues to explode with considerable strides in the treatment paradigm, whether it relates to the use of induction therapy, transplant, and maintenance treatment in the up-front setting or research regarding quadruplet, BCMA-directed, or other novel regimens in the relapsed/refractory setting, explained Noopur S. Raje, MD.

“We have a lot of good new drugs in myeloma. We just had the 2020 ASCO Virtual Scientific Platform and the 2020 European Hematology Association (EHA) Congress. Both meetings were virtual because of the coronavirus disease 2019 pandemic. However, that did not detract from the impact of the data that was presented,” said Raje.

In an interview with OncLive, Raje, professor of medicine at Harvard Medical School and director of the Multiple Myeloma Program at Massachusetts General Hospital, discussed some of the most noteworthy research presented at the 2020 ASCO Virtual Scientific Program and the 2020 EHA Congress in multiple myeloma.

OncLive: Several studies were recently presented at the 2020 ASCO Virtual Scientific Platform and the 2020 EHA Congress. Could you highlight the key takeaways from these studies?

Raje: We saw the Blood and Marrow Transplant (BMT) Clinical Trials Network (CTN) 0702STaMINA data, which evaluated whether a tandem transplant had any benefit. In a post-hoc analysis of the intent-to-treat population presented by Parameswaran Hari, MD, MRCP, of the Medical College of Wisconsin, we saw that tandem transplant may be of benefit in a small subset of very high-risk patients.

Another question, which was asked of the BMT CTN database, was the role of maintenance treatment and whether we can stop [this type of therapy] at a certain time point. The investigators selected a 3-year cutoff and found that patients who stopped lenalidomide (Revlimid) early had a worse outcome, suggesting that maintenance should be continued until progression.

Another important trial that was presented was the randomized ENDURANCE study. Shaji Kumar, MD, of Mayo Clinic, very nicely presented the data in the newly diagnosed setting. These patients were supposed to be transplant-deferred patients. Investigators randomized patients to receive carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd) versus bortezomib (Velcade), lenalidomide, and dexamethasone (RVd), which are 2 of the most commonly used regimens in practice. Close to 500 or so patients were included in the trial.

There is a second randomization to this trial as well, asking the same question as the BMT CTN data set had asked. We don’t have data to speak to that yet. However, we did see that the response rates were comparable between the 2 groups. The duration of response (DOR) and progression-free survival (PFS) did seem to favor the RVd arm. This was largely dictated by the fact that a lot of patients were older than 70 years and were not necessarily transplant eligible. About 30% of the patient population ended up undergoing transplant. The bottom line was there was a little more toxicity in the elderly patient population getting KRd.

Another important caveat to remember is that investigators didn’t include patients with high-risk cytogenetics, only those with standard-risk cytogenetics. Although RVd and KRd had equal efficacy, we saw more toxicity with KRd, specifically in the older patient population.

The toxicity was fairly expected. We mostly saw fluid retention, shortness of breath, and cardiac-related toxicities, which we’re familiar with, with carfilzomib. The trial did not necessarily address a transplant-eligible patient population. In a fit, healthy patient, you could use KRd or RVd. In an older patient, RVd is the more favorable triplet regimen because it causes less toxicity.

A new drug application was submitted to the FDA for melflufen in triple-refractory myeloma, based on the results of the phase 2 HORIZON trial. Could you highlight these findings?

Melflufen is a newer version of melphalan, which we’ve had in myeloma for many years. It’s essentially an alkylating agent. It’s a novel drug with less toxicity. The combination of melflufen and dexamethasone was effective in about 20% or 30% of patients with triple-refractory disease, and the median DOR was also quite significant, at approximately 3 months.

The trial did include a lot of patients who already had melphalan. A lot of patients had seen prior high-dose chemotherapy, and even so the intravenous formulation of an old alkylating agent still had efficacy. This is a good tool to have in our armamentarium, specifically in the triple-refractory patient population where response rates are quite dismal.

We have some data from the MAMMOTH trial, which comprised a real-world data set, in which investigators looked at patients who were refractory to lenalidomide, pomalidomide (Pomalyst), carfilzomib, bortezomib, daratumumab (Darzalex) and isatuximab (Sarclisa). These patients’ response rates are extremely low with a PFS ranging from weeks to a couple months. This translates to poor overall survival of about 6 or 7 months. Melflufen was not used in this patient population, but now there is some evidence to suggest it has efficacy in triple-refractory patients. It’s also a very convenient regimen. Melflufen gives us another tool in our armamentarium to use, mostly to bridge a patient to their next therapy.

Could you highlight the data from the phase 2 GMMG-CONCEPT trial?

This was the phase 1/2 study that evaluated KRd plus isatuximab, which is a CD38-directed monoclonal antibody. Three-drug combinations have been accepted as [standards of care] in the up-front and relapsed settings. The question is, “Can we do better?” With this particular quadruplet, we saw a 100% response rate with a very high proportion of patients achieving minimal residual disease (MRD) negativity. Other trials are ongoing, a couple of which have already been presented.

In 2019, we saw data from the CASSIOPEIA trial with daratumumab plus bortezomib, thalidomide (Thalomid), and dexamethasone (VTd). VTd was used because it is sort of the standard of care in Europe, since lenalidomide was not yet approved there. Here too, investigators saw very high response rates and MRD negativity. The depth of remission or response is very clear with these 4-drug combinations.

In the United States, we have the GRIFFIN trial, which evaluated RVd plus daratumumab. These data were presented by Peter Voorhees, MD, of Levine Cancer Institute, and showed a very high and deep responses and MRD negativity. It’s still too early for all of these 4-drug combinations. We know they are well tolerated.

The question is, “Can these patients continue on therapy and for how long? Will it in some way impact whether they get to transplant?” We’re not asking those questions yet. Most of these studies have transplant built into them, so [the regimen] could be used as induction. Ultimately, will the depth of response translate into improved DOR and improved PFS? Will MRD negativity enable a curative strategy in myeloma? The bottom line is 4-drug regimens are here. We’re using them, and they seem to be well tolerated and have really good efficacy.

Would you like to highlight other data from either medical meeting?

We saw the results of the BOSTON trial with selinexor (Xpovio), which is an oral selective inhibitor of nuclear export proteins that causes cell death in myeloma. Selinexor had been studied previously in the STOMP and STORM trials, the latter of which served as the basis for the agent’s accelerated approval in 2019. The BOSTON trial is the confirmatory trial.

In the trial, patients were randomized to receive selinexor plus bortezomib and dexamethasone (Vd) versus Vd alone. We saw a 4-month PFS benefit with the triplet in patients who had received up to 3 lines of treatment. Selinexor is here to stay, but we’re struggling with the dosing and schedule of selinexor. We need to better understand how to incorporate the agent with some of our other combinations. I do believe we’ll use the agent at a different schedule and in a different combination in the future.

Another thing that should be mentioned are the cellular modulators, which are the next generation of immunomodulatory drugs. These drugs are even more potent than lenalidomide and pomalidomide. At nanomolar concentrations, they can block downstream targets of lenalidomide and pomalidomide, these being Ikaros and Aiolos, which are the downstream transcription factors of cereblon. They bind to cereblon, and in doing so degrade Ikaros and Aiolos at very low concentrations. They also have an immunomodulatory arm to boost the immune system.

Data on iberdomide have already been presented. These patients were refractory to lenalidomide and pomalidomide. Despite that, this oral compound caused a response rate of 30% in combination with dexamethasone. A lot of patients who responded had durable responses. The drug is being combined with a whole host of agents. This is something we’re all looking forward to in the near future. It’s a good drug to combine with; it’s extremely well tolerated.

In terms of BCMA-directed strategies, we’re waiting for the FDA approval of the antibody-drug conjugate belantamab mafodotin. At the 2020 ASCO Virtual Scientific Program, Ajay Nooka, MD, MPH, of Winship Cancer Institute, presented data with the agent in combination with bortezomib. We saw a very high response rate of 70% or 80%. Our hope is that the FDA will approve it.

Data from the DREAMM-2 trial showed a response rate of about 30% to 35%, which translated to a PFS of around 3 to 4 months, depending on the dose. There are a couple of toxicities to keep in mind, one of them being ocular toxicity that results in corneal irritation. We also see thrombocytopenia. As long as we can manage that, this is going to be a good off-the-shelf approach we can use.

In terms of CAR T-cell therapy, we saw 3 very exciting trials at the 2020 ASCO Virtual Scientific Program. The KarMMa trial, presented by Nikhil Munshi, MD, of Dana-Farber Cancer Institute, is probably the biggest CAR T-cell therapy trial in myeloma. We saw data on approximately 128 patients with a very high response rate and very tolerable toxicity, translating to a PFS of about 10 months. If you look at patients who achieved a complete response, the PFS was close to 20 months. We also saw data from the CARTITUDE-1 trial with LCAR-B38M, as well as the EVOLVE trial with JCARH125, both of which showed really high response rates. The difference here is that the duration of follow up is a lot shorter [and the patient population is more limited] than in the KarMMa trial. We have to wait on the durability of those responses. However, all of them have response rates north of 90%, which is pretty amazing.

What did you enjoy discussing at the Medical Crossfire?

There’s so much going on in myeloma that it’s hard for us to pull it all together. We had Kenneth Anderson, MD, of Dana-Farber Cancer Institute, who is fantastic. I participated in the Medical Crossfire in 2019, and it was a lot of fun. We all don’t necessarily agree on everything, but [it’s nice to] talk about all of these data in the context of cases and have a discussion.

There’s so much to talk about. When we put [these advances] in the context of patients, one can begin to understand and appreciate how to use [these agents] in practice, which is really the purpose of the Medical Crossfire, to bring in that debate and discussion and come up with ideas on how to apply this information in the real world.

What are some of the biggest challenges in this space right now?

We have patients who have extramedullary disease, which is very difficult to treat. However, some of the new drugs that we have can treat these patients. Part of the problem is clinical trials do not allow us to enroll those patients because we don’t have a way of measuring disease burden. As soon as we get these drugs approved, we can change the natural history of high-risk disease and extramedullary disease, which will be a game-changer.

Where should future efforts should be focused?

We have a lot of different agents in the BCMA space, which is great, but we need to begin to think about how we can sequence and combine them.

We’re also still struggling with the definition of smoldering multiple myeloma, and we’re still thinking about treating patients with smoldering myeloma. In an ideal world, I would like to get rid of smoldering myeloma, so that patients either have myeloma or they don’t, so we’re not undertreating or overtreating a subset of patients. Better risk identification is absolutely critical.

We have MRD as a tool, and we talked about that at the Medical Crossfire. With MRD, we should be able to identify not just the depth of response but follow the kinetics of MRD negativity and use that as a tool to tailor therapy. It is so important that we don’t overtreat or undertreat patients. Having these tools in our toolbox will allow us to better get at those questions. Hopefully, 5 years from now, we’ll have some answers to these questions.