Rapid Changes in Multiple Myeloma Provide a Windfall of Treatment Options

S. Vincent Rajkumar, MD

In the last decade, multiple myeloma has seen a change in diagnostic criteria, an updated staging system, new response criteria, and several novel therapeutic options, explained S. Vincent Rajkumar, MD.

“Newly diagnosed multiple myeloma is a challenge, and relapsed disease is a bigger challenge because there are so many more trials and so many more regimens,” said Rajkumar, a professor of medicine at the Mayo Clinic, during his presentation at the 15^th International Conference on Malignant Lymphoma. “We are going to have many more complex problems in the future. Many [investigational drugs] are in phase III trials and many of them will get approved for multiple myeloma. We have several different options coming up, which will eventually impact the management of relapsed and maybe even newly diagnosed patients.”

New treatment options include an expanded use of quadruplet regimens, including, most recently, the combination of daratumumab (Darzalex) plus bortezomib (Velcade)/thalidomide/dexamethasone (DVTd), which has been evaluated in the phase III CASSIOPEIA (MMY3006) study.

In the trial, demonstrated improved depth of response in patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant. The stringent complete response rate at day 100 post-ASCT was 28.9% in patients who received the daratumumab regimen compared with 20.3% in those who received VTd alone following induction and consolidation therapy (odds ratio [OR], 1.60; 95% CI, 1.21-2.12; P = .001).

In May 2019, the FDA granted a priority review to the quadruplet regimen for the treatment of patients with transplant-eligible newly diagnosed multiple myeloma.

In an interview with OncLive, Rajkumar, a professor of Medicine at the Mayo Clinic, Rochester, Minnesota and 2019 Giant of Cancer Care^® winner, discussed the rapidly changing landscape for the treatment of multiple myeloma, the future of immunomodulatory drugs, and whether quadruplet regimens will become more frequent.

OncLive: Are developments in multiple myeloma moving so rapidly that there is a new standard every year?

Rajkumar: Yes, whether it’s smoldering myeloma, newly-diagnosed myeloma, relapsed myeloma, things are changing really fast. We used to just watch patients with smoldering myeloma and now we are talking about treatment. We used to do VRD for induction for newly diagnosed [patients], and now we have 2 or 3 regimens that are competing with that [approach]. The same thing is happening in relapsed [myeloma]; there is an explosion of options. The standard of care seems to be changing rapidly, but it is all for the good.

What framework can clinicians use to evaluate and implement emerging treatments into their practice? Are there guiding principles for when to introduce a new regimen?

You want data from good, randomized, controlled trial; that should be your guiding principle. Is whatever regimen you want to use supported by a randomized controlled trial that shows benefit? Benefit being defined as improved overall survival or improvement in patient-reported outcomes. Sometimes it is hard to get survival improvements in the newly-diagnosed setting or the smoldering myeloma setting, so you may have to rely on a surrogate endpoint, such as a minimal residual disease (MRD)-negative state or, sometimes, progression-free survival (PFS).

Other principles would be, [for example], for a relapsed patient, you have to look at the timing of the relapse, how they have done with a prior therapy, their performance status, and then make a decision on what the best regimen would be.

In general, for myeloma, we prefer a triplet regimen for frontline therapy and a triplet regimen for relapse as well. That might evolve to some high-risk patients [eventually] needing a 4-drug regimen.

Are quadruplet regimens going to become more frequent in multiple myeloma?

I believe so. There have been 3 studies with quadruplets that have been reported; 2 have been published in the peer-reviewed literature and 1 has been presented in abstract form. These [studies] show better outcomes, at least in terms of target outcomes, such as response, MRD-negative rate, and PFS.

The one that really impressed me was the CASSIOPEIA trial which was recently published in the Lancet. [Investigators] looked at a triplet VTD versus a quadruplet of daratumumab plus VTD and saw an improvement in PFS as well as a trend in improvement to overall survival. Therefore, I believe that as these data mature, we are going to start seeing more [use of] quadruplet regimens [in the treatment of these patients].

From a safety or efficacy standpoint, I am not too concerned. However, from a cost standpoint we have to really consider [whether] [this approach] is going to be affordable, and even if it is affordable for the [United States], will other countries have access to 4-drug regimens?

Are there any emerging therapies that you’re excited about?

There are many investigational drugs that are showing high levels of activity in myeloma. When you start talking about the immunotherapy options, you start talking about CAR T. These CAR Ts are directed against BCMA and at least a couple of them are in late-stage development—1 by Bluebird Bio, and 1 by Legend Biotech with Janssen. [These therapies] are showing very high response rates in relapsed/refractory patients and we’ll see where [the data] goes.

Then there is an antibody-drug conjugate made by GSK (GSK2857916) that is also demonstrating [single-agent activity] and promise; this agent is being evaluated in a phase II trial. There is also AMG 420, a bispecific T-cell engager that has shown promise. Furthermore, there is an antibody called isatuximab, which is a similar to daratumumab, an anti-CD-38 monoclonal antibody that is also in phase III and that data has been reported as well.

That makes for multiple immunotherapy options. Besides that, in terms of drugs, we have selinexor, venetoclax (Venclexta), filanesib, a whole variety of [drugs] that have shown activity in the relapsed/refractory setting as single agents and more and more of these will come.

What are the most significant unanswered questions in myeloma?

There are several unanswered questions. Number one being, if you are going to treat patients with high-risk smoldering myeloma, should you treat with mild prophylactic type therapy with lenalidomide (Revlimid), lenalidomide plus dexamethasone, or do you use a myeloma-like regimen? That [question] is going to be addressed by a current ECOG trial that just opened.

In the newly-diagnosed setting, which is the best triplet to use? Should it be RVD or VRd (lenalidomide, bortezomib, and dexamethasone)? That’s what we’ve been using. Or should it be one of the newer triplets? There are at least 3 or 4 new, different triplets being developed to compete with that.

Are we better off using 4 drugs? Should we use 4 drugs for only some patients and reserve triplets for some other patients? [For example] if a patient is already MRD-negative, do they really need the fourth drug? Can we be more judicious in who receives 4 drugs and who gets 3 drugs?

Is myeloma really 1 disease or is it 6 different diseases? Does each [disease] require a different approach to therapy or shall we still continue to treat all of them the same way? If we are going to treat patients at relapse, should we give treatment indefinitely or should we just try to give treatment for a limited period and give patients a break from therapy?

[There are] many more unanswered questions, [such as] supportive care. It goes on.

What are the research priorities in this space?

The research priorities continue to be to try to cure the disease rather than just to continue to prolong life [because] the patients keep relapsing. There are 2 curative trials: the ASCENT and the CAESAR trials. These trials are targeting patients who are asymptomatic early in the stage of the disease with very aggressive therapy and the goal is [to answer], can we cure a subset of patients? That is one research priority, to try and cure the disease.

Other priorities would be: Try and deliver the most cost-effective care with the options we have available; work out the optimum sequence of therapy—that is important; Figure out duration of therapy—whether it’s duration of maintenance, duration of relapse therapy, what is the optimum duration? Is [the patient] going to receive indefinite continuous therapy or can we get away with shorter durations of therapy and longer breaks without treatment?

Also, what is the role of stem cell transplantation? Can we move immunotherapy to the frontline setting? Right now, most of the CAR T trials are in the relapsed/refractory advanced end-stage population, but a goal would be to see if we could move it earlier and see more benefit that way. Those are all important priorities.

Early therapy of myeloma is critical. Redefining the role of MRD-negative status as a regulatory endpoint and as a goal of therapy is something that we need to act on to change therapy.

Where do you see immunomodulatory drugs, such as lenalidomide, fitting in to the paradigm in the future? Will they remain a backbone of treatment?

Yes, I believe right now you can see that lenalidomide is there for frontline; it is there in the relapse setting; and it is there in maintenance. Many therapies are lenalidomide-based.

Lenalidomide and dexamethasone, basically the RD regimen, is the backbone. It will stay like that for a while because most of the trials—even the ones that are currently being conducted—use the same backbone, at least in the smoldering and in the frontline settings.

As time evolves, Celgene is developing a new drug that seems to be very active, CC220, and [have released results] that it is working, so there might be some attempts to develop more effective immunomodulatory drugs, or drugs that can take the place of lenalidomide. We will just have to wait and see. However, those trials are in very early [stages]. As such, for the foreseeable future, I believe that lenalidomide will play a big role in myeloma, especially in the smoldering and the newly diagnosed space.

Moreau P, Attal M, Hulin C, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 1 results. J Clin Oncol. 2019;37(suppl; abstr 8003).

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