Relapsed Myeloma: With Great Options Comes Great Responsibility

Noopur Raje, MD

There is no shortage of treatment options for relapsed/refractory multiple myeloma, with the armamentarium set to further expand amid the emergence of BCMA-targeting CAR T-cell therapies and antibody-drug conjugates.

The challenge for oncologists, said Noopur Raje, MD, is determining the optimal therapeutic choice given the unique relapse circumstance of each patient.

“A lot depends on the nature of the relapse and how aggressive that relapse is. Was it a symptomatic relapse, or biochemical relapse?...I do think one has to take patient preferences into account as well,” said Raje. “Myeloma is a very heterogeneous disease—it's not one-size-fits-all. The good news is we have a lot of options, but with those options, it becomes very difficult for both the provider and the patient to come up with a decision.”

In an interview with OncLive, Raje, director, Center for Multiple Myeloma, Massachusetts General Hospital, highlighted the multitude of available and emerging options in relapsed myeloma, as well as the key factors for treatment selection in this heterogeneous population.

OncLive: What are the options for patients with relapsed multiple myeloma?

Raje: We have a lot of options for relapsed multiple myeloma and it depends on where they are in their relapse. We have a bunch of different approvals in the context of relapse, up to 1 to 3 lines of treatment. It's also important to recognize what the nature of the relapse is and what kind of treatment the patient has been on prior to the relapse. Are they relapsing on lenalidomide (Revlimid) maintenance, for example, or have they received a triplet combination upfront?

I would argue that the majority of patients today do relapse on lenalidomide maintenance because that is the standard of care for first-line multiple myeloma. When they [do relapse], you want to switch from lenalidomide. Most of the first- to third-line approvals are lenalidomide-based combinations [along] with something else new. That doesn't necessarily apply to this patient population—you want to use something different. I think pomalidomide (Pomalyst)-based combinations should be used earlier and we do have several different pomalidomide-based combinations available. We have pomalidomide with elotuzumab (Empliciti), we have pomalidomide with daratumumab (Darzalex)…The [research] for pomalidomide with isatuximab has been submitted and will hopefully be approved soon. Pomalidomide with bortezomib (Velcade) is approved already and there's ongoing work with pomalidomide and ixazomib (Ninlaro). There's also phase II data with pomalidomide in combination with carfilzomib (Kyprolis).

Depending on the nature of relapse, we have these choices. You can either use a monoclonal antibody or you can use it with a proteasome inhibitor in this context.

How do you decide which of these of these regimens is best for each patient with relapsed multiple myeloma?

A lot depends on the nature of the relapse and how aggressive that relapse is. Was it a symptomatic relapse, or biochemical relapse? If it was a biochemical relapse, you can get away with using pomalidomide and oral combinations. I do think one has to take patient preferences into account as well.

The good news is that we have many choices now. With these choices, we can tailor somewhat to the kind of relapse patients have presented with.

For example, if a patient presents with a skeletal-related event, I would want to have a proteasome inhibitor in the mix. If you have high-risk disease, I would want to have the proteasome inhibitor as well as maybe a monoclonal antibody. If you have renal failure, then you pick one versus the other. Those are the kinds of things that [physicians] have to take into account.

What are the biggest challenges with this patient population?

Myeloma is a very heterogeneous disease—it's not one size fits all. The good news is we have a lot of options, but with those options, it becomes very difficult for both the provider and the patient to come up with a decision. That's where I do think it's very important for patients to be referred to high-volume centers, at least for an opinion, because people who do this work often have a better sense of what would work best in a specific situation.

So, although it's an opportunity, it's also a challenge because sometimes there's difficulty in picking the right regimen. And, I think having that secondary input from someone who is a myeloma expert will probably make a difference.

The other challenge in this space is that despite the fact that we have lots of treatment options, depending on the nature of relapse, the patient's performance status has to be adequate in order for them to be able to tolerate the treatment. This is generally true in early relapses, like second, third, and fourth.

If you look at it, we now have [about] 8 or 9 lines of treatment that patients are on, mostly in academic centers. If you look at the community data though, there's a huge falloff in terms of what patients receive after their second and third relapses. I think a lot of this has do with associated comorbidities that patients have. The fatigue of treatment [is preventing] patients from seeking out treatment after their [second or third relapse]. I think that's a challenge and we need to be able to reach out to the community to educate the patients about the options they have that could alleviate some of the symptoms of their disease.

Is there any new research that you find particularly promising for myeloma?

Every time you look at myeloma there's something new going on. In the relapsed/refractory space, we are studying the BCMA targets and I do think looking at BCMA targets has been very impactful. So, you have 2 different strategies that are on a fast-track for approval.

One is a CAR T-cell approach where you're using cellular therapy to target the B-cell maturation antigen and the second one is a conjugated antibody which is more of an off-the-shelf approach. Both of these, hopefully, will be filed by the end of the year and [we will have these approved]. Along with this, we have a bunch of other approaches targeting BCMA as well. I think we've seen exciting data both at ASCO and at ASH looking at the BCMA BiTE antibody and seeing deep responses and MRD-negative disease in this patient population.

The data look extremely exciting and encouraging and I do think referring these patients early to disease centers that are doing some of these clinical trials is going to be very important.

A few weeks back, selinexor [was approved], which is a transport/export inhibitor. This is for patients who are penta-refractory. When I say penta-refractory, it includes refractory to both the proteasome inhibitors (bortezomib and carfilzomib), both the IMiDs (pomalidomide and lenalidomide) and a CD38 monoclonal antibody. Generally, for this patient population, the outcomes are quite dismal. So, to have a drug that has been approved in this setting is a good thing for our patients. We still have a little bit of work to do with selinexor in terms of understanding how it will be tolerated in the patient population and what the best combinations are going to be. But, we do even have oral drugs in that setting.

As of right now, the BELLINI trial, which included venetoclax (Venclexta) is on hold. But, if you look at the data in the 11;14 translocated population, this is the first trial that is looking at a specific genetic subgroup of multiple myeloma where a specific drug (a BCL-2 inhibitor) may be of benefit. There are lots of different options, which is why, again, I would urge people to work with a center that has expertise in these areas.

Where do you see the myeloma field heading in the next decade?

I hope I can say that we are curing a very significant subset of patients with multiple myeloma. At least 40% of patients with myeloma are now living a very long time. I would say 40% to 50% are living more than 10 years on average and a proportion of those are going to be cured.

There is still that high-risk subset of patients, like the ones who have deletion 17p at the time of diagnosis or those with t(4;14) and t(14;16) high-risk features. Typically, their survival is still a lot lower than the average patient with myeloma. I think using some of the strategies that I've mentioned earlier on will get them to the next level. [In my opinion], this is an absolute unmet need, the high-risk population. If we can have better tools for identifying these patients early, that will be very useful.

From a technology standpoint, we are doing well. We have tools like MRD, [which is helpful] whether you use next-generation flow cytometry, or you use next-generation sequencing. In 2019, we're still saying 10 times minus 6. [This might change in the future.] We have that to help us direct in terms of depth of response and what we need to do for treatment.

As far as combinations, [according to an early press release] we're going to see data from the GRIFFIN trial at ASH this year. [The trial is combining] the RVD regimen (lenalidomide, bortezomib, and dexamethasone) with daratumumab. So, we are already using 4-drug combinations. [We already saw the CASSIOPEIA trial data], which is combining VTd (bortezomib, thalidomide, and dexamethasone) in combination with daratumumab.

I think the future in the front-line setting is going to be these 4-drug combinations. The question is do all patients 4 four-drug combinations and in which patients can we peel off treatment or stop treatment after a certain time period. That's where diagnostics, such as the MRD testing, will come into play and the in next 10 years, we will be doing studies to try and address this. I think will have a significant number of patients who will be long-term disease-free and, in my mind, that is the definition of cure.