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Selinexor Approval Shows Promising Future for R/R Multiple Myeloma Treatment

Published Online:9:00 PM, Thu August 8, 2019
Noopur Raje, MD
Noopur Raje, MD
Selinexor (Xpovio) has recently received FDA approval for the treatment of heavily pretreated patients with relapsed or refractory (R/R) multiple myeloma, resulting from the findings of the phase II STORM trial. The approval is indicated for patients who have received at least 4 prior therapies with refractory disease, including at least 2 proteasome inhibitors, a minimum of 2 immunomodulatory drugs (IMiDs), and an anti-CD38 monoclonal antibody.1
 
The rationale behind the STORM study was designing another treatment option for inevitable quad-refractory, and eventually, penta-refractory status in patients with multiple myeloma. The researchers evaluated 122 patients, 48 with quad-refractory multiple myeloma and 31 with penta-refractory disease. These patients were treated with selinexor and low-dose dexamethasone and they demonstrated an overall survival of 9.3 months and more than 11 months in responders.2
 
Researchers found selinexor with dexamethasone to be active in patients with R/R multiple myeloma who were anti-CD38 refractory and in patients with high-risk cytogenic abnormalities. The adverse events seen in the study were considered manageable. The study was the first report of antitumor activity in this patient population.
 
Based on expert opinions, outcomes for patients with penta-refractory or quad-refractory multiple myeloma are dismal, making the approval of selinexor an important and encouraging advancement in multiple myeloma treatment.
 
In an interview with Targeted Oncology, Noopur Raje, MD, director, Center for Multiple Myeloma, Massachusetts General Hospital, talked through the current options for the treatment of patients with relapsed/refractory multiple myeloma and the clinical trial data that will shape the future of the field.

TARGETED ONCOLOGY: 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 1 to 3 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 phase II is approved. 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. 

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

Raje: 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.

TARGETED ONCOLOGY: What are the biggest challenges with this patient population? 

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. 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.

TARGETED ONCOLOGY: What advice would you give to community oncologist in particular about treating this patient population? 

Raje: The best advice is to work closely with an expert in your region. We have a lot of exciting options in this space and they're all in the context of clinical trials, so they're not going to be available in the community setting. But, these options have real potential for long-term disease control. We're seeing minimal residual disease (MRD)–negative disease in the seventh and eighth lines of treatment, which would have been unheard of several years back. There's a lot of potential.
It's important for community oncologists to refer these patients early on and work in partnership with an expert because the whole myeloma landscape is very busy. That's a good problem to have, but it can also get confusing for both the provider and the patients. So, having that expertise would [lead to] the best possible outcome for both.

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

Raje: 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. 

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

Raje: 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.
 
References
  1. FDA grants accelerated approval to selinexor for multiple myeloma. FDA. Published July 3, 2019. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-selinexor-multiple-myeloma. Accessed August 8, 2019.
  2. Chari A, Vogl DT, Dimopoulos MA, et al. Results of the pivotal STORM study (Part 2) in penta-refractory multiple myeloma (MM): deep and durable responses with oral selinexor plus low dose dexamethasone in patients with penta-refractory MM. In: Proceedings from the 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego, CA. Abstract 598.


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