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Treating Triple-Class Refractory Myeloma With Ajai Chari, MD

Ajai Chari, MD.

With increasing frequency, multiple myeloma is becoming triple-class refractory, or refractory to all three primary classes of drugs used in its treatment. What is to be done in such cases? In the phase 2b STORM study, now published in The New England Journal of Medicine, Ajai Chari, MD, and colleagues report that a combination of oral selinexor and dexamethasone shows efficacy in patients with triple-class refractory disease. In this interview with i3 Health, Dr. Chari discusses the importance of STORM's results regarding selinexor/dexamethasone and shares his perspective on other agents that are in development for triple-class refractory multiple myeloma.

Can you comment on the significance of your study's findings concerning selinexor/dexamethasone in triple-class refractory multiple myeloma?

Ajai Chari, MD: The first point to make is that this is a very hard-to-treat population. Triple-class refractory means that patients are refractory to the three major classes of drugs we use in myeloma: proteasome inhibitors, immunomodulatory drugs (IMiDs), and the CD38 antibody. When patients are triple-class refractory, there is no FDA-approved treatment. The patients in this study had a median of seven lines of prior therapy in 6.6 years, which indicates that not only were they heavily treated, but they also were at high risk because they had used up so many drugs in such a short time. In addition, approximately 50% of the patients were genetically high risk.

From the date of consent to the first day of treatment, a median of 12 days, there was a 22% increase in the paraprotein, or the tumor marker. This is a population for which a reasonable option would be hospice because the median overall survival can be as short as three months. In these heavily pretreated patients, we saw a response rate of 26%. That is on par with other drugs that have received accelerated approval in myeloma in the past. The major difference is that this population has had all of those previous drugs, so this agent fulfills an unmet need. I think that's what led to its approval.

How does the selinexor/dexamethasone regimen compare to other treatments in development for triple-class refractory myeloma in terms of efficacy?

Dr. Chari: There are some promising agents in development, in particular the anti-BCMA therapeutics, which include chimeric antigen receptor (CAR) T-cell therapy, bispecific T-cell engagers, and also an antibody-drug conjugate. However, none of those are yet FDA approved, and also none of those studies required what this study required: not only exposure to all five drugs, including bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab, but also disease that was refractory to each class. Some of these studies will have some of that patient population, but that is something that is very different about STORM, and it is important because this is really a difficult-to-treat population. Also, the blood count parameters for our study were relatively permissive, and in terms of renal function, creatinine clearance only had to be 20 mL/min. A lot of novel agents require a much better renal function and much higher blood counts. In spite of that, this study showed favorable results.

Can you comment on the safety of the selinexor/dexamethasone regimen?

Dr. Chari: There certainly are toxicities with all novel therapeutics. This is an oral agent, which is nice and convenient for patients. However, it does have toxicities, which I think are manageable. What's most gratifying to patients in terms of staying on treatment is the response. At our site, our response rate was even higher because we were able to use aggressive supportive care and keep people on drug therapy longer; as a result, we were able to see these great responses. I think that's what's really important about the safety and tolerability: to be aggressive with the supportive care.

The main toxicities are hematologic, which is important to mention. This drug is being studied in other tumor types, and in those tumor types, such as lymphoma and solid tumors, you don't see as much hematologic toxicity as you see in myeloma patients in this study because these patients are very heavily pretreated and myeloma typically has a higher bone marrow involvement. For this reason, some of these low blood counts are partly due to the disease and not just the drug. However, blood counts are one issue. The gastrointestinal symptoms, including nausea or anorexia, present another side effect. Because our site was very aggressive with supportive care, we were able to really have almost none of the patients discontinue for toxicity at our location. Fatigue and low sodium, the other two of the big four side effects, are generally manageable.

The other important thing about this drug is that it has a relatively short half-life of six to eight hours, although we think its pharmacodynamic or clinical impact is up to 48 hours. I mention that because even if a patient does have side effects, holding the drug and then reducing it can be quite helpful in managing them. The important thing to remember is that this patient population has disease that is explosive, rapidly progressive, and once we get a handle on the disease control, we very readily can back off on the drug.

Is any further research underway on selinexor/dexamethasone in this population?

Dr. Chari: Yes, there are several efforts underway. One is looking for biomarkers of response or resistance. Our institution has led some work on that, and we presented this year at the American Society of Hematology (ASH) Annual Meeting.

Other work being done is combination therapy. We have to recognize that relapsed/refractory myeloma with such heavily pretreated patients is very genomically complex, and no drug in this setting typically works in a high enough number of patients without combination therapy. If you look at all of the drugs in myeloma that have been granted accelerated approval, the point of these accelerated approvals is to show that this drug works in combination with dexamethasone, but the reality is that in the relapsed/refractory population, we're going to be using a combination strategy. A lot of those studies are already underway and are very encouraging, showing much higher response rates. Importantly for the side effect profile, because you're using combination therapy, you can use a lower dose intensity than you would as a single agent because you have another drug to synergize or have additive efficacy. Therefore, rather than was the case in STORM, for example, where 80 mg twice weekly was used, some of these other regimens are using only once-weekly selinexor. I think that will be good from a risk-benefit optimization point of view.

How do you see treatment continuing to evolve for relapsed/refractory multiple myeloma?

Dr. Chari: Fortunately, there is so much work being done in myeloma, thanks to a lot of collaborations between academia, pharmaceutical companies, nonprofits, and the FDA through organizations such as the Multiple Myeloma Research Consortium. I think that this brain trust with a lot of stakeholders is the reason behind a lot of drug development in this space. As I alluded to, I think that the next big target will probably be anti-BCMA therapies.

It's important to mention that for a lot of the patients that we would like to put on treatments like CAR T-cell therapy, for example, there are not enough slots, and you have to keep patients stable long enough to get to the actual CAR T treatment. After collecting the T cells, having that four- to five-week manufacturing period to get to the infusion is challenging, so that might be another space where selinexor may be able to play a role in keeping patients' disease under control. Interestingly, we've seen responses in CAR T failures with selinexor; in the STORM study, there were two patients who were CAR T refractory and had a partial response. We have submitted additional information about this population—post CAR T failures, which is also a very unmet medical need—to this year's ASH conference.

In closing, what advice can you give to community oncologists and hematologists who are treating patients with triple-class refractory myeloma?

Dr. Chari: I would recommend collaboration with academic institutions. With selinexor, for example, it is very important in that first cycle to be aggressive with the dosing and supportive care followed by disease control because the time to response is within the first month. If a community doctor doesn't have as much experience, either the patient could be treated in an academic center or at least that should be available as a resource by phone for that community doctor to partner with so that the patient can get optimal care and an optimal risk-benefit profile, not only with selinexor but with any agent. If a patient is triple-class refractory, it is essential that he or she gets access to clinical trials. I would strongly recommend that community doctors refer to academia for the very exciting studies that are going on in this space.

About Dr. Chari

Ajai Chari, MD, is an Associate Professor at the Icahn School of Medicine at Mount Sinai, where he is also the Director of Clinical Research in the Multiple Myeloma Program and the Associate Director of Clinical Research in the Cancer Clinical Trials Office. His clinical interests lie in the area of plasma cell disorders, including multiple myeloma, plasmacytoma, amyloid light-chain (AL) amyloidosis, monoclonal gammopathies of uncertain significance (MGUS), and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell proliferative disorders, and skin changes). His research interests include novel chemotherapy regimens for the treatment of these conditions. He has published extensively and is a prominent lecturer on these topics.

For More Information

Chari A, Vogl DT, Gavriatopoulou M, et al (2019). Oral selinexor–dexamethasone for triple-class refractory multiple myeloma. N Engl J Med, 381:727-738. DOI:10.1056/NEJMoa1903455

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