Selinexor/Daratumumab Combo Shows Promise in Relapsed/Refractory Myeloma

Cristina Gasparetto, MD

The combination of daratumumab (Darzalex), selinexor, and dexamethasone continued to demonstrate deep and durable responses in patients with multiple myeloma who have previously received ≥3 lines of therapy, which include an immunomodulatory (IMiD) agent and a proteasome inhibitor, according to updated phase Ib findings presented at the 2018 ASH Annual Meeting.

Although there are a number of treatment options available for this patient population, including bortezomib (Velcade), carfilzomib (Kyprolis), lenalidomide (Revlimid), and pomalidomide (Pomalyst), selinexor is a novel drug that pairs well with daratumumab. Results from this study also showed that the unique combination is well tolerated in this patient population.

“For patients who have failed pomalidomide, using daratumumab in a different combination, like this one, is very exciting, showing an incredible response rate. As I said, it’s a novelty of a drug, unique and different class, so we will see what is happening with the different combinations now,” said Cristina Gasparetto, MD.

OncLive: Can you give an overview of this trial?

In an interview with OncLive, Cristina Gasparetto, MD, professor of medicine and director of the myeloma program at Duke Cancer Institute, discussed the findings from this trial and how the results compare to data from the STORM trial.Gasparetto: This was a combination of selinexor, daratumumab, and dexamethasone. This combination is actually one of the arms of the STORM study. Selinexor is an oral selective inhibitor of exportin 1 (XPO1), which is the major nuclear export for many tumor suppressing proteins, oncoproteins, and glucocorticoid receptors. Selinexor has been tested in combination with low-dose dexamethasone and yields an overall response of about 26% in heavily pretreated patients.

What are the safety and efficacy findings so far?

The STORM study was designed to target relapsed/refractory multiple myeloma. Selinexor was combined with different backbone therapies for myeloma, bortezomib plus dexamethasone, carfilzomib plus dexamethasone, lenalidomide, pomalidomide, etc. I presented the results for selinexor [plus] daratumumab.We enrolled 28 patients so far, and the primary objective of this study was to determine the recommended dose for a phase II portion of this study, to find the maximum tolerated dose. [Of the] enrolled 28 patients, 3 patients were enrolled in the first cohort where selinexor was given biweekly, but it was not really well tolerated in combination with daratumumab, so the next cohort was [given] 100 mg once a week. That was clearly relatively well tolerated. We didn’t have any dose limiting toxicities, so selinexor 100 mg with daratumumab as prescribed and dexamethasone once a week is the recommended phase II dose for the phase II portion.

The toxicity was similar to the STORM study, where selinexor was given in combination with dexamethasone, but in the STORM study, selinexor was given twice a week. In this study, it was once a week. We have seen the same type of toxicity, but the majority of patients have grade 1 and grade 2 gastrointestinal toxicity with only few patients having grade 3 nausea and vomiting. The majority were manageable. We also had some constitutional symptoms: fatigue, weight loss, and hyponatremia, with a few patients having grade 3 hyponatremia. Overall, I think the once a week administration was more tolerable, and with proper care and dose adjustment, these patients are able to tolerate the drug for a long period of time. We also have seen an immunologic toxicity, such as in the STORM study, with thrombocytopenia most predominant, but also some anemia and neutropenia.

In terms of efficacy, we had 26 patients evaluable for response, and 24 were daratumumab-naïve. They’ve never received daratumumab. As part of the inclusion criteria, the study patients had to have failed at least 3 prior lines of therapy, including proteasome inhibitors and IMiDS, or were refractory to PIs and IMiDS. The median prior regimens was about 3. All patients were exposed to IMiDs and PIs and the overall response was 79% for patients who were daratumumab-naïve. We then dissected the population, and the responses remained the same, still very high in the 80% range, even in patients who were exposed to both lenalidomide, pomalidomide, carfilzomib, bortezomib, so their response really didn’t change based on their prior lines of therapy.

The median time on treatment for patients achieving a good response, at least a good partial response, was about 7.3 months, which was not bad. The progression-free survival (PFS) has not been reached yet, so you know the conclusion was that was definitely a good combination. It was an amazing combination in this population of patients, relatively well tolerated with administration now once a week, and with the phase II dose of 100 mg we determined, we are still following a lot of these patients. Half of them are still on treatment, and some of the patients, about one-third, have achieved a deep response. We’re still waiting to determine if patients will achieve a complete remission. Sometimes with daratumumab, you have to wait several months.

What is the significance of these results?

Is there anything else that is important to highlight about these data?

Overall, it was a good study. The clinical benefit was actually even higher at 88%, so we were all pleasantly surprised by the fact that it was more tolerable and given once a week, and of course this population was more robust than the STORM study where they were more heavily pretreated. They have more of a better performance status, but some patients are able to continue therapy for a prolonged period of time, so it was exciting.We do have several options now for this population of patients, but a new drug with a different mechanism of action that we can actually partner with other drugs like daratumumab is becoming very important because, as you know, when patients fail the lenalidomide, bortezomib, and pomalidomide, daratumumab is approved in combination with pomalidomide. However, for patients who have failed pomalidomide, using daratumumab in a different combination, like this one, is very exciting, showing an incredible response rate. As I said, it’s a novelty of a drug, unique and different class, so we will see what is happening with the different combinations now.Gasparetto: Clearly, both daratumumab and selinexor have single-agent activity in heavily pretreated patients. Daratumumab monotherapy is about 29% in STORM, while selinexor was about 26%, so combining these 2 drugs and achieving a response rate of 79%, we actually have preliminary data in vitro suggesting that selinexor could potentially be associated with increasing the activity of daratumumab, causing myeloma cells to go in apoptosis. I don’t know yet if this is just additive or synergistic, but I think there is an important association of this fact, and the fact, I think again, is that it’s a new class, a new drug, a new option for many patients with myeloma and I’m excited to be a part of this study.

Gasparetto CJ, Lentzsch S, Schiller GJ, et al. Deep and durable Responses with selinexor, daratumumab, and dexamethasome (SDd) in patients with multiple myeloma (MM) previously exposed to proteasome inhibitors and immunomodulatory drugs: results of phase 1b study of Sdd. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 599.