Cristina Gasparetto, MD
Combining selinexor with daratumumab (Darzalex) and low-dose dexamethasone demonstrated an impressive safety profile and early signs of clinical activity in a phase Ib/II dose-escalation study of patients with relapsed/refractory multiple myeloma previously treated with proteasome inhibitors and immunomodulatory drugs (IMiDs).
In the small study, investigators enrolled patients on 1 of 2 cohorts of selinexor at 100 mg weekly or 60 mg twice weekly, both with 16 mg/kg of intravenous daratumumab weekly and 40 mg weekly or 20 mg twice weekly of oral dexamethasone.
All 3 evaluable patients in the 100-mg selinexor cohort had a partial response following 1 cycle, although 2 were unconfirmed. Following this preliminary efficacy, 3 additional patients were enrolled in this cohort. At the time of the analysis, the 3 patients in the 60-mg selinexor cohort had not yet completed dose-limiting toxicity (DLT) evaluation.
In an interview with OncLive
, Cristina Gasparetto, MD, assistant professor of medicine, member of Duke Cancer Institute, discussed this study of selinexor in combination with daratumumab and dexamethasone in patients with relapsed/refractory myeloma.
OncLive: Please provide an overview of this study.
These are very preliminary results of this combination with selinexor, daratumumab, and dexamethasone in patients with relapsed/refractory myeloma that has been previously exposed to IMiDs and proteasome inhibitors. Selinexor is an interesting new drug. It is an oral selective inhibitor of this protein XPO1, which reactivates tumor suppressor proteins. In myeloma, some of the most relevant [proteins] such as p53 and IκBα reactivates the glucocorticoid receptor and reduces levels of c-Myc. Also, in vitro, there are preliminary data showing that selinexor resensitizes myeloma cells to daratumumab.
In this phase Ib portion of the study, we are trying to identify the dose of selinexor in combination with daratumumab. In the first cohort, selinexor was given 60 mg twice a week, and the dexamethasone also twice weekly at 20 mg, and the daratumumab 60 mg/kg. With the patients enrolled in this cohort, we had 2 DLTs, and then 6 additional patients were enrolled on the next cohort where selinexor was given once weekly at 100 mg, dexamethasone also weekly at 40 mg, and daratumumab at the same dosage [as the previous cohort]. There were no DLTs so far, so these will remain the dosages for the phase II portion of the study.
Therefore, these are limited results with only 9 patients, but we actually started to see very rapid responses in this population of heavily pretreated patients. In patients who were daratumumab-naïve, the response rate was 83% with 50% of patients achieving a PR. Again, it is a very small number of patients, but these are very encouraging data. The overall response rate, including patients who are refractory to daratumumab, was about 60%, and the responses were very rapid after only 1 cycle of therapy.
In terms of toxicity, we have seen some myelosuppression with thrombocytopenia and neutropenia. In fact, on the first cohort of the 3 patients with the biweekly administration, one of the DLTs was thrombocytopenia. We also observed some fatigue and some gastrointestinal side effects, which we managed.
We are still trying to understand the role of this drug, but the fact that it resensitizes myeloma cells to daratumumab makes it a very appealing combination. Preliminarily, the response rates in this heavily pretreated population was very encouraging.
What are the next steps?
This study will now go on to the phase II portion with weekly selinexor, dexamethasone, and daratumumab. We will proceed with the enrollment of more patients, so that we will have more definitive data regarding effectiveness, durability of response, and side effects.
Are there any other studies with selinexor that are particularly interesting?
This combination was a part of a study called STOMP. In this study, selinexor was added to a backbone therapy for myeloma. The selinexor/bortezomib/dexamethasone combination is now ongoing in a phase III randomized study comparing selinexor and bortezomib to bortezomib and dexamethasone. The response was enormous in sensitive patients—up to 83%—and about 60% of patients were responding, even if they were refractory to bortezomib. Therefore, with the addition of selinexor, the response was able to be captured in these refractory patients.
We are learning about the drug and how to manage the toxicities. It is unclear what the dosage is in different combinations and if it’s weekly. However, it is a new potential addition to the drugs that we have available in myeloma right now. The advantage for the patients is that this is an oral drug.
Are there any challenges with this drug?
I would say the myelosuppression. There are hematologic toxicities—we see a fair amount of thrombocytopenia, leucopenia, and neutropenia—so it is something that we will need to aggressively support the patients on.
Gasparetto CJ, Lentzsch S, Schiller GJ, et al. A phase 1b study to assess the combination of selinexor and daratumumab in patients with relapsed / refractory multiple myeloma previously exposed to proteasome inhibitors (PI) and immunomodulatory drugs (IMIDS). In: Proceedings from the 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, Georgia. Abstract 3100.