In a phase Ib/II dose escalation study, rapid and tolerable responses were seen with the combination of selinexor, daratumumab, and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma who were previously exposed to immunomodulatory and proteasome inhibitors.<br />
Cristina Gasparetto, MD
In a phase Ib/II dose escalation study, rapid and tolerable responses were seen with the combination of selinexor, daratumumab (Darzalex), and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM) who were previously exposed to immunomodulatory (IMiDs) and proteasome inhibitors (PIs).
As a single agent, selinexor, a selective inhibitor of the protein exportin-1 (XPO1), has demonstrated antitumor activity in patients with RRMM. The study concluded that selinexor, in combination with daratumumab and dexamethasone, can be safely and effectively administered at 100 mg.
“With limited results of only 9 patients, we started to see very rapid responses with this population of mainly pretreated patients. In daratumumab-naïve patients, the response rate was 83% and we had 50% of patients achieving a very good partial response…it is very encouraging data,” said Cristina Gasparetto, MD.
In an interview withTargeted Oncology, Gasparetto, associate professor of medicine, leader of Myeloma Program, Duke University Medical Center, discussed these encouraging findings, as well as other ongoing data showing promise for new treatments in the field of RRMM.
TARGETED ONCOLOGY:Can you provide some background information on this study?
Gasparetto:Preliminary results were presented on the combination of selinexor, daratumumab, and dexamethasone in patients with relapsed/refractory myeloma previously exposed to IMiDs and PIs.
Selinexor is an interesting new drug. It is an oral selective inhibitor of the protein XPO1, which reactivates some of the tumor suppressor proteins. In myeloma, some of the most relevant proteins [such as] p53 and Ikappa-beta, activate the glucocorticoid receptors and reduce the level of c-MYC. Additionally, in vitro, there are preliminary data showing that selinexor resensitizes myeloma cells to daratumumab.
In the phase Ib portion of the study, we were trying to identify the dose of selinexor in combination with daratumumab. In the first cohort, the selinexor was given at 60 mg twice a week. The dexamethasone was also given twice weekly at 20 mg with daratumumab at 60 mg. Three patients were enrolled into this cohort and we had 2 dose-limiting toxicities (DLTs). Six additional patients were enrolled in an additional cohort where selinexor was given once weekly at 100 mg. Dexamethasone was also given weekly at 40 mg, and daratumumab stayed at the same dosage. There are no DLTs so far, so this dosage will remain the same for the phase II portion of the study.
With limited results of only 9 patients, we started to see very rapid responses with this population of mainly pretreated patients. In daratumumab-naive patients, the response rate was 83% and we had 50% of patients achieving a very good partial response. We need to remember that this was a very small number of patients, but it is very encouraging data. The overall response rate (ORR), including patients who were refractory to daratumumab, was about 60% to 63%. The response, as I mentioned, was very rapid after only 1 cycle of therapy.
In terms of toxicity, we have seen myelosuppression with thrombocytopenia and neutropenia. In fact, in the first cohort of 3 patients with the biweekly administration, [there was] 1 DLT of thrombocytopenia. We also observed some fatigue and gastrointestinal (GI) side effects, which were manageable with antiemetics.
We are still trying to understand the role of this drug. But the fact that it resensitized myeloma cells to daratumumab makes it a very appealing combination. And, preliminarily, the response rate in this heavily pretreated population was very encouraging.
TARGETED ONCOLOGY:What are the immediate next steps for this trial?
Gasparetto:I think that we are going to expand the study to a phase II portion now that the dosage of weekly selinexor with weekly dexamethasone and daratumumab seems to be the correct dosage. We will expand and proceed with the enrollment of more patients so we can have more definitive data regarding effectiveness, durability of response, and side effects.
TARGETED ONCOLOGY:What are the main challenges you’ve found with this new drug?
Gasparetto:The myelosuppression and the hematologic toxicity. We also see a fair amount of thrombocytopenia, leukopenia, and neutropenia, so we need to support the patients aggressively or empirically or cover them for risk of infection. We didn’t have a very high risk of infection in the study, but this was very preliminary.
TARGETED ONCOLOGY:Are there any other combination studies with selinexor that you are interested in?
Gasparetto:This combination was a part of the STOMP study [NCT02343042]. In this study, selinexor was added to the backbone therapy for myeloma: selinexor in combination with lenalidomide (Revlimid) and dexamethasone, selinexor in combination with pomalidomide (Pomalyst) and dexamethasone, and selinexor in combination with bortezomib (Velcade). The selinexor/bortezomib/dexamethasone study is now ongoing with a phase III randomized study, comparing selinexor and bortezomib to bortezomib and dexamethasone. The response was enormous. In sensitive patients, [the ORR] was up to 83%, and there was a very high number of patients, around 60%, responding even if they were refractory to bortezomib. With the addition of selinexor, the drug was actually able to recapture the response in these refractory patients.
We are learning about the drug and how to manage the toxicity. It is unclear what the dosage should be and the different combinations that should be used, but I think there is a potential new addition to the drugs which we already have available for myeloma right now. The advantage is that it is given by mouth, it is an oral drug, which is always key for patients. These are just preliminary, but very exciting, data for this new drug.
TARGETED ONCOLOGY:Are there any other studies that you are excited about?
Gasparetto:While I am excited about a lot of different studies and concepts, I was personally involved in the phase II study with venetoclax (Venclexta) and dexamethasone. Venetoclax is another new agent, a BCL-2 inhibitor, and it was presented last year as a single agent. The phase II study is the expansion with the addition of dexamethasone, and the study that we are going to present on this combination is only for patients with a 11;14 translocation, the target of the drug.
The overall response in this population of patients was also very promising. We do have several patients that showed, with a relatively short follow up, sustainable response. With venetoclax, we were concerned with tumor lysis syndrome in the beginning. But in myeloma, it has not been a major problem. We had some patients showing some tumor lysis, but it was not very severe and it was manageable with intravenous fluids. We used to start the drug at a very low dose and lead up to the proper dose, but now we start the drug out of the gate at a dose of 800 mg, which is the established dose, with no real issues. There are some GI side effects with this drug, also some myelosuppression, but they are not very pronounced. I think, overall, it is very well tolerated.
TARGETED ONCOLOGY:What is the significance of those results?
Gasparetto:Venetoclax is targeting a specific subset of patients, patients with an 11;14 translocation. The significance is that we are switching to more personalized medicine. This is one of the first targeted therapies that we have. Venetoclax is given in combination with other agents and we are going to learn more about this drug. Specifically, we want to position which one is going to be the best combination.
In my opinion, it is very well tolerated. There are patients with plasma-cell leukemia that carry the 11;14 translocation, so it would be very interesting to add the venetoclax to more aggressive combinations for this population of patients as well.
These studies fall under the new agent category, so they are not yet approved by the FDA, but we are accumulating more data. There are both on to phase III studies, so hopefully we will have 2 additional drugs [selinexor and venetoclax] available for the treatment of our patients relatively soon.
I think these are very preliminary, the number of patients treated on the STOMP study and the combination with selinexor was very small. But we are all very excited by the signal. Additionally, selinexor was reported as a single agent in combination with dexamethasone and it has activity even in penta-refractory and quad-refractory patients. So, as a single agent, it is effective, which is very important.
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). Presented at: the 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, GA. Abstract 3100.