Selinexor, Bortezomib, and Dexamethasone for Relapsed Multiple Myeloma
PracticeUpdate: One of the important studies presented at the conference provides data on a selinexor based treatment combination for multiple myeloma. How is selinexor designed to work?
Dr. Fonseca: Selinexor is one of the most recent drugs that has been approved by the FDA for the treatment of patients with multiple myeloma. This compound is quite interesting in that it blocks a pump that removes tumor suppressor genes, or the proteins associated with this tumor suppressor genes, from the nuclear environment. The idea is that it enriches the nuclear environment for tumor suppressor genes, potentially enhancing the anti-tumor activity of drugs to be used in combination.
Selinexor has been approved in combination with dexamethasone and has been studied in a number of other clinical trials as an adjunct, perhaps as an enhancer, if you may, to the cytotoxic activity of other anti-myeloma therapies. What was presented at the ASCO meeting is known as the BOSTON trial. This is a very important clinical trial, which was a phase III randomized study, that compared to selinexor in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone for the treatment of relapsed and refractory multiple myeloma.
PracticeUpdate: Prior to this report, what data had existed on the activity of selinexor for multiple myeloma?
Dr. Fonseca: Before this particular clinical trial we had very limited data, mostly in the form of phase I and phase II studies and then subsequent comparisons with real world data. But the BOSTON trial was very important because we needed to show conclusively that selinexor does add to the management of patients with multiple myeloma. There was a sense that there would be benefits from selinexor, there were some concerns about the depth of the responses, the durability of some of those responses, and also the management of its toxicity which we will describe further. But in the context of the phase III clinical trial, then you can tease out and identify the specific contributions of this drug for the treatment of myeloma patients. We had seen the results of the STORM trial and also they have the STOMP trial, but in reality, it is the BOSTON trial that becomes a definitive answer for the use of selinexor in advanced multiple myeloma.
It is worth noting that this clinical trial was designed for patients who had received one to three prior lines of therapy and with prior knowledge of the toxicity of the drug and alternative schedule was presented for it to be used in combination.
PracticeUpdate: What was the design of this study?
Dr. Fonseca: The BOSTON trial was designed as a 1:1 randomization between selinexor, bortezomib, and dexamethasone versus bortezomib and dexamethasone. For the selinexor arm, the medication was given once weekly, which is a very important change from how selinexor had been tested before for myeloma, which it was used twice per week. This was dosed at 100 mgs once a week: days 1, 8, 15, 22, and 29. Patients received subcutaneous bortezomib [on] days 1, 8, 15 and 22 and also dexamethasone, this was 20 mgs a day of the bortezomib and the day after.
In contrast, patients who received bortezomib and dexamethasone, they received this twice a week. They received this on days 1, 4, 8, and 11, with the dexamethasone again 20 mgs the day of and the day after the bortezomib infusion. It's important to note that as was presented by the authors that based on this, there was a planned 40% lower bortezomib and 25% lower dexamethasone dose at 24 weeks. That is eight cycles, for both treatment arms.
Being that this was a trial for patients with one to three prior lines of therapy, the idea was to treat until there was progressive disease or unacceptable toxicity. The primary end points for this trial was progression-free survival, but there were some key secondary end points. Overall response rate, the percent of patients achieving a VGPR, the development of a grade II or higher peripheral neuropathy. As well as other secondary end points, such as overall survival, duration of response, time to next treatment, and safety.
The efficacy was assessed by an independent review committee. They stratify the patients according to prior proteasome inhibitor therapy yes or no, the number of regimens one versus more than one, and also the revised ISS stage at the study entry. There was one or two versus stage three. Patients had the usual criteria for progressive myeloma per IMWG. The patients with moderate or severe renal impairment were allowed, except those patients that required dialysis and they needed to have a good performance status of 0 to 2 and adequate hematopoetic as well as hepatic function. Patients with significant neuropathy, so that was more than grade 2 neuropathy were excluded and also prior exposure to selinexor was exclusion for this patient. All in all, it's a very clean the sign of this particular clinical trial.
PracticeUpdate: How does the selinexor-based combination perform in this setting?
Dr. Fonseca: The clinical trial enrolled a total of 402 patients which were, for the most part, equally distributed between those who received selinexor and those who did not. We see that the patients who receive selinexor, there was a cease progression observed in 34% of patients at the time of data cutoff versus 52% for those who achieved treatment with BD alone. Toxicity was seen in a higher proportion of patients treated with selinexor, so 17% versus 11% and the number of deaths was slightly lower in patients being treated with selinexor. Before we explore and talk a little bit about the outcomes, it’s also worth noting that this particular clinical trial, did test for high risk cytogenetic markers and prior exposure of therapies and the treatments were well balanced because this will be relevant as we start talking about the progression free survival.
The results of the BOSTON trial show a progression-free survival that is significantly longer with the addition of selinexor compared with bortezomib alone. The numbers that were reported were close to 14 months versus 9.4 months for the dual medication. This hazard ratio of 0.7 with a significant P value. In other words, they had about a 30% reduction in mortality with the three drug combination. Again, it's interesting and somewhat hypothesis generating, but when you look at the force blot, you start seeing that across the different subgroups, selinexor does seem to favor ... the data favors the administration of selinexor for patients. Also, when you start looking at the response rate, this was superior for the selinexor combination. Overall response rate was 76.4% versus 62%, but then you start looking across the board for the different subgroups of patients and the benefit seems to hold true.
Also, the depth of the response was greater in the selinexor arms. If you look at VGPR, for instance, which may be a good indicator perhaps a little bit more stable in the relapse refractory setting. It was 44.6 versus 32.4 for patients without the selinexor and there's a number of other analysis.
I think it's somewhat early to start looking at them by particularly as one starts thinking of overall survival and time to next treatment. But certainly, from the ones that I think we have maturity, the time to next treatment was 16.1 versus 10 months, which was also statistically significant. All in all it seems that selinexor in this way, when it comes down to efficacy, was a superior combination.
There are some significant toxicities that have been reported with selinexor and we have some aspects of myelosuppression. But perhaps the one that concerns most people is related to the gastrointestinal tract toxicity. There's nausea, vomiting, and decreased appetite and what was seen in this particular clinical trial, nausea was clearly more common in the selinexor arm. It was reported in 50% of patients [in] all grades, 7% [in] grade III and IV versus 10% all grades, no grade three and four for bortezomib and dexamethasone.This is clearly a factor as we think about the administration of selinexor. Also, decreased appetite was 35% versus 5%. We see vomiting, which is present in 20% of patients versus 5%. This is significant, it is important. For this patient population, obviously the symptom management becomes critical for the proper administration of these medications, but I think the trial does show that this is possible.
In my mind, this is a very interesting clinical trial. I think selinexor was off to a difficult start as the drug for the treatment of myeloma, because the initial ways in which it was administered. It was poorly tolerated, but it seems that with dosage and schedule modifications and, as we start thinking of selinexor being part of other combinations, I think there's quite a bit of interest in seeing how this is going to perform in other combinations. There were other posters that were presented at ASCO that included combinations with carfilzomib [and] daratumumab. Not quite the phase III we see here, but I think it's good to keep an eye on selinexor as we go into the future.
PracticeUpdate: Which patients would you consider using the regimen for in clinical practice?
Dr. Fonseca: Clearly, the field of myeloma is moving quickly from an intense induction with either three or four drugs, transplants for those that are suitable, and maintenance perhaps with consolidation. Then, at first relapse, we're seeing that there's a preponderance of evidence that would suggest the treatment with something like a daratumumab combination. We often use daratumumab, pomalidomide, or dexamethasone or carfilzomib, pomalidomide, and dexamethasone would be adequate. I think where the space is moving very rapidly now is for that second relapse.
We have the emergence of T-cell engagers, like CAR T-cells and by specific antibodies. We obviously had some very exciting data presented with a GSK compound, belantamab, but I think that's a space to where selinexor could play a role. Particularly for those patients that are not considered good candidates for T-cell engaging therapy, who may not be good candidates for CAR T-cell. As we learn how to manage the toxicities of the other drugs, including belantamab, I think that's a space that is going to be moving quite quickly. If selinexor were not to be used in the treatment of second relapse, I think clearly it should be considered an option for the third relapse for patients with multiple myeloma. But again, we'll have to see what happens with alternative dosing and schedule.
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