Clinical Data for Selinexor Use in Myeloma

Joshua Richter, MD: The last couple of years have seen this explosion not only of the pipeline of myeloma drugs, but drugs that have obtained FDA approval. And the buzzword around myeloma lately is BCMA [B-cell maturation antigen]; BCMA-targeted antibody-drug conjugates, bifunctional antibodies, CAR Ts [chimeric antigen receptor T-cell therapies]. Now that we have one of these in the clinic, belantamab mafodotin, I was wondering if you could tell us a little bit about it and how you use it in your clinic.

James Hoffman, MD: Yes, belantamab is a drug where you have a monoclonal antibody connected to a cytotoxic, and the target on the myeloma, as you referenced, is BCMA. It’s the first foray into BCMA-targeted therapy, the first approved, an off-the-shelf drug, fairly convenient schedule, given every 3 weeks. It’s been nice to have this. Some of the challenges are, certainly from an [adverse] effect profile, the eye toxicity, keratopathy, is clinically relevant. And it’s tethered to the need to get eye examinations before every single treatment, so you have to in practice have a protocol in place to ensure that gets done appropriately, because these patients will get some keratopathy. The degree of keratopathy, how clinically impactful, will determine whether you dose adjust. It’s a good drug; it certainly can work. Some responses will be deep. To me, one of the challenges is we’re all so excited, we’ll talk in a second about CAR T. But we’re all so excited about BCMA-targeted therapies, and at least in my estimation, this may not be the most effective BCMA-targeted therapy and the least toxic that we get a chance to use. So you have to think before you use this drug, is someone eligible for a trial with BCMA-targeted therapy that this is going to exclude them from? Or are you going to maybe miss a chance to give a more potent BCMA-targeted therapy over time? I’ve definitely used it in multiply relapsed patients who are not trial eligible who need therapy, who can’t wait around for commercial CAR T, etc, and have anecdotally have had some good results, and, again, have had to navigate this eye toxicity on a regular basis. How about you in your practice?

Joshua Richter, MD: Again, one of the wonderful things about this is that so far you and I are practicing essentially identically. I have been using this for people who are not eligible for trial because I agree that pound for pound some of the other BCMA therapies that are coming out are probably better. The one thing I think about in the back of my head is the other modalities, the BiTEs [bispecific T-cell engagers] and the CAR Ts, especially in someone who’s been extremely heavily pretreated, they may not have the most robust T cells. And the benefit of this is that it doesn’t use the T cells to kill myeloma as much as the others. But again, it’s really for those patients more toward the end. I’m excited that, like all drugs in myeloma, it’s approved as a single agent, and there are some interesting trials coming down the pike, especially trials like DREAMM-6, which is combining this with Velcade [bortezomib]. I agree the BCMA landscape’s going to become extremely complicated, and we’re going to have to pick the right patient for a drug like this, but it’s definitely nice to have that in our armamentarium.

James Hoffman, MD: That’s an excellent point in terms of not relying on the immune system. And again, I agree with everything you said. Another new drug with a novel mechanism of action that I know you’re very familiar with is selinexor. Initially it was approved with dexamethasone as part of the STORM study and then more recently with data from the BOSTON study in combination with bortezomib. I’m curious in terms of how you’re using selinexor, how you’re mitigating toxicity, and what your thoughts are in terms of where it fits in the landscape of relapsed myeloma.

Joshua Richter, MD: Absolutely. I’m excited to have selinexor approved now almost 2 years ago. But one of the great things is every time we get a new drug in myeloma or a new mechanism of action, we don’t just get 1 drug, we get many different potential combinations. The BOSTON regimen of SVd [selinexor, bortezomib, dexamethasone] has been great, and the reason I like it so much is that most patients in the US get Velcade as part of their upfront therapy: VRd [bortezomib, lenalidomide, dexamethasone], CyBorD, [cyclophosphamide, bortezomib, dexamethasone], dara/RVd [daratumumab/lenalidomide, bortezomib, dexamethasone], if you’re in a fancy center like one of ours. But Velcade’s not used as commonly in the relapsed setting. We use a lot of dara [daratumumab] and Kyprolis [carfilzomib], and I find a lot of patients are still Velcade-sensitive in kind of the mid relapse. The benefit of this regimen is that it brings back in Velcade, which many patients do quite well with up front, and can do well with again. It’s given once weekly here at a dose of 100 mg as opposed to the original STORM study, which was 80 mg twice a week. Selinexor is tolerated much better if you give it once a week at 100 mg as opposed to twice a week at 80 mg. We use a lot of odd drugs to help prevent symptoms. The 2 biggest ones are Varubi, which is rolapitant. It’s basically similar to Emend, except it has fewer drug-drug interactions with selinexor than Emend does. It’s 180 mg every 2 weeks orally. And for patients who have issues or we think may have issues, there’s olanzapine, old-fashioned Zyprexa, doses ranging from about 2.5 to 7.5 mg. With these approaches, we’ve had a much better ability to use prophylaxis and prevent toxicity with selinexor. I have a number of patients on this type of regimen for years doing well, because some patients don’t respond as well to the IMiDs [immunomodulatory imide drugs], but respond much better to the SINEs [selective inhibitors of nuclear export]. How about you?

James Hoffman, MD: I agree generally. We kind of copied your supportive-care regimen from a patient we once shared in terms of the Varubi. We’ve sometimes struggled to get Varubi for patients, and when that happens, we use Emend, like you referenced. We’ll use this since patients are coming in for their Velcade anyway. They’re in the treatment room. I would agree with you that it was a huge advance from the STORM study, which the benefit/risk was somewhat marginal, and it allows us to get this drug that has a novel mechanism of action and can work for people for whom the classic classes of medicines have stopped working in a way that’s much more tolerable. It’s become a little tricky when you have all of these options after patients have failed the IMiDs, the PIs [proteasome inhibitors], and the monoclonals, where you fit this in. But it certainly has a place, and I have seen it work well for patients who had limited options. There’s a fair amount of supportive care, following counts, etc, and we can dose reduce from 100 mg, and some patients still get good efficacy and find a happy place in terms of [adverse] effects. I was a little more dubious of the drug based on the STORM trial, but in this combination, it is much more tolerable and can be beneficial for some patients.

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