Sborov and Participants Discuss Later-Line Treatment in Multiple Myeloma

Douglas W. Sborov, MD, MS (MODERATOR)

Associate Professor, Division of Hematology and Hematologic Malignancies

Department of Internal Medicine

University of Utah School of Medicine Huntsman Cancer Institute

Salt Lake City, UT

EVENT REGION Arizona, Colorado, New Mexico, Utah

PARTICIPANT LIST Christopher Chen, MD | Muhammad Anas Tarajki, MD | Darshil Shah, MD, MPH | David Kahn, MD, MPH | Miguel Gonzalez-Velez, MD

CASE SUMMARY

• In 2019, a 70-year-old White woman was diagnosed with stage I multiple myeloma.
• Medical history: stage 3 chronic kidney disease (CKD), moderate renal impairment
• Fluorescence in situ hybridization showed deletion 17p (del[17p]).
• The patient declined autologous stem cell transplant.
• She was treated with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone.
• Best response: very good partial response (VGPR)
• Lenalidomide maintenance therapy was continued.

Two years later (2021)

• The patient’s first relapse occurred.
• She was still on lenalidomide maintenance.
• On routine follow-up, she reported having mild fatigue but continued to work full time.
• Her bone marrow plasma cells, light chains, and M protein levels were all rising.
• Her kidney function was worsening (now stage 4 CKD).
• The patient received daratumumab (Darzalex), pomalidomide (Pomalyst), and dexamethasone with a best response of VGPR.

One year later (2022)

• The patient’s second relapse occurred.
• Her kidney function continued to decline.

DISCUSSION QUESTIONS

• What regimen would you most likely recommend for this patient now?
• What are the goals of therapy for a patient like this?

SBOROV: This patient is now 73 years old, and we’ve moved through a couple lines of therapy in a short period of time. For someone who’s gotten through induction and first-line and second-line therapy at 3 years, has already progressed, and is definitely showing aggressive disease, would you say to the patient, “You have aggressive disease, so it’s reasonable to think about hospice and moving more toward palliative treatment?” Or do you feel like we have enough effective and decently tolerated drugs that we could be continuing to recommend therapy for a patient like this?

CHEN: [I would recommend palliative care] only if she doesn’t want [to continue treatment]. Otherwise, I think further treatment is worth trying.

SBOROV: I agree. The different options [in the National Comprehensive Cancer Network (NCCN) guidelines] are not entirely exhaustive for this patient. CAR [chimeric antigen receptor] T-cell therapy and bispecific antibodies are not listed.¹

There is some room in the NCCN guidelines to be utilizing these options earlier, but if we’re going by the FDA approvals, [these options are used after] 4 prior lines of therapy with exposure to an immunomodulator, proteasome inhibitor, and anti- CD38 antibody. We have carfilzomib [Kyprolis]/cyclophosphamide/ dexamethasone, selinexor [Xpovio], and maybe elotuzumab [Empliciti] that we can consider for this patient.

CASE UPDATE

The patient was started on selinexor plus bortezomib/dexamethasone based on her worsening renal impairment, del(17p) status, and prior therapies.

She achieved VGPR.

DISCUSSION QUESTION

• If you have used selinexor, what was your experience?

TARAJKI: I don’t have [many patients with] advanced-stage disease. Most of my patients are in first-, second-, [or] maybe third-line therapy. I don’t have a patient who would use selinexor. Also, I don’t have a [lot of] experience with it. I have more experience with other drugs.

SBOROV: What have you heard about selinexor?

TARAJKI: Yes, I have [heard of using it] for refractory disease, fourth or fifth line. I’ll probably consider CAR T-cell therapy before using this for my patients.

SBOROV: Anybody else who’s not used selinexor, I’m curious to hear why you have not used it.

SHAH: My patients haven’t gotten to that point, plus it just carries a bad reputation with the gastrointestinal toxicity and some cytopenia. I feel like I need to exhaust everything else before I move to selinexor.

SBOROV: I think that’s fair. I can talk more about the BOSTON trial [NCT03110562] and some of the toxicities.² Selinexor’s reputation is well founded, and the question is, can we do things to improve the tolerability?

I think the answer to that is yes. I’ve been a part of the development of selinexor since it was in its infancy, and over the years we’ve seen the drug become more tolerated. I’ll bring up a couple of things you can think about if you choose to use selinexor in the future.

DISCUSSION QUESTION

• In what combinations and dosages do you use selinexor?

SBOROV: For those of you who have used selinexor, are you using it with dexamethasone? Are you using it with daratumumab? With a proteasome inhibitor? How are you using it? I’m curious to hear your experiences.

KAHN: I’ve used selinexor once in combination with dexamethasone. The patient did OK but unfortunately progressed on that line. She was on it for a few months before progression.

SBOROV: Did you use the regimen per the STORM trial [NCT02336815], where you’re giving 80 mg twice a week?³

KAHN: I think back then the recommended regimen was different, so I would say no.

SBOROV: We found that giving that much selinexor was extremely hard for patients. Some patients did quite well, but a lot of patients had a difficult time tolerating the doublet, primarily because of the intensive dosing. Does anybody else want to share their experience with selinexor?

GONZALEZ-VELEZ: I’ve used it in combination with bortezomib, with the selinexor at 100 mg weekly, and I think that’s better.

SBOROV: Good, so you’re following the BOSTON data.² Was this a relatively early line, or was this a later line that you decided to go with it?

GONZALEZ-VELEZ: It was third line, pretty similar to a case you’ve presented.

SBOROV: As far as tolerability and response, how did things go?

GONZALEZ-VELEZ: They went OK. I think response lasted for about a year, so it was a reasonably good experience.

SBOROV: That’s great. Did you have to reduce the dose of selinexor at all, or were you able to keep that 100 mg going weekly?

GONZALEZ-VELEZ: We were able to continue.

SBOROV: At that time, did you incorporate significant supportive care, or were you able to just start the drug?

GONZALEZ-VELEZ: The patient did better than what I expected. I had some patients on the clinical trials on the higher dose, and I was pretty worried, but it was a [relief] that the 100 mg weekly was better tolerated than the previous higher doses.

SBOROV: OK, good. Before I move on, I want to point out the FDA-approved [indications] for selinexor.⁴ Selinexor in combination with bortezomib/ dexamethasone is approved for patients who have received at least 1 prior therapy. In combination with dexamethasone alone, it’s approved for patients who have received at least 4 prior therapies and who are penta-refractory. Selinexor/dexamethasone was investigated in the STORM trial, and the triplet with bortezomib was in BOSTON.^2,3

DISCUSSION QUESTION

• How do you counsel patients when discussing selinexor as an option?

SBOROV: Patients are pretty savvy. They’ve been reading on [patient information and advocacy sites, such as] HealthTree, or MMRF [Multiple Myeloma Research Foundation], or whatever else about these different drugs. They see all these toxicities. They come to you, they say, “I don’t know if I want to try this drug because of the potential problems.” How do you advise your patient? What do you say?

CHEN: I used single-agent selinexor for my patient because it was almost a last-ditch effort to try treatment for him. Only because of selinexor’s bad reputation, I gave the patient low-dose olanzapine [Zyprexa], at 2.5 mg, to take every night before starting the selinexor. I told him, at least in the first couple of days, to be aggressive about using ondansetron [Zofran]. Even if he felt a little queasy, to take the ondansetron and then back off on the ondansetron to see how he does. He did OK on it.

SBOROV: Great. Did you have to use a longer-acting antiemetic?

CHEN: The olanzapine was the only long-acting one; otherwise, he used ondansetron and promethazine [Phenergan] for rescue.

SBOROV: Were his blood counts OK?

CHEN: He had other issues that ended up causing him to stop treatment, but from the myeloma standpoint he responded well. His cardiac issues [resurfaced] about probably 5 or 6 months into treatment, and that eventually caused his death. He had preexisting cardiac issues.

SBOROV: We were talking about all these things and needing to put patients on ondansetron, and olanzapine, and everything else. When I’m talking to my patients about selinexor, I’m very blunt.

I say, “This can cause you problems, and it’s going to require us to potentially be very aggressive with supportive care at the beginning.” Every single one of my patients starts olanzapine a couple of days before they start selinexor treatment. We bring them in once a week to make sure that we’re watching their electrolytes. Some of these patients need fluids. Sometimes they need an appetite stimulant, but I generally have not found that, primarily because I don’t start selinexor at 100 mg per week.

I start it at 40 mg per week, sometimes 60 mg per week, and then I work up from there. I think [the main goal] is starting and keeping [the patient on the drug]. When getting down to doses like 40 or 60 mg, I’m still seeing responses, especially when I use a triplet combination. But I’m not afraid to drop that dose and then work up. I find usually that 60 mg per week is the sweet spot. Every once in a while, I can push it to 80 mg per week.

Occasionally we’ll have to employ a thrombopoietin agonist or something, but for the most part with that lower dose, we’re not running into those profound cytopenias either. I’m blunt about these adverse events, but I also tell patients that I’m confident we can support them through those first couple of cycles.

Anecdotally, I had a patient who had received 13 lines of therapy with a BCMA [B-cell maturation antigen] CAR T-cell therapy on clinical trial in Seattle. [She] got approximately 2 years out of it, so a nice response. She came in and had nonsecretory progression. She felt fine, but her PET scan [results were] horrible. She wasn’t willing to travel to get cevostamab or teclistamab [Tecvayli] because they were only [available] on trial at the time. I said, “You haven’t seen selinexor. You’ve seen basically everything else.”

So put I put her on selinexor/carfilzomib/dexamethasone. I started the selinexor at 80 mg and carfilzomib at 56 mg once a week. Twelve months later, she’s still having a response. This is a patient who’s seen a lot of therapy, and the selinexor/carfilzomib/ dexamethasone has done a nice job. We’ve backed the selinexor down to 40 mg at this point. I think I started a little bit high with her, but with selinexor at 40 mg and carfilzomib 56 mg once a week, she’s had a nice response.

_References

_{1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 3.2023. Accessed August 16, 2023. https://bit.ly/36TOWx6}

_{2. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563-1573. doi:10.1016/S0140-6736(20)32292-3}

_{3. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727-738. doi:10.1056/NEJMoa1903455}

_{4. Xpovio. Prescribing information. Karyopharm Therapeutics Inc; 2022. Accessed April 4, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212306s010lbl.pdf}