Roundtable Discussion: Ziari Assesses Therapy Sequencing in Relapsed/Refractory Multiple Myeloma

Mohammadbagher Ziari, MD

Assistant Clinical Professor

Department of Medical Oncology & Therapeutics Research

City of Hope

Corona, CA

CASE SUMMARY

A 70-year-old woman received a diagnosis of stage I multiple myeloma. She had a medical history of stage 3 chronic kidney disease and moderate renal impairment, and fluorescence in situ hybridization testing showed deletion 17p. The patient declined autologous stem cell transplantation and received lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd). Her best response was a very good partial response (VGPR), and lenalidomide maintenance continued.

Two years later she had her first relapse while on lenalidomide maintenance. On routine follow-up, the patient reported having mild fatigue, but continued to work full time. Her bone marrow plasma cells, light chains, and M protein were rising while her kidney function was worsening, and she now has stage IV chronic kidney disease. The patient received daratumumab (Darzalex) plus pomalidomide (Pomalyst) with a best response of VGPR. One year later a second relapse was discovered, and her kidney function continued to decline.

DISCUSSION QUESTIONS

• What are the preferred regimens for previously treated multiple myeloma?
• How often are your patients triple exposed at second relapse?
• Now that this patient has relapsed while receiving daratumumab, pomalidomide, and dexamethasone (Dara-Pd) in the second line, what are her unmet needs?

ZIARI: Based on the NCCN [National Comprehensive Cancer Network] guidelines, there are preferred regimens for [patients with] early relapses with 1 to 3 prior treatments. If the patient has a relapse after more than 6 months, the regimen used primarily can be repeated. Patients who are still sensitive to bortezomib and lenalidomide have options that include ixazomib [Ninlaro], lenalidomide, and dexamethasone, which is a category 1 recommendation, and then RVd.

For bortezomib-refractory patients, one can use any of the regimens that have lenalidomide or a combination of daratumumab, carfilzomib [Kyprolis], and dexamethasone. For patients with lenalidomide-refractory disease, you can do daratumumab, carfilzomib, and dexamethasone; or daratumumab, bortezomib, and dexamethasone; or isatuximab [Sarclisa], carfilzomib, and dexamethasone.¹

CHALLAGALLA: Most of them are exposed in my practice already. So in this patient, if she’s still not going to go to stem cell transplant or CAR [chimeric antigen receptor] T-cell therapy, I think I would go with isatuximab, carfilzomib, and dexamethasone.

SOLANKI: There’s still selinexor [Xpovio] and other drugs. This has become such a chronic disease.

ZIARI: Right…I mean, now that your patient has relapsed with Dara-Pd. We have used the anti-CD38, the IMiD, and the PI. The unmet need seems to be a new agent, probably with a different mechanism of action.

BHANDARI: I think this is when we start getting into either sending the patient for some trials at a tertiary center or sending the patient maybe for evaluation for CAR T-cell therapy or another BCMA [B-cell maturation antigen] type of therapy.

DISCUSSION QUESTION

• How would a switch in mechanism of action (MOA) address that unmet need?

ZIARI: What do you consider? Is there any other MOA that you think we need to address?

ARJUNAN: Yes, I think that’s always a thought in my mind when we’re switching therapies. In this patient, I think you certainly would be looking at switching MOA, so you kind of think about selinexor, elotuzumab [Empliciti], and some of those other drugs out there. The big concern I have, regardless of the MOA, is the tolerance issue. It becomes worrisome trying to get these patients who are a little bit beat up on their first line of therapies onto some of these other ones.

ZIARI: You touched a great point, exactly. We have other regimens that are recommended like bortezomib, liposomal doxorubicin, and dexamethasone or carfilzomib and dexamethasone. There is CyBorD [cyclophosphamide (Cytoxan), bortezomib, dexamethasone]; carfilzomib, cyclophosphamide, and dexamethasone; or ixazomib, cyclophosphamide, and dexamethasone. Also, [we have] selinexor, bortezomib, and dexamethasone, or other selinexor-based regimens such as daratumumab and dexamethasone.

We also have venetoclax (Venclexta) and dexamethasone only in [patients with] t(11;14). Elotuzumab, pomalidomide, and dexamethasone is another option for a patient who had an IMiD [immunomodulatory drug] and PI [proteasome inhibitor] and progressed within 60 days of completion of last treatment. Pomalidomide and dexamethasone is category 1, and selinexor, pomalidomide, and dexamethasone is another option. There are other older regimens like DCEP [dexamethasone, cyclophosphamide, etoposide (Toposar), cisplatin (Platinol)].¹ I don’t know if any of you have used it recently, but I know that a long time ago I used it, but not anymore.

DISCUSSION QUESTIONS

• What regimen are you most likely to recommend for this patient now?
• What are the goals of the therapy for a patient such as this?

ZIARI: You have used RVd and the patient was on maintenance lenalidomide and then progressed in 2021 [after 2 years]. After the first relapse, the patient was on Dara-Pd and now that you have utilized those MOAs that we talked about, it comes to the second relapse. Now you have options like an XPO1 inhibitor and CAR T-cell therapy, an anti-BCMA, or others. We have used a PI, anti-CD38, and IMiD.

MAZHARUDDIN: Well one thought that comes to mind is that the patient seems to have been off the bortezomib when they progressed. So it kind of opens the potential of reintroducing a proteasome inhibitor.

CHALLAGALLA: I agree with that. I think I would use carfilzomib, selinexor, and dexamethasone.

ZIARI: Would you do selinexor, bortezomib, and dexamethasone?

CHALLAGALLA: [This patient] doesn’t have any history of cardiomyopathy or CHF [congestive heart failure]. I’d like to avoid neuropathy. I would still try to push her toward stem cell transplant or CAR T-cell therapy because she does not seem to be refractory but is just relapsing.

SOLANKI: In the BOSTON trial [NCT03110562], most of the patients had been exposed to multiple agents. But they reintroduced bortezomib in those patients, and some of them got it within the last 6 to 9 months or less than 1 year, and they still showed a response. In fact, in the [bortezomib and dexamethasone] arm of the study, there was a response to bortezomib.² So if [this patient] is otherwise suitable—I don’t know what her creatinine clearance is, was it good enough for CAR T-cell therapy?

ZIARI: Yes, you’re correct.

DISCUSSION QUESTION

• What patient-, disease-, and therapy-related factors influence your recommendation for next-line therapy for this patient who is no aged 73 years with worsening kidney function at second relapse?

ZIARI: There is the genetic risk, like deletion 17p. Also, patient comorbidities like renal impairment and hypertension, or prior toxicities such as neuropathy. Is neuropathy something that you see in your patient after you use triple regimen for 2 lines of therapy? Is it something that you see despite using subcutaneous proteasome inhibitors? Is this something that is a challenge in your practice?

KANNAN: It’s concerning. I think it affects their quality of life because it’s a chronic disease. Most of my patients develop it with bortezomib-based therapy at first-line therapy, so it tends to be a major problem.

ZIARI: What do you think, Dr Kannan, about the regimen that you would choose for your patient who had 2 lines of triple treatment in the past and now you’re going to third-line therapy? What would you use?

KANNAN: Sometimes I’ve done carfilzomib-based therapy because they’ve had RVd followed by Dara-Pd. I’ve tried selinexor. I push them toward CAR T-cell therapy, obviously if they are not refractory, but I still don’t understand why this patient did not have a bone marrow transplant. Or did they have a transplant in between? If they have not had a transplant, they should be considered for transplant with the option of CAR T-cell therapy for the future, but I would collaborate with my [transplant physician] for them.

ZIARI: How far [away] is the transplant or CAR T-cell therapy center?

KANNAN: 20 miles.

ZIARI: I see; not bad, not bad at all. The MOA is important, too, if your patient has progressed on a treatment. If you use something new, think of the safety, exactly as you mentioned about neuropathy and different safety issues. We want to just use something that will not only keep the longevity but also the quality of life the same as much as we can. Always consider cost to the patient too: how much is out of their pocket and the distance they’re dealing with. I don’t know how much geography is a problem when it comes to using oral regimen vs not oral regimen. Is it something concerning if the patient lives far away from you?

KANNAN: I don’t think distance is a problem, but cost can be a major problem in our patient population, which is a little bit lower socioeconomically, and that affects [adherence].

ZIARI: That is true in every single practice, and you feel it more in the community practice.

CASE UPDATE

The patient was started on selinexor plus Vd based on her worsening renal impairment, deletion 17p status, and prior therapies. She achieved a VGPR.

DISCUSSION QUESTIONS

• What has been your experience using selinexor?
• How do you counsel patients when discussing selinexor as an option?

ARJUNAN: I’ve used it once. We ran out of options for the patient. I was working in conjunction with [The University of Texas] MD Anderson [Cancer Center]. It was tough. A lot of fatigue, diarrhea as well, and it was quite a lot of monitoring.

ZIARI: Did you use it after multiple lines or…in combination with bortezomib or anything else?

ARJUNAN: I used it after multiple lines.

ZIARI: You used it as a doublet treatment with dexamethasone or with bortezomib?

ARJUNAN: Yes, a doublet treatment with dexamethasone.

CHALLAGALLA: I’ve used it as a doublet treatment, too, in an elderly person with terrible neuropathy. The indication was triplet therapy with bortezomib, but there was no way I could use bortezomib, so I did the 80-mg selinexor with dexamethasone.

I mean, it’s a different mechanism, except you must watch out for hyponatremia in this older population from the nausea, vomiting, and diarrhea, and I think we are all pretty good with the hematologic toxicities. We are pretty good at treating them. I think it’s the neurologic toxicity and the hyponatremia that we need to be careful of.

ZIARI: I have the same experience that you both had before. … Just the hyponatremia is something to monitor closely, and fatigue too.

ZIARI: The BOSTON study data showed the efficacy and the adverse effects [AEs] of selinexor. Some of you have experience with it and some of you don’t. But based on the data, how would you discuss this with your patient?

BHANDARI: Were there any patients on dialysis on that study?

ZIARI: They included patients who had kidney function less than 40%,² so patients on dialysis [were] included.

ARJUNAN: Yes, so I think it’s a discussion about the data, to some extent. What concerns me about these data is that [the study] used, in my opinion, kind of a comparator arm that was questionable. About 70% of the patients had prior exposure to bortezomib already and then they’re using that as a comparator arm, so it’s kind of like you’re expecting that comparator arm to fail, basically. I don’t see what the data show me beyond telling the patient, “Hey, maybe let us add selinexor, which has a different mechanism of action. It might help you.” But I think when we’re looking at the data, it’s hard to use that as a convincing reason.

I don’t know if there was, perhaps, a better comparator arm that could have been used in this trial instead of Vd alone. But otherwise, it’s about discussing the AEs and just counseling [the patients] through that. It is kind of difficult because with the other options you might have other toxicities. [As with] belantamab [Blenrep], you have the ophthalmic toxicity. So it’s weighing what the patient would be tolerant to.

ZIARI: I think there are data that we have also that compared pomalidomide, bortezomib, and dexamethasone with Vd. Also, they did a similar [study] but with Dara-Vd vs Vd and looked at the PFS [progression-free survival] difference too. I guess for the data that we have, the control arm was the old regimen that in the past had been a standard. That’s the reason that they always have something in addition to the doublet, with a different MOA to see if it is better than the standard.

DISCUSSION QUESTIONS

• If you use selinexor, what steps and supportive care do you routinely perform to help patients with tolerability?
• What is your approach to dose reduction?
• What is your approach to nausea/vomiting prophylaxis and hydration?

CHALLAGALLA: We always dose reduce. Nausea/vomiting is easily controlled, but we dose reduce if there [will] be AEs.

ZIARI: For the dose that we reduce to, there are data about that dose, so that you don’t lose the efficacy. Have you used olanzapine [as an antiemetic]?

CHALLAGALLA: That’s the problem I have with all these drugs. There is no drop in efficacy by dose reduction, so why do we have to use the full dose and make the patient suffer?

ZIARI: In the BOSTON study, most patients had [dose modifications] eventually. You can always lower the dose too. This is what we’ve learned—that maybe a lower dose is not a problem. I mean, again, in the BOSTON study, eventually they had most patients on the 80-mg dose.

SOLANKI: This question came up way back when panobinostat [Farydak] was introduced. It clearly disappeared mainly because it had severe GI [gastrointestinal] toxicity, mainly diarrhea. This has been a recurring problem with drugs, like now with selinexor. What Dr Challagalla pointed out is a recurring theme. We say, “Oh well, 70% of the patients had to have dose reductions.” Well, how did we come up with this dose in the first place?

The same thing happened with bortezomib way back. We used to use much higher doses, and then we went to weekly dosing. It turns out that the total dose of bortezomib we give is considerably less than what was originally used, and we still see wonderful responses. So there’s a significant issue with the starting dose that is used in trials. Nobody seems to report what was the delivered dose—how much did the patient get, not what was planned.

ZIARI: In the BOSTON study they did. The majority [of patients received] 80 mg.

SOLANKI: I think what happened with the BOSTON [From the Data²] trial was because of the design, it became a once-a-week regimen of selinexor, and that considerably decreased the GI toxicity. Still, there was considerable dose reduction in those patients. So it’s still a pretty tough drug, although I was surprised how effective the combination was in patients who were penta refractory. Even in the Vd arm, there was a response rate of about 35% or 30% which is remarkable, so it was an interesting study, but not an easy one on the patients.

ZIARI: …I have patients on this and I have been dose reducing, even down to 40 mg and they still have a response to it. I have 2 patients currently on it and down to 40 mg once a week, and I see the efficacy. I had to dose reduce to different things. But one other thing I do is olanzapine on day 1 of the treatment, and then I do it for 3 days in a row. I ask the patient how they feel after 3 days. If they’re fine, then I just ask them to use it as needed. If you do it days 1 to 3, and 1 hour before the starting day, then continue for 3 days or use a different cocktail plus hydration, it pretty much gets easier. Typically, after the first 2 months, the patient tolerates it and the AEs get less and less.³

DISCUSSION QUESTION

• Based on the available BOSTON clinical trial data, how likely are you to use selinexor, bortezomib, and dexamethasone (XVd)?

CHALLAGALLA: My choice would depend on the comorbidities of the patient. If the patient has severe neuropathy, bortezomib is out. Cardiomyopathy, carfilzomib is out, or kidney disease too. If they’ve been exposed to daratumumab, I don’t think I would use any anti-CD38 drug again because I don’t believe that reusing it is going to be helpful. I don’t know what’s the right answer. It depends on the patient. In my practice, if I have used RVd and then daratumumab, etc, then XKd [selinexor, carfilzomib, and dexamethasone] seems most reasonable because if the same patient had kidney disease, I would have probably used pomalidomide before.

ZIARI: I see. So if you want to use a combination with selinexor, where do you think it fits in your line of treatment?

CHALLAGALLA: One can use selinexor and dexamethasone. One could use anything. We have so many choices right now, and we must weigh the AEs and patient’s comorbidities, then choose. That’s the way I would think.

ZIARI: That’s correct. We have great choices available now, but you’re talking about a different MOA when you use selinexor. We’ve pretty much run out of many other MOAs, and we were thinking about something new.

_REFERENCES

_{NCCN. Clinical Practice Guideline in Oncology. Multiple Myeloma, version 1.2023. Accessed February 22, 2023. https://bit.ly/3KqmxUF}

_{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}

_{Xpovio. Prescribing information. Karyopharm Therapeutics Inc; 2020. Accessed February 22, 2023. https://bit.ly/3eG0OqV}