Physicians Discuss Recommended Therapies for R/R Multiple Myeloma

Sumit Madan, MD (Moderator)

Hematologist-Oncologist

Banner MD Anderson Cancer Center

Phoenix, AZ

CASE SUMMARY

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

Two years later (2021), the patientwas continuing on lenalidomide maintenance​. On routine follow-up, the patient reported having mild fatigue, but continued to work full-time​. Bone marrow plasma cells, light chains, and M protein were rising, and kidney function was worsening to stage 4 chronic kidney disease. The patient received daratumumab (Darzalex), pomalidomide (Pomalyst), and dexamethasone (DPd) with a best response of VGPR​. One year later (2022), a second relapse was discovered​, and kidney function continued to decline​.

DISCUSSION QUESTION

• What regimens do the National Comprehensive Cancer Network (NCCN) guidelines suggest for patients with multiple myeloma refractory to multiple lines of therapy, and how do you use these regimens?

SUMIT MADAN, MD: These are all the regimens that we have, and a lot of these regimens can be used after early relapses. Selinexor [Xpovio] and bortezomib plus dexamethasone is certainly up there as well; it’s category 1.¹ You use it once weekly. Selinexor in combination with carfilzomib [Kyprolis] and selinexor in combination with pomalidomide can also be used. You can also pick a PI [proteasome inhibitor] in combination with a monoclonal [antibody], a monoclonal antibody in combination with an IMiD [immunomodulatory drug], or a PI in combination with an IMiD. Studies have shown that these combinations work well.

DAVID SHIN, MD: Nobody mentioned elotuzumab [Empliciti]. I have very little experience. Why is this so unpopular?

MADAN: That’s a good question. I have some experience. What does everybody feel about elotuzumab?

ASHKAN LASHKARI, MD: I used to use it quite a bit in second or third relapse, particularly for patients who had slow progression. Aside from the infusion reaction, it’s pretty well tolerated. In my experience with the drug and my review of the literature, it tends to work better with an IMiD than other types of therapies, including PIs. But it’s fallen out of favor with the arrival of the CD38 antibody agents and some of these newer therapies. Also, it doesn’t appear to combine well with other drugs from a synergistic standpoint. I’m curious to see if other physicians are still using it, and, if they are, when they’re using it.

NEERAJ AGNIHOTRI, MD: I used it 2 years ago but wasn’t impressed with the response rate, so I’ve not been using it lately.

MADAN: What have you used it with?

AGNIHOTRI: I’ve used it with an IMiD and dexamethasone. It was very well tolerated most of the times, but most patients came off within 3 or 4 months because of disease progression. That’s been my experience.

MADAN: Did you use it with lenalidomide or pomalidomide?

AGNIHOTRI: Mostly I used pomalidomide.

MOHAMMAD ZIARI, MD: I have used it and not [had a] good response for any patient I had on it. I felt that there was no efficacy.

MADAN: I agree. It has no single-agent activity. [Elotuzumab has] 0% [overall response rate (ORR)] compared with daratumumab, which has close to 30% ORR as a single agent.^2,3

Elotuzumab/lenalidomide/dexamethasone was in a phase 3 study but did not look very impressive.⁴ Elotuzumab, pomalidomide, [and dexamethasone] was in a randomized phase 2 study and it was a positive study; it doubled the progression-free survival, but [it did not have] too many patients.⁵ I would only use it in patients who are having a slow biochemical type relapse, not in anybody who’s having a clinical relapse or patients who have high-risk cytogenetics. With so many other treatment options, elotuzumab as well as ixazomib [Ninlaro] are in the same bracket—probably not as effective as some of the other agents that we have.

You have this patient already on first-relapse with DPd. The most commonly used daratumumab-based combination would be DPd or daratumumab, carfilzomib, and dexamethasone. Then you’re looking for a class switch and your approved drugs such as your CAR [chimeric antigen receptor] T-cell therapies and teclistamab [Tecvayli], which cannot be used in the third line of therapy because patients have to use 4 prior lines.^6-8 That’s where I feel an XPO1 inhibitor plays a big role. A combination of carfilzomib and cyclophosphamide can be used as well at that time.

CASE UPDATE

• The patient was started on selinexor, bortezomib, and dexamethasone based on her worsening renal impairment, del(17p) status, and prior therapies​. She achieved VGPR​.

DISCUSSION QUESTION:

• If you have used selinexor, please share your experience(s) ​
  • In which combination(s)?​
  • What schedule/dosage was used?​
  • In which clinical scenario(s)?

XINTING FU, MD: I’d like to try selinexor sometime, but I have heard so many stories about the adverse events [AEs]. Usually, this drug is used in patients with triplet or quadruplet refractory status, the patients not being in good shape. I’m thinking about it. In that case, I’m more pushing toward the CAR T-cell therapy or most recently a bispecific antibody rather than this. But I’d like to try it at some time point.

ANDREW HAMPSHIRE, MD: I’ve used it twice [before], and [again] recently. [I used it] in combination as I shied away from its AE profile when it was used without the weekly dosing and with higher doses in terms of the profound effect on the stomach in terms of poor appetite, nausea, and vomiting. I have used it very recently but not long enough to gain much experience about how it’s been tolerated in combination therapies. I’m thinking about how it fits into my toolbox; it’s for that patient who may not be easily eligible for B-cell maturation antigen [BCMA]-targeted therapies or CAR T-cell therapy, but you’re still trying to add it in. I haven’t seen it as a way to get to 4 lines of therapy before you get to a BCMA-targeted therapy or CAR T-cell therapy. I’ve seen it more as something else to try in combination for those patients who aren’t going to get a BCMA therapy or CAR T-cell therapy.

VEENA CHARU, MD: I haven’t used it. I had 1 patient whom I was ready to start but he didn’t do well [before starting]. He had a [stem cell] transplant and multiple lines of treatment. He was also previously in a City of Hope trial for a bispecific antibody, and then we were talking about [selinexor] and then he didn’t do well [on the trial], so I didn’t use it.

ANDREW PHAM, MD: I used it just a handful of times as a single agent but not recently.

MADAN: What about in combinations?

PHAM: I haven’t had the chance since the combination’s been approved.

SHIN: I haven’t used it, but because of the toxicity I heard about, I’ll start at a lower dose and maybe [increase the dose] as tolerated.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 3.2023. https://bit.ly/2T0mDYS}

_{2. Zonder JA, Mohrbacher AF, Singhal S, et al. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood. 2012;120(3):552-559. doi:10.1182/blood-2011-06-360552}

_{3. Lonial S, Usmani S, Singha UK, et al. Phase II study of daratumumab (DARA) monotherapy in patients with = 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). J Clin Oncol. 2015;33(suppl 18):LBA8512. doi:10.1200/jco.2015.33.18_suppl.lba8512}

_{4. Dimopoulos MA, Lonial S, White D, et al. Elotuzumab, lenalidomide, and dexamethasone in RRMM: final overall survival results from the phase 3 randomized ELOQUENT-2 study. Blood Cancer J. 2020;10(9):91. doi:10.1038/s41408-020-00357-4}

_{5. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018;379(19):1811-1822. doi:10.1056/NEJMoa1805762}

_{6. FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. News release. FDA. February 28, 2022. Accessed May 17, 2023. https://bit.ly/3Mb7hdv}

_{7. FDA approves idecabtagene vicleucel for multiple myeloma. News release. FDA. March 26, 2021. Accessed May 18, 2023. https://bit.ly/3OmFQ2U}

_{8. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. News release. FDA. October 25, 2022. Accessed May 18, 2023. https://bit.ly/3pTfZFO}