Orlowski Discusses Treatment Path Through Successive Relapses of Multiple Myeloma

Robert Z. Orlowski, MD, PhD

Director, Section of Myeloma

Division of Cancer Medicine

The University of Texas MD Anderson Cancer Center

Houston, TX

CASE SUMMARY

• The patient is a 60-year-old man diagnosed 6 years ago with IgG-κ multiple myeloma (60% plasma cells, t[14;20]).
• Most recent laboratory results show recurrence of M protein (0.6 g/dL), and imaging shows a new hypermetabolic lytic lesion.
• Medical history: hypertension controlled with lisinopril
• He normally works in his garden and walks 2 miles daily; he has noticed a progressive decline in his stamina where he needs to take breaks more often and has shortened his walking route.
• His ECOG performance status is 1.
• He received frontline daratumumab (Darzalex), lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone followed by autologous stem cell transplant and lenalidomide maintenance, with a complete response lasting 5.5 years until relapse.
• His disease was considered lenalidomide refractory, and options including other regimens and chimeric antigen receptor (CAR) T-cell therapy were discussed with his oncologist.
• He received daratumumab, carfilzomib (Kyprolis), and dexamethasone as second-line treatment.
• He achieved a complete response lasting 13 months.

PEERS & PERSPECTIVES IN ONCOLOGY: What are the treatment options available for this patient with relapsed/refractory multiple myeloma?

ORLOWSKI: These are the NCCN guidelines for relapsed/refractory multiple myeloma.¹ They’ve broken out the available regimens, which you can pick based on prior therapy and what drugs they were refractory to. For example, [they identify] the lenalidomide-refractory options, because this is somebody whom we would consider to have lenalidomide-refractory [disease who experienced progression] on maintenance. Some of the regimens are daratumumab/bortezomib/ dexamethasone, daratumumab/carfilzomib/ dexamethasone, and isatuximab [Sarclisa]/carfilzomib [with dexamethasone] if you want to do proteasome inhibitors. You can do pomalidomide [Pomalyst]/bortezomib, and there’s also carfilzomib/ pomalidomide and dexamethasone, although that one isn’t Category 1 because there’s no large phase 3 option. Then you’ve got CAR T-cell therapy after 1 prior line of therapy….

[There are regimens listed] you can do for [those whose disease is] anti-CD38 antibody refractory if you had this patient on both lenalidomide and daratumumab as maintenance, and [there are guidelines] for what to do for bortezomib-refractory [disease] if you had decided because of the molecular high risk [to do] lenalidomide and bortezomib as maintenance, so that’s a handy development there.

Some other recommended regimens to consider that are Category 1 are boxed for particular attention. Carfilzomib/dexamethasone as a doublet is a good option, especially if you think the patient can tolerate higher doses of carfilzomib. Twice-weekly [dosing] is listed [on the guidelines]; I usually don’t do twice weekly. I do once weekly at the higher dose. They’ve got elotuzumab [Empliciti], lenalidomide, and dexamethasone; because this patient [has] lenalidomide-refractory [disease], I probably wouldn’t go with that. The same thing with ixazomib [Ninlaro], lenalidomide, and dexamethasone, because in the trial for that regimen, lenalidomide refractoriness was not allowed. But I think one regimen that does deserve some attention is the selinexor [Xpovio], bortezomib, and dexamethasone combination, and we’ll get to that.

CASE UPDATE

• The patient experienced relapse for a second time and wished to proceed with CAR T-cell therapy.

What is the role of bridging therapy before CAR T-cell therapy?

There are a couple of types of bridging therapy that include chemoimmunotherapy, which can avoid previously used regimens, and some that are associated with myelosuppression or lymphopenia. For example, bendamustine, which used to get some use in myeloma. You do not want to do it before you collect T cells for CAR T because it can be very difficult to get T cells from patients after bendamustine. Also, [one can use] targeted therapy, which can avoid agents that have the same antigenic agent as the chosen CAR T-cell therapy. Right now, what we have are B-cell maturation antigen [BCMA] CAR T-cell therapies. We’re hoping to get others in the future, but keep in mind you don’t want to do a BCMA bispecific and then have a BCMA CAR T-cell therapy given right after that.

These are consensus guidelines from the International Myeloma Working Group on this topic.² The recommendations are logical. Consider disease burden and previous kinetics of disease progression. If you’ve got very slow progression, you may not need bridging therapy. Due to increased risk for cytokine release syndrome as well as late neurological symptoms, if patients have high disease burden or are rapidly [experiencing progression], you probably want to do something to reduce their disease burden. But as I mentioned earlier, if you have low-burden disease that’s not rapidly progressing, you may not need any bridging or minimal bridging. Immunomodulatory drugs and anti-CD38 antibodies may improve T-cell function and CAR T-cell activities, although you have to have a washout to allow for possible CAR T-cell manufacturing failure. Fortunately, that doesn’t happen too often, but if it does, you don’t want to have given a lymphotoxic regimen because you may need to go back to the patient to say we need to collect more T cells. The effect of other BCMA-targeted therapy immediately before CAR T is unknown but typically not recommended.

What data support the use of selinexor in a patient such as this?

To review some of the data around selinexor that you may want to consider when you get to thinking about a bridging therapy, the main study is the phase 3 BOSTON trial [NCT03110562], which enrolled over 400 patients and randomly assigned them to bortezomib and dexamethasone, with bortezomib given twice weekly, vs the experimental arm that had selinexor, bortezomib, and dexamethasone with bortezomib given only weekly and not twice weekly. It was an interesting design because usually the standard of care, which at that time was bortezomib/dexamethasone, is kept the same in the combination arm. Here there was a reduction in dosing. The primary end point [was progression-free survival (PFS), and secondary end points] are typical for this kind of trial.

With a median follow-up of over a year, there was a median PFS of essentially 14 months for the triplet vs 9.5 months or so for bortezomib and dexamethasone [HR, 0.70; 95% CI, 0.53-0.93; P = .0075].³ But keep that in mind because if this gives you a median 14-month PFS and you’re thinking about a bridging therapy for a month or 2, this is a very reasonable option.

[In terms of] some of the treatment-related adverse events, the main ones to focus on in the selinexor/bortezomib/dexamethasone arm included peripheral neuropathy, fatigue, nausea, vomiting, decreased appetite, and thrombocytopenia. The interesting thing is that the selinexor arm had less neuropathy than the bortezomib/dexamethasone arm because the bortezomib was only given once per week [in the triplet arm]. Keep in mind [when using] selinexor that you do have to do vigorous antiemetic prophylaxis as well as in some cases make sure to encourage patients to do some fluids, including oral and sometimes intravenous.

CASE UPDATE

The patient had a stringent complete response with CAR T-cell therapy but eventually experienced relapse for a third time.

After discussing the various options available to him, the patient and his oncologist decided to proceed with selinexor, pomalidomide, and dexamethasone to allow time between subsequent BCMA-directed therapies .

What data support other selinexor combinations besides the BOSTON regimen?

The rationale for that choice is in part based on [findings from] a trial called STOMP [NCT02343042], which tested a number of different selinexor-based combinations. [They included] selinexor with lenalidomide and dexamethasone, with pomalidomide and dexamethasone, the more common [combination] with bortezomib and dexamethasone, then with carfilzomib [and dexamethasone]. At least in my experience, selinexor/carfilzomib/dexamethasone may be better tolerated than selinexor/bortezomib/dexamethasone. The last arm had selinexor with daratumumab and dexamethasone.

A number of different results [were reported], including overall response rates [ORRs]. For selinexor/lenalidomide/dexamethasone, the overall response rate was 92%.⁴ Keep in mind those were lenalidomide-naive patients, so they were relatively less treated than some of these other groups. But the ORRs for the others range from 54% for selinexor/pomalidomide/dexamethasone all the way up to 78% for selinexor/carfilzomib/dexamethasone.⁵ These are good numbers. Median PFS is anywhere from about 9 months on the low end up to 15 months on the higher end,⁶ so [these are regimens] that would do very well in the setting of bridging while you’re waiting for additional therapy options like CAR T cells.

[There are data on] some selinexor-based triplet regimens and how they work after prior anti-CD38 therapy.⁷ There were a couple of different ones that were used, including selinexor/pomalidomide/dexamethasone, selinexor/bortezomib, and selinexor/carfilzomib. The selinexor dose ranged from 60 mg all the way up to 100 mg, although the 100-mg [dosage] was a 35-day cycle.

[Looking at] the efficacy of these triplets, a lot of these patients had prior anti-CD38 therapy and the ORRs were on the low end in the low 50% [range] and on the high end [at] about 65%, [with] a very good clinical benefit rate as well. Clinical benefit rate includes patients with minor response, so now you’re getting into as high as the 80% range for selinexor/bortezomib/dexamethasone and still having some good results with selinexor, carfilzomib, and dexamethasone as well. There were [data] on what happens for patients with high-risk cytogenetics, which were a few of the patients in the relapsed/refractory setting. Even there you can see that you’ve got response rates as high as 80% to 85% or even a little more [for selinexor, carfilzomib, and dexamethasone], which is pretty good for something in the heavily relapsed and refractory setting.

You can see good numbers for PFS that range anywhere from 6 months for all patients up to 15 months for the carfilzomib combination. The overall survival data range from 9 months on the low end up to 33 months, which again is good for patients who [have] daratumumab-refractory [disease] and definitely something to consider when you’re talking about something as a bridging therapy.

For…the treatment-emergent adverse events in these various cohorts, with a focus on those events that were in at least 20% of patients, most of them at the grade 3 or 4 range [were] the hematologic adverse events, which many [oncologists] are reasonably comfortable [with] managing. These are things that we can monitor and hopefully take care of well.

CASE UPDATE

The patient had a very good partial response to selinexor, pomalidomide, and dexamethasone. He and his oncologist discuss various options available to him, one of which is to proceed with a bispecific antibody.

What treatments could be considered at this point after a fourth relapse?

The current guidelines for patients in this setting after 3 prior lines of treatment [include] ciltacabtagene autoleucel [Carvykti] and idecabtagene vicleucel [Abecma].1 After 4 prior therapies, you now have BCMA bispecifics, which include elranatamab [Elrexfio] as well as teclistamab [Tecvayli]. There may be others that get approved soon, and you’ve got one GPRC5D bispecific, which is talquetamab [Talvey]. Then you’ve got other recommended regimens, which mostly are bendamustine and cyclophosphamide-based therapies. These can be helpful, but remember to not do those if you’re planning on a bispecific or a CAR T-cell therapy because you’re going to have trouble with T-cell function.

DISCLOSURES: Orlowski previously reported research funding from Asylia Therapeutics, Biotheryx, and Heidelberg Pharma AG and has served on advisory boards for Amgen, Bristol Myers Squibb, Celgene, EcoR1 Capital, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech, Molecular Partners, Sanofi, Servier, and Takeda Pharmaceuticals North America. He is a founder of Asylia Therapeutics and has an equity interest.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 1.2025. Accessed October 2, 2024. https://tinyurl.com/37vy9pm2}

_{2. Lin Y, Qiu L, Usmani S, et al; International Myeloma Working Group. Consensus guidelines and recommendations for the management and response assessment of chimeric antigen receptor T-cell therapy in clinical practice for relapsed and refractory multiple myeloma: a report from the International Myeloma Working Group Immunotherapy Committee. Lancet Oncol. 2024;25(8):e374-e387. doi:10.1016/S1470-2045(24)00094-9}

_{3. 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}

_{4. White D, LeBlanc R, Venner C, et al. Safety and efficacy of the combination of selinexor, lenalidomide and dexamethasone (SRd) in patients with relapsed/refractory multiple myeloma (RRMM). Abstract presented at: 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA. Abstract 353.}

_{5. Lentzsch S, Lipe B, Tuchman SA, et al. Efficacy and safety of selinexor-containing regimens in patients with multiple myeloma previously treated with anti-CD38 monoclonal antibodies (αCD38 mAb). Blood. 2021;138(suppl 1):1651. doi:10.1182/blood-2021-150232}

_{6. Mo CC, Jagannath S, Chari A, et al. Selinexor for the treatment of patients with previously treated multiple myeloma. Expert Rev Hematol. 2021;14(8):697-706. doi:10.1080/17474086.2021.1923473}

_{7. Schiller GJ, Lipe BC, Bahlis NJ, et al. Selinexor-based triplet regimens in patients with multiple myeloma previously treated with anti-CD38 monoclonal antibodies. Clin Lymphoma Myeloma Leuk. 2023;23(9):e286-e296.e4. doi:10.1016/j.clml.2023.06.001}