Lack of Comparative Trials in R/R MM Complicates Treatment Selection
Binod Dhakal, MD
Moderator
The variety of new and older regimens in use for patients with multiple myeloma has created a challenge in selecting treatment for patients with relapsed/refractory multiple myeloma (R/R MM), particularly those with worse performance status and comorbidities. Randomized trials establishing a standard of care in the relapsed setting are unlikely to be performed, which leaves the decision to the physician based on whichever agents are still unused, as discussed in a recent virtual Case-Based Roundtable meeting for oncologists in Great Lakes and Great Plains. Binod Dhakal, MD, associate professor of medicine at the Medical College of Wisconsin in Milwaukee, who moderated the event, presented the case of an older patient with 1 prior line of treatment and discussed data from the phase 3 BOSTON trial (NCT03110562). Participants weighed in on whether this regimen is promising for this type of patient and the limitations of the available trial data.
This article is part 2 of a 2-part series from a Case-Based Roundtable event.
CASE SUMMARY
The patient is an 81-year-old woman who was diagnosed 7 years ago with IgG-κ multiple myeloma; 75% plasma cells, t(14;20)
She lives in a rural community, 150 miles from an academic center.
Medical history: type 2 diabetes; hypertension, well controlled with medication
ECOG performance status: 1
- Clinical Workup
- Bone marrow plasma cells: 50-60% plasma cells
- Lactate dehydrogenase elevated, complete blood count normal
- Assays: serum free light chains λ - 240 mg/L
- Serum protein electrophoresis: M-protein spike present
- Serum immunofixation electrophoresis: IgG (immunoglobulin G)- λ present
- Fluorescence in situ hybridization: standard risk
- PET-CT: positive uptake in some ribs and collapse of T7; No extramedullary disease.
- β2-Microglobulin: 6 mg/dL
- ECOG performance status: 2
- International Myeloma Working Group Frailty Status: intermediate-frail
- International Staging Score (ISS) III/Revised ISS-II
Treatment History:
Patient was previously referred for stem cell transplant evaluation.
Based on age and comorbidities, was determined to be a non-transplant candidate.
She was initiated on daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone.
Best response: complete response
Time to relapse/progressive disease: 49 months
DISCUSSION QUESTION
How likely are you to change your practice with respect to management of this patient with R/R MM based on discussion of the data, particularly selinexor (Xpovio) with bortezomib (Velcade) and dexamethasone?
Binod Dhakal, MD: How likely are you to change your practice with respect to management for this patient discussed?
Vinay Gupta, MD: Maybe I'm biased against [selinexor], but it has not made into my practice in a second-line setting. Maybe [it will] with more data, more follow-up, or another trial. Let selinexor prove itself in an early-line setting. Right now, I'm not ready.
Dhakal: Do you think that this is inferior compared with other triplet regimens being studied in this patient population?
Gupta: When the drug came out, it was so toxic. We always felt that the benefit was driven by dexamethasone and bortezomib. The drug has not made its mark and it's against a plethora of other drugs that have a good track record. I have sent people for bispecific antibodies before they have gotten selinexor. If the patient can get chimeric antigen receptor (CAR) T-cell therapy or can get bispecific T-cell engagers [BiTEs], I don't wait.
Dhakal: That's valid. If you're getting the patient to CAR T and BiTEs, I think you should choose that option, because the responses…are quite unprecedented. But I think in a situation like this patient—and we have so many of these kinds of cases in our practice when we’re seeing a lot of myeloma—do you limit it to that?
Gupta: If you claim that using selinexor earlier than other drugs is better vs the other way around, I need a trial to prove that. It is another drug with multiple other regimens in place. I do not have a preference for selinexor because I have other drugs; this is a late-comer drug.
Ashley Frith, MD: I [would be] very likely [to use it]. The data were really impressive; you always want to see that when you're doing dose reductions, you're not affecting the progression-free survival….1 I like that and I like the different mechanism of action. I would probably use it mostly in the proteasome inhibitor [PI]–naive class…specifically for certain patients. I haven't had experience with it yet, but I think I want to, after seeing [the BOSTON trial data].
Puni Gada, MD: It's good to have an option. In certain patients like her, carfilzomib [Kyprolis] is a great option, but I sometimes worry about the cardiac adverse events in older patients, so it's nice to have an alternative drug from a different class.
Dhakal: What would be a choice of regimen for this patient in the second line?
Gupta: You have a good point there. This patient has not been exposed to a bortezomib-based regimen. The question is, what other agent do I combine it with? Do I have to combine it with selinexor vs all the other choices that I have? That is my hesitation. I'm going to use the drug when the time comes and I lack of options. The question is, when I'm combining bortezomib with something, is this my best choice? There are multiple drugs that could be even better than selinexor as a bortezomib partner. I think the burden of proof lies with selinexor to prove that it is superior...unless we do cross-trial comparisons.
Daniel Walden, MD: You're picking your partner based off adverse events and patient aspects. With the PIs, carfilzomib has less neuropathy than bortezomib. I've seen that in our practice that nausea is a hard symptom. It’s hard to [decide], is nausea worse than neuropathy or worse than [AEs] from immunomodulatory drugs? If you have someone who can tolerate [selinexor] and nausea is not too high on their problem list to begin with, I think it's not an unreasonable partner, but I agree. I think there are other options too, and there are missing data in the myeloma world where there's no triplet vs triplet trial, and that's still the problem.
Dhakal: I think that's a good point.… The problem is myeloma has an embarrassment of riches. There are so many options. That’s a problem, but at the same time, that's good, because you can tailor a particular regimen for that patient. You don't have a time when you say, “I don't have any options for you. You're done,” in the second or third line, because you have so many options that you can tailor.
None of these treatments are curative. Some patients, especially the young patients, are so desperate. When you see a patient with ultra high-risk myeloma, you would be scrambling for any drug that could work in this setting. I think we're lucky to have this drug, and sometimes you never know. I have a patient on selinexor for almost 3.5 years now. You do not know until you try it.… But at the same time, it’s not a curative treatment, and this patient will probably need this drug at some point in the journey.
Camille Abboud, MD: You are limited by the fact that the drug company has not done extensive clinical trials, so you're stuck with what was presented from the BOSTON trial. If they were to develop additional trials, which would be hard to do, given how effective the quadruplets are in the first line, then you have more options. But when you want to combine selinexor in a patient with R/R MM, you're limited by [trial data].
Dhakal: That's a good point. I think what you said is right; there are so many trials on different drug combinations, but here, we're limited by the few trials.
DISCLOSURES: Dhakal previously reported honoraria from Celgene, Karyopharm Therapeutics, Sanofi, GlaxoSmithKline; consulting or advisory role with Amgen, Takeda, Janssen Oncology, GlaxoSmithKline, Natera, Sanofi, Genentech/Roche, Pfizer, Arcellx, and speakers' bureau with Janssen Oncology. There were no other known relevant disclosures.
