Joshua Richter, MD: Natalie brought up the notion of 1Q [gain in chromosome] and Susan talked about…the double hits—could you give us your thoughts [on] what is high risk? And don’t give me the cop-out answer—everyone has it. But as a newly diagnosed person coming in, how do you define high risk?

Alfred L. Garfall, MD: I really trust the staging systems that have tried to integrate the clinical factors and the cytogenetic abnormalities—so [the] revised ISS [International Staging System] stage 3 or the R2-ISS that gives you a bit more granularity and incorporates the 1Q gain. So the [patients] who are revised ISS stage 3 or the revised R2-ISS stage 4—that’s a good reliable system for high risk. There’s high risk in terms of [not only] long-term prognosis but also the clinical complexity of the presentation. Patients who come in with acute renal failure who are very sick from their myeloma may not necessarily have the high-risk prognostic factors for long term, but they clearly are quite sick with their initial presentation and often require some specialized management. They’re high risk from a different perspective, in terms of the complexity of their initial management. Maybe they need therapy started in the hospital [or] maybe they’re on dialysis. Some of those clinical factors may be not reflected in the staging system, maybe more in the Durie-Salmon staging system with renal insufficiency and aggressive lytic bone disease. Those also color the risk of the presentation.

Joshua Richter, MD: Any other thoughts that anyone else in incorporate into their definitions?

Susan Bal, MD: The risk is not necessarily static. We may see a patient who presents with what appears to be standard-risk multiple myeloma without significant end organ damage, but we see that refractory presentation and difficulty getting them into a deep remission. MRD [minimal residual disease] helps prognosticate that, and the patients [who] stay MRD positive overall don’t do quite as well. Some of the risk is also evident as we go through therapy and find those patients [who] we originally didn’t think appeared to be standard-risk disease but are behaving more aggressively because we can’t control their disease to the depth we desire.

Joshua Richter, MD: I completely agree. We see this reflected as a functional high risk in our colleagues who have their mSMART [Stratification for Myeloma and Risk-Adapted Therapy] guidelines. The difference between the newly diagnosed [patients] and [those who have] relapsed [is] that one [gets] sent to the top. If you relapse within 12 months of your initial therapy or within 12 months from transplant, something bad is going on. We’re also starting to incorporate outside factors, [such as] social frailty and other comorbidity indices, because you may not have a 17P [loss of the short arm of chromosome 17] and you may not be relapsing immediately, but if we can’t even get a triplet into you for some reason—either travel or comorbidities—that might put you at some disadvantages.

Susan Bal, MD: I agree.

Alfred L. Garfall, MD: And we focus a lot on the choice of induction regimen for patients based on the risk status. But [what is just] as important—maybe more important—is the real bread-and-butter medicine that happens as you start therapy, [as well as] the adjustments you make in response to what’s going on clinically, where a lot of those other factors that are maybe not in a risk that was derived from clinical trial data but are very present in our everyday practices—frailty, social support, the toxicities that emerge in patients’ comorbidities, and the interactions there. It’s just as important to make the adjustments along the way based on how your patient’s doing as the initial choice of regimen.

Natalie S. Callander, MD: One point I want to make, because this always gets lost these days now that we have more choices, is [clinicians] will say, “Well, if my patient didn’t get at least a partial remission to my induction, I’m not sending them for transplant. I’m going to give them 4 more regimens.” It’s important to realize that [stable disease got you in] all our transplant trials. We’ve all seen patients who convert after they get their transplant. We’re still struggling now with more drugs to say [whether you] should now go to a different triplet or quadruplet before I take them to transplant. But that gets lost sometimes in these discussions.

Elizabeth O’Donnell, MD: I would make the argument that those are the patients [who] should go to transplant. If you’re not getting a benefit of a triplet or a quad, then those are the patients [who] I’m most likely to take to transplant.

Natalie S. Callander, MD: But we tend to see [patients] sent in the community who’ve now had 3 lines of therapy and they’re stuck there, racking up more [adverse] effects and not necessarily better control.

Alfred L. Garfall, MD: We are spoiled by these amazing responses. For decades, autologous transplant was done on the back of relatively ineffective regimens that only got patients into less than PR [partial response]. Many transplants were done that way, and we can still do transplants in patients who are in PRs.

Susan Bal, MD: One of the points I always like to make to the patient is [to] think of how we can change therapy pretransplant to improve the depth pretransplant. If you think about it, you are changing therapy. What is a transplant? It’s a way to deliver a high-dose alkylator, and that is a change of therapy, which is really where we derive most benefit.

Elizabeth O’Donnell, MD: It’s a completely different type of therapy than anything we’re going to get.

Natalie S. Callander, MD: One point I want to make, being a physician who does work through the VA [Veterans Affairs] as well, is that we now have excellent data, that when we talk about health disparities—differences between Black and White [patients with] myeloma—if Black patients get the same treatment through the VA system, there’s been a wonderful data set looked at. They do great with transplant. I almost feel like we shouldn’t be pulling back from transplant, we should be expanding the use in many ways.

Joshua Richter, MD: There’s 5 of us, [and] we’re all agreeing on 1 topic, which never happens in myeloma.

Transcript edited for clarity.