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Clinical "Gray Areas" Persist Amid Evolving Multiple Myeloma Treatment Strategies

Ajai Chari, MD, expanded on areas of uncertainty in multiple myeloma from the Bridging the Gaps in Leukemia, Lymphoma, and Multiple Myeloma Conference.

Ajai Chari, MD

Ajai Chari, MD

Although the multiple myeloma treatment landscape has evolved substantially in recent years, several “gray zones” of clinical uncertainty remain, particularly regarding optimal integration of novel therapies, according to Ajai Chari, MD.

At the inaugural Bridging the Gaps in Leukemia, Lymphoma, and Multiple Myeloma meeting, Chari and colleagues delved into key challenges and unresolved questions in multiple myeloma management. A subsequent consensus manuscript outlined expert recommendations for the management of newly diagnosed multiple myeloma and functional high-risk disease, as well as the role of CAR T-cell therapy, among other emerging considerations.

Chari expanded on these topics in the below interview with OncLive®

“[The higher risk a patient is, whether it's functional or genomic, the more we consider things like CAR T-cell therapy with ciltacabtagene autoleucel [cilta-cel; Carvykti], now FDA-approved in 1 to 3 lines of therapy,” Chari, director of the Multiple Myeloma Program and a professor of medicine at the School of Medicine, University of California San Francisco, explained. “CAR T-cell therapies do have some risks, like neurotoxicity and secondary malignancy. [However,] that risk is more worth taking if this patient already has writing on the wall that they're genomically or functionally high risk.”

OncLive: In newly diagnosed multiple myeloma, what is the debate regarding the determination of transplant eligibility vs ineligibility?

Chari: Historically, transplant eligiblility meant that patients had good organ function, like ejection fraction, good lung function, were generally fit, and had a good performance status. Having good renal function is not required because we can do [transplants] in patients receiving dialysis. There is no absolute age cutoff; even insurance can cover up to age 80.

Where the field is now struggling, though, is that some of our nontransplant approaches are doing so well. For example, the [phase 3] MAIA study [NCT02252172] evaluating daratumumab [Darzalex], lenalidomide [Revlimid], and dexamethasone gives us a 5-year progression-free survival [PFS]. Now with quadruplet therapies potentially even doing better than that, [the question is:] do we need to be subjecting every patient to transplant? Particularly, for patients over 70, where you might consider dose reduction, the field needs to evolve beyond transplant eligibility vs. ineligibility. If we're going to have to reduce the dose of the chemotherapy for the transplant, do we really need to do [transplant], or could they do just as well with a nontransplant approach? It's a gray zone right now that we need to figure out.

More recently, the incorporation of quadruplet induction therapy has shifted the newly diagnosed multiple myeloma treatment paradigm. What does the utilization of Dara-RVd as new standard of care mean for clinical practice?

The quadruplet regimen of [daratumumab plus bortezomib (Velcade), lenalidomide, and dexamethasone has produced] great results, [including] better responses, depth of response, [minimal residual disease] negativity, and PFS. Those are encouraging data, and they're calling into question whether quadruplets [are appropriate] only for some groups. Particularly when you drill down to the older population, it's the dosing intensity that really matters. The field is moving towards quadruplets for everybody, [in which case] maybe we don't even need to decide on transplant eligibility. When we start [treatment], we can see how they do if they have a great response to therapy, and if they have no adverse effects [AEs]. Do we need to take these older patients to transplant? Conversely, maybe somebody started off frail, and then there's this concept of dynamic frailty. They improved, but maybe they're having some AEs with the treatment, or suboptimal response. We could consider transplant for those patients. The quadruplets are giving us more options and more ability to individualize that transplant decision for each patient.

How do you approach treatment selection for patients with functional high-risk multiple myeloma, particularly without head-to-head studies available?

Functional high risk [disease] means that these patients relapse sooner than they were expected to, but that's intercalated with what therapy they received. There's a difference between relapsing on 2 drugs vs 3 drugs vs 4 drugs vs 4 drugs with transplant and double drug maintenance. As we increase the [duration of] therapy, the definition of functional risk can change, but many will say it is somewhere between 1 to 2 years of initial therapy, particularly for transplant patients. We consider these to be suboptimal responders, and not all of them will have baseline genomic or international staging characteristics that would have predicted that. The higher risk these patients are, the more we need to do novel therapies, because these are the ones that we worry about with attrition. [They may] not experience a later relapse, because they may succumb to the disease. We also want to get the best outcomes for the patient.

Regarding delayed toxicities associated with CAR T-cell therapies, what are some of the challenges with CAR T-cell therapy timing?

The flip side of the previous conversation is [the consideration of] a low-risk patient with have plenty of options available. Let's say that this patient only got lenalidomide maintenance. When they relapse on lenalidomide, they could do very well with a CD38 carfilzomib [Kyprolis]/dexamethasone regimen, with a potential PFS of 3 years, and that's without having to have any risk of CAR T-cell therapy toxicities. Many may not receive CAR T-cell therapy right away, and they may be given it as the next line of therapy. However, for those who are already double-drug refractory and have relapsed early, these low but non-zero risks may be worth taking. Specifically, when you look at [data from] the [phase 1b/2] CARTITUDE-1 trial [NCT03548207] with the CARTITUDE-4 trial [NCT04181827], we know that Parkinsonism, for example, went from say, 9% to 1% in less heavily treated patients. Cranial neuropathies went up, but those generally tend to reverse, and [the incidence of] secondary malignancies, which initially wase as high as 10%, is now also lower at 1%. Therefore, perhaps these risks of CAR T-cell therapy are not as high as we would have initially thought [as long as we] can control the disease. That is another reason to do CAR T-cell therapy early, because we can control the disease in a non–heavily treated patient.

Reference

Chari A, Bal S, Ailawadhi S, et al. Expert Perspectives on Current Challenges and Emerging Approaches for Multiple Myeloma: Narrative Review of an Inaugural Bridging the Gaps in Leukemia, Lymphoma, and Multiple Myeloma. Clin Lymphoma Myeloma Leuk. Published online March 11, 2025. doi:10.1016/j.clml.2025.03.008


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