ACHIEVING CURE IN MULTIPLE MYELOMA

Since the beginning of this century, advances in understanding the biology of multiple myeloma have transformed the disease from universally fatal to curable for a substantial proportion of patients. Many more patients attain long-term survival with good quality of life, or what some researchers and clinicians call "functional cure."

From 2000 to 2020, median overall survival for myeloma increased from 3 years to 8-10 years. Still, myeloma experts often were reluctant to use the "c" word. Earlier this year, many of them were persuaded when a landmark clinical study showed that 12 of 45 (27%) patients with long-term survival remained disease free (minimal residual disease [MRD]-negative) 5 or more years after treatment with the CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel, Carvykti). Moreover, 32 of the 45 were alive and progression-free without any treatment beyond the single infusion of cilta-cel.

Results of the CARTITUDE-1 trial suggest "a potential cure, or at bare minimum, unprecedented durability of complete response," said Peter Voorhees, MD, of Wake Forest University School of Medicine in Charlotte, North Carolina, at the American Society of Clinical Oncology (ASCO) meeting.

ASCO discussant Krina Patel, MD, of the University of Texas MD Anderson Cancer Center in Houston, noted, "Ciltacabtagene autoleucel is the first potential functional cure for patients with modern-day relapsed/refractory multiple myeloma."

Defining Cure

A featured speaker at the recent Society of Hematologic Oncology (SOHO) meeting, dispensed with qualifiers in discussing the current clinical environment of multiple myeloma.

"It is time to say 'cure' in multiple myeloma," said Sundar Jagannath, MD, of the Icahn School of Medicine at Mount Sinai in New York City. "Why is defining cure important? To me, personally, it's very important. That's why I keep harping on it. For patients, it gives hope that they can be cured, not inflicted with an incurable, always-fatal disease."

In the 1990s and early 2000s, myeloma specialists called the disease treatable but not curable. More recently, specialists described myeloma to patients as a disease that can be controlled with continuous therapy.

"That is terminology we should get rid of," Jagannath told MedPage Today. "We can cure patients. For physicians, it changes their approach to management. If you feel like you're going to cure the patient, it is a completely different approach. How you treat the patient, how you manage them, how you talk to them, and more important, you are attuned to the recent developments and enthusiastic and supportive of all the clinical trials -- designing a treatment paradigm for cure."

Use of the term "cure" also has practical implications, providing an earlier time point (5 years, for example) for pharma-supported clinical trials.

"With a 5-year time point will come funding," said Jagannath. "You cannot follow the patient for 15 years for a survival outcome. Funding of clinical trials in newly diagnosed myeloma becomes feasible, and introduction of drugs in a randomized fashion, even in first relapse or second relapse, can be done."

Describing treatment in terms of a time-limited endpoint also fosters collaboration with regulatory agencies.

"Say you have a protocol that is going to cure myeloma and pharma wants to be in on it," said Jagannath. "You will have an evidence-based drug approval at an earlier time point for newly diagnosed multiple myeloma patients. So, it is very important that we change the topic and we say we can cure myeloma."

The definition of cure should be very clear and hold up over time, he continued. Regardless of the technology used, cure should mean no MRD (defined as 10^-6 in bone marrow), no circulating plasma cells, and negative by functional imaging, such as PET/CT or whole-body MRI. In the CARTITUDE-1 trial, the 12 patients that were "cured," met that stringent criteria after a minimum follow-up of 5 years.

Importantly, the definition applies equally to patients with newly diagnosed or relapsed multiple myeloma, said Jagannath. Patients in CARTITUDE-1 had relapsed through three or four prior regimens, showing that cure remains possible even in the relapsed state.

"Five years' MRD negativity predicts for cure," he said.

Pushing the Envelope

The challenge ahead is to increase the proportion of patients who achieve cure, said Thomas Martin, MD, of the University of California San Francisco, at the SOHO meeting. The emphasis on cure starts with front-line therapies, and the latest data show "unprecedented" responses rates of 95-100% and MRD-negative rates consistently exceeding 50% and ranging as high as 77%.

An analysis presented at SOHO based on the results from the PERSEUS trial showed that patients who remained MRD negative for 2 years had an estimated progression-free survival of 150-200 months.

"That means that after 10 to 15 years, patients are going to be in remission from their first-line therapy," said Martin. "Can we do better?"

Hope for the future rests heavily on MRD-guided treatment. The trials involve bi-specific and tri-specific antibodies as well as CAR T-cell therapy and MRD-guided sequencing of the therapies.

Recent results also have raised questions about the role of stem-cell transplantation. The MIDAS trial of MRD-guided consolidation therapy showed that patients randomized to autologous stem-cell transplant did no better than those who continued drug therapy. In MRD-positive patients, tandem transplant offered no advantage over a single transplant.

For patients with relapsed myeloma, novel CAR T-cell designs hold promise for the future, as do tri-specific antibodies, and T-cell engager therapy, which uses a bi-specific antibody to connect autologous T cells to cancer cells.

So-called off-the-shelf CAR T-cell therapy has attracted considerable attention as a means to avoid the time-consuming processing of conventional CAR T-cell therapy, said Martin. A four-patient series from China involving in vivo CAR T-cell therapy had "amazing data" related to clearance of circulating disease and stringently defined responses in advanced disease.

"This is what's going on," said Martin. "This is where CAR T-cell therapy is headed in the future."

Clinical and laboratory definitions of cure are meaningful to patients, but the prospect of prolonged, good-quality life, with or without cure, might be even more important to some patients, particularly given the advanced age of most, said Rahul Banerjee, MD, of Fred Hutch Cancer Center in Seattle.

"None of us would all agree on [the definition of cure]," he told MedPage Today. "Functional cure is what I tend to use with my patients. I tell them that compared to an age-matched 70-year-old, your twin somewhere else in America who has the same chronic conditions as you but doesn't have myeloma, you'll live as long as they will. That's been my goal, I'm actually satisfied with that. I think that goal is attainable."

MRD negativity will remain a prerequisite for cure and remain a hot topic for debate in academic medicine, Banerjee continued. To many patients, however, "cure" has a more nuanced meaning.

"You may still be MRD positive, you may still have some abnormalities in the blood work," he said. "The myeloma is there. It's not gone. It's just there in a quiet state, in a dormant state. They may have an MGUS [monoclonal gammopathy of undetermined significance]-like state, a pre-cancer state. They are 6 or 7 years out but still have a tiny M spike. They're neither in remission nor are they cured. But they're probably going to live their whole life without needing a treatment change for myeloma.

"For someone like that, what do you call them? Some patients like that say 'we're basically cured.' Some patients don't like that word and they don't use it themselves, even if I use it. So it's tricky."

2025-11-05T22:59:41Z