Preventing the First Relapse: Why the Best Upfront Treatment is the Key to a Better Myeloma Future

The most effective way to manage "functional high-risk" myeloma—an early and aggressive relapse—is to prevent it from ever happening. In her presentation at the International Myeloma Society 2025 conference, Dr. Katja Weisel delivered a clear and powerful message: by using our best, most powerful quadruplet therapies as the first line of treatment for all eligible patients, the medical community can dramatically reduce the number of people who face this devastating outcome.

What is "functional high-risk" myeloma?

Functional high-risk is not defined by a genetic test at diagnosis, but by the cancer's behavior. A patient is considered functionally high-risk if their myeloma comes back within 12 to 18 months of starting their first treatment. This has historically affected up to a quarter of all patients and is a clear indicator of aggressive disease, leading to a much poorer prognosis.

While patients with high-risk genetics are more likely to fall into this group, many who relapse early are considered "standard risk" by older, narrow genetic definitions. This is why Dr. Weisel strongly advocated for using the new, more comprehensive International Myeloma Society (IMS) criteria to better identify patients with the worst prognosis from the very beginning.

A clear treatment path if early relapse happens

For patients who do experience an early relapse, there is now a clear hierarchy of treatment options based on powerful clinical trial data.

The Gold Standard: CAR-T Therapy. If it is available, CAR-T cell therapy is unequivocally the best treatment. Data from trials like KarMMa-4 showed that patients treated with cilta-cel had a progression-free survival that was vastly superior to those receiving standard care. Given its approval in many countries for second-line treatment, CAR-T should always be the first consideration for this group.

The Next Best Option: When CAR-T is not accessible, the most effective conventional treatments are triplets that combine a CD38 antibody (like daratumumab) with carfilzomib and dexamethasone (Kd). While not as effective as CAR-T, these specific combinations offer the best possible outcomes among standard drug regimens for this patient population.

Making prevention the standard of care

The central theme of the presentation was that the entire field should shift its focus from treating early relapse to preventing it. This is achieved by giving every patient the best possible therapy from day one. Dr. Weisel presented stunning data from recent trials that prove this strategy works:

The PERSEUS trial, using a daratumumab-based quadruplet regimen for transplant-eligible patients, reduced the rate of patients relapsing within 24 months to an unprecedented 3%.

The IsKia trial, using an isatuximab-based quadruplet for transplant-ineligible patients, reduced the rate of functional high risk to less than 10%.

These results provide a clear mandate: optimized, quadruplet-based first-line therapy should be the standard of care for all eligible patients to give them the best chance of a long and deep first remission. For patients identified at diagnosis with high-risk genetics, an even more intensified approach is needed, with the goal of achieving a deep and sustained MRD-negative state (a highly sensitive measure showing no detectable cancer cells), which is the foundation for long-term survival.

Functional high-risk myeloma represents a major clinical challenge, historically defining a group of patients with very poor outcomes. While we now have superior treatments like CAR-T cell therapy for when this early relapse occurs, the real paradigm shift is in prevention. By accurately identifying high-risk patients from the start using modern genomic criteria and treating all patients with optimized quadruplet-based first-line therapies, the myeloma community has a clear roadmap to drastically reduce the incidence of early relapse. This strategy of hitting the cancer hard and early is the most effective way to improve long-term outcomes for everyone diagnosed with myeloma.

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