When to initiate treatment in a relapsing MM patient?

During the 2025 IMS meeting in Toronto, Prof Fredrik Schjesvold, head of the Oslo Myeloma Centre of the Oslo University Hospital in Norway, addressed the increasingly relevant question when to start a treatment for a multiple myeloma (MM) patient with a disease relapse. In fact, as clinicians become more focused on achieving and sustaining measurable residual disease (MRD) negativity in frontline therapy, the question has become what to if MRD pops up in a patient who was initially MRD negative. Should this patient immediately start treatment or is it ok to wait until a true biochemical relapse is detected

To address this question, Prof Schjesvold and colleagues have set up the randomized controlled REMNANT study. In this randomized trial, approximately 200 patients who have achieved complete response (CR) and are MRD-negative are followed closely. When MRD re-appears, patients are randomized into two groups. One group (Arm A) begins treatment as soon as they lose MRD negativity, while the other group (Arm B) starts treatment only once they meet formal criteria for progressive disease. Both groups receive the same therapy (DaraKd), allowing for a direct comparison of both strategies. The primary goal of this study is to determine whether initiating treatment earlier, i.e., before overt progression, can lead to improved progression-free survival (PFS) and overall survival (OS). While the trial results are still pending, Prof Schjesvold does see a strong (pre)clinical basis for an early intervention.

In fact, several clinical observations suggest that treating earlier in the disease course may lead to better outcomes. For example, patients whose disease is detected before the onset of full-blown myeloma have better survival rates, indicating a benefit from earlier diagnosis and treatment. Similarly, data on treating smoldering myeloma has shown an overall survival benefit, again pointing toward the value of initiating therapy earlier than the standard approach. At diagnosis, patients with a high tumour burden have worse survival, and this also holds true at relapse. This reinforces the idea that delaying treatment may allow the disease to reach a more aggressive and less manageable state.

In addition to clinical observations, there is a also a biological rationale for an early intervention. Refractoriness to treatment emerges through the accumulation of mutations. These mutations occur during cell division, a natural and ongoing process independent of whether the patient is receiving treatment. While therapy itself does not cause the mutations, it does exert selective pressure, allowing resistant clones to thrive. The greater the tumour burden, the higher the number of dividing cells, and therefore, the greater the likelihood of new mutations. As such, keeping the tumour burden as low as possible by initiating treatment early may reduce the emergence of resistance and help preserve future treatment options.

The potential benefit of an early treatment has already been demonstrated when we moved from the treatment of a MM relapse at the time of a clinical manifestation, to a treatment initiation at the time of biochemical progression. In fact, two large studies have shown that patients who begin treatment at the time of biochemical relapse (i.e., before symptoms arise) have a better progression-free and overall survival than those who wait for clinical progression.

In conclusion, while definitive prospective trial data are still awaited, there is a growing body of evidence that supports the strategy of treating relapse earlier rather than later. Ongoing trials like REMNANT will hopefully provide the robust data needed to formally confirm the benefits of early treatment in relapsed MM.