Optimal Cytoreduction and Early Trial Referral in High-Risk Newly Diagnosed Myeloma

Asked how clinicians should approach high-risk cytogenetics, extramedullary disease (EMD), or plasma cell leukemia features at diagnosis, Saad Z. Usmani, MD, MBA, FACP, FASCO, named one objective for all of them: those patients need optimal cytoreduction. Usmani spoke with CancerNetwork® ahead of the 44th Annual Chemotherapy Foundation Symposium (CFS).

The regimen he described starts with quadruplet induction with or without transplant and at least 2-drug maintenance, typically being a proteasome inhibitor and an immunomodulatory drug. Where initial induction has not produced a deep response, he said triple maintenance or an extended period of maintenance is something his group would do.

The reason for that intensity is a definition that has recently changed. Usmani pointed to the International Myeloma Society (IMS)/International Myeloma Working Group (IMWG) 2025 consensus recommendations, which define high-risk multiple myeloma genomically, and said that even in the era of quads these patients may have a higher likelihood of relapse within the first 3 years. The consensus requires at least 1 high-risk feature, including del(17p) with a cancer clonal fraction of at least 20% or a TP53 mutation; t(4;14), t(14;16), or t(14;20) with 1q gain or del(1p32); and monoallelic del(1p32) with 1q gain or biallelic del(1p32).¹

What follows from that is a posture rather than a regimen. Usmani said to maximize what is available in the frontline setting, then keep a very close eye on relapse risk and channel those patients to appropriate clinical trials.

He split the advice by practice setting. Clinicians at an academic center should be on the lookout for trials. Clinicians in the community, he said, should have a multiple myeloma center with available trials as a backup in their back pocket and reach out at the first sign of trouble. He noted that frontline high-risk trials exist that allow one to 2 more cycles of treatment before a patient is enrolled, which leaves room to refer without interrupting care.

Usmani is a hematologist-oncologist and chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center.

Transcript:

CancerNetwork: How should clinicians approach high-risk cytogenetics, extramedullary disease, or plasma cell leukemia features at diagnosis? Are there specific regimens you favor?

Usmani: The approach for high-risk cytogenetics, extramedullary disease, or phenotypic high-risk features such as extramedullary disease or plasma cell leukemia at time of diagnosis—those patients need to get optimal cytoreduction. While starting with quad induction with or without transplant and at least 2-drug maintenance, typically a proteasome inhibitor and an immunomodulatory drug, is something that we do. Sometimes even triple maintenance treatment or an extended period of maintenance treatment for these patients, if they haven’t achieved deep responses with initial induction, is something that we would do.

The point I want to make about high-risk disease is that we have the new definition with the [IMS]/IMWG 2025 criteria, where even in the era of quads, these patients may have a higher likelihood of disease relapse within the first 3 years.¹ I would say to maximize what you can with available frontline strategies, but then have a very close eye on the risk of relapse, and channel those patients to appropriate clinical trials.

If you’re already at an academic center, be on the lookout for clinical trials. But then, if you’re out in the community, just make sure that you have a [multiple] myeloma center with available clinical trials as a backup in your back pocket, and reach out to them at the first sign of trouble. There are frontline, newly diagnosed, high-risk clinical trials as well that allow one to 2 more cycles of treatment before patients get enrolled on treatment. Think about sending your patients in for those trials if you’re out in the community. Those will be very important options for those patients.

References

1. Avet-Loiseau H, Davies FE, Samur MK, et al. International Myeloma Society/International Myeloma Working Group consensus recommendations on the definition of high-risk multiple myeloma. J Clin Oncol. 2025;43(24):2739-2751. doi:10.1200/JCO-24-01893