“One of our hopes is that in the future we will be able to use novel immunotherapeutic approaches to target patients who have extramedullary disease,” Dr Fonseca said.

A new term, “extragenomic” therapy, has been proposed to describe treatment strategies that do not depend on inducing apoptosis signals using “the intrinsic machinery of the intracellular component” in tumor cells, Dr Fonseca said. “Perhaps, that will be more useful in patients who have, for instance, mutations of genes like p53? If this hypothesis were true, then that would mean that some of the high-risk myeloma patients could be better suited for treatment with strategies such as CAR T-cell and bispecific antibodies. Again this is just a hypothesis, but a rational one nevertheless.”

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There are no validated, established biomarkers to predict extramedullary myeloma at diagnosis or at relapse, but efforts are underway to develop new imaging tracers to detect minimal residual disease (MRD), including extramedullary disease, he noted.

“Taking advantage of myeloma-specific immuno tracers loaded in PET/CT machines, there are ongoing studies looking into radiolabeled antibodies and small molecules that are tumor specific,” he explained. “In the future, such technologies may replace current imaging and may be used to determine tumor burden at diagnosis and MRD status after therapy.”

“Clinically, a myeloma patient who, for example, is relapsing for the seventh or eighth time (compared with the first or second time) is more likely to have extramedullary disease,” Dr Landgren said. “Many times, such extramedullary cells are lacking typical myeloma proteins in their surface. [For example,] they may lack CD38.

“If the disease is able to grow outside the regular niche (the bone marrow), that is a sign that the tumor cells have a more aggressive biology and the disease is more resistant to conventional therapy,” he explained. “Therapy may result in a response, but on average, the disease is more likely to relapse again. Systemic therapy is used to treat a patient with bone marrow involvement and additional extramedullary disease.”

Radiotherapy may also be given in patients with a single site of extramedullary disease, Dr Landgren said.

Expression of p53 has been recognized for several years to be a risk factor for extramedullary spread, but relatively little is known about the exact molecular interactions that drive myeloma’s extramedullary dissemination.2