A Time for Action

If you have smoldering multiple myeloma, should you seek treatment?

That question has been hotly debated by experts over the past five years.

Smoldering myeloma is a blood condition that can develop into myeloma. Although it brings on few if any myeloma symptoms, such as anemia, bone damage or organ complications, it can be detected through a blood test: It announces its presence through slightly elevated levels of plasma cells in the bone marrow and a small rise in monoclonal (M) antibody or antibody fragment proteins — which, in myeloma, are produced abnormally and excessively, crowding out normal proteins.

The treatment for smoldering myeloma is a watch-and-wait strategy, and no therapies are approved for the condition. However, clinical trials are testing the use of drugs for cases considered high-risk: those that show evidence of increasing or more concentrated levels of M protein, plasma cells producing M protein of the immunoglobulin A subtype, plasma cells with certain genetic abnormalities (such as deletion 17p) and bone marrow lesions.

At the 2017 annual meeting of the American Society of Hematology, several teams reported promising results after treating high-risk cases of smoldering myeloma. Patients seemed to tolerate the therapies well, and 80 percent to more than 95 percent responded to treatment.

A phase 2 Spanish study reported that 85 percent of 19 patients achieved complete remission after treatment with a triplet therapy of the targeted Kyprolis (carfilzomib), a proteasome inhibitor; Revlimid (lenalidomide), a drug in the same class that modulates the immune system; and dexamethasone, a steroid. The combination was given before and after autologous stem cell transplant. That investigation followed a 2016 phase 2 Dana-Farber Cancer Institute study, whose results revealed good responses to another triplet therapy: Empliciti (elotuzumab), a monoclonal antibody against signaling lymphocytic activation molecule F7; Revlimid; and dexamethasone.

Findings from another phase 2 study, which was conducted at The Ohio State University, showed promise for treating smoldering myeloma with daratumumab. This monoclonal antibody targets CD38, which appears on the surface of lymphocytes and acts as both an antigen and a protein. The drug seemed to be tolerated well and resulted in a progression-free survival rate of 95 percent among those who received dose-dense treatment and 88 percent of those who received less frequent dosing.

For this population, the groundbreaking chimeric antigen receptor (CAR)-T cell immunotherapy regimens now being tested in patients with myeloma are a distant possibility. Experts say that the strategy might emerge after CAR-T cells have been successfully tested in patients with earlier-stage myeloma — but those clinical trials are not yet in progress.

“Eventually, CAR-T cell might be a good place to go for smoldering myeloma,” says Larry Anderson, M.D., Ph.D., of the University of Texas Southwestern Medical Center in Dallas. “But there are other places to go sooner.”

For now, defining the best therapeutic options for some cases of smoldering myeloma remains important, says C. Ola Landgren, M.D., Ph.D., chief of the myeloma service at Memorial Sloan Kettering Cancer Center in New York City. “I can think of a scenario when we would want to go to treatment really early,” he says. “It’s always a balance between toxicity and efficacy. Of course, if we could cure, then we would do treatment early on.”

Through its Black Swan Initiative, the International Myeloma Foundation is working on the largest trial to date to identify and treat the condition. The foundation seeks to monitor 120,000 adults over age 40 in Iceland for smoldering myeloma, diagnose all cases and enroll those patients in a randomized clinical trial to determine the best treatment strategies and create a new model for assessing progression toward myeloma. The ultimate goal: Prevent smoldering myelomas from turning into myelomas.

The trial could better define the demarcation line between smoldering myelomas that do or do not need treatment. Research is already heading in that direction: In 2014, the diagnostic criteria for myeloma were revised, folding some patients with high-risk smoldering myeloma into the pool of patients with cancer who were eligible for treatment.

Eventually, the category could be eliminated, Landgren says: Patients will either have multiple myeloma and need treatment or they won’t. The “almost” zone of smoldering myeloma may disappear.

A 2017 review in the journal Blood, which recommended close follow-up for those with smoldering myeloma, supported that concept. “We foresee that (smoldering multiple myeloma) will disappear in the near future with the use of better diagnostic criteria,” the authors wrote.