NEW STUDY RESULTS SHOW that Darzalex (daratumumab), a targeted therapy, lowered the risk of smoldering multiple myeloma progressing to multiple myeloma by 50% in patients at high risk for disease progression. The findings, presented in December 2024 at the annual meeting of the American Society of Hematology, could change clinical practice.

Each year, about 10% of patients with smoldering myeloma, a precursor to multiple myeloma, progress to active multiple myeloma, according to the International Myeloma Foundation. Monitoring is the standard of care for smoldering myeloma, and there are currently no treatment options approved by the Food and Drug Administration (FDA) for the condition.

The phase III trial presented in December, called AQUILA, evaluated whether patients with smoldering myeloma at high risk for developing multiple myeloma would benefit from Darzalex, a human monoclonal antibody that fights cancer by targeting CD38, a cell surface protein expressed at high levels on plasma cells, compared with standard monitoring of the condition.

In the study, 194 patients received Darzalex while 196 patients were assigned to the observation arm. The treatment group was given Darzalex by injection for up to six 28-day cycles over three years, which mirrored the standard dose regimen for treating active multiple myeloma. Patients in both study arms had regular myeloma laboratory monitoring plus yearly whole-body imaging to check for bone lesions and examinations of the bone marrow every other year to monitor for disease progression.

Darzalex reduced the risk of progression to active multiple myeloma by 50% compared with observation alone. The Darzalex group also showed statistically improved progression-free survival at five years—63.1% for patients given Darzalex and 40.8% for patients in the observation arm. Treatment-related side effects led to discontinuation in 6% of patients in the Darzalex group. “That number, compared to other smoldering myeloma trials, is very low,” says hematologist and medical oncologist Peter Voorhees, the study lead investigator and chief of the plasma cell disorders division at Atrium Health Levine Cancer Institute in Charlotte, North Carolina.

“Our study has a very good chance of changing the treatment paradigm for high-risk smoldering multiple myeloma. It provides the most robust evidence we have to date that early intervention should be strongly considered for any patient with high-risk smoldering myeloma,” Voorhees says.

Smoldering myeloma is often diagnosed incidentally during a routine blood test for something else, when the test detects an abnormal protein called myeloma (M) protein. Monitoring typically involves regular blood tests to check for M protein levels of plasma cells in bone marrow. “In all cases, we know that active multiple myeloma starts from the smoldering myeloma stage,” Voorhees says. But in some patients, smoldering myeloma never develops into active multiple myeloma, so why expose patients to a treatment for a disease they may never develop? “In the smoldering myeloma community, there are some providers who strongly feel that observation is the right thing to do,” Voorhees says.

Still, in patients with high-risk smoldering myeloma, as defined by the International Myeloma Working Group diagnostic criteria, AQUILA may provide enough evidence for treatment before multiple myeloma develops. “AQUILA has put a line in the ground that says there are benefits to treating with Darzalex, that it can make a difference in progression-free survival and survival for patients with high-risk smoldering multiple myeloma,” says medical oncologist Irene Ghobrial, director of the Center for Early Detection and Interception of Blood Cancers at Dana-Farber Cancer Institute in Boston, who was not connected with the study.

Darzalex is currently FDA-approved for treating multiple myeloma. AQUILA study data were recently submitted to the FDA and to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines committee.

“There has never been regulatory approval for smoldering multiple myeloma treatment in any country,” Voorhees says. “If Darzalex gets regulatory approval or, in the absence of that, NCCN designation, it will certainly expand access to this therapy for patients with high-risk smoldering multiple myeloma by paving the way for payers,” he says. “Without insurance coverage, the therapy is prohibitively expensive for the vast majority of patients anywhere in the world.”

Sandra Gordon is a medical writer in Stamford, Connecticut.