Bloodlines Series: What Is Smoldering Myeloma?

Learn about smoldering myeloma and the first treatment approved by the U.S. Food and Drug Administration to prevent its progression to active multiple myeloma.

Circulating throughout our bodies are various types of immune cells that work in an elegant, tightly regulated coordination to help us fight infection and disease. Some cells keep an eye out for problem cells or micro-organisms, others sound the alarm, and others spring to action to eradicate the threat. 

Disruption of this tight regulation can lead to various malignancies, including multiple myeloma. A form of blood cancer, multiple myeloma causes bone tumors, kidney failure, anemia, and other debilitating symptoms. With thousands of people affected by—and dying from—this disease each year, researchers continue to study new ways to prevent and treat it. One emerging approach is to stop multiple myeloma in its tracks by targeting an early, asymptomatic form of the disease known as “smoldering myeloma” or “smoldering multiple myeloma.”

How Does Smoldering Myeloma Develop?

Among the many immune cells tasked with protecting us from infection and disease are antibody-producing cells known as plasma cells, which develop, mature, and proliferate in the bone marrow under the control of a highly regulated system. 

Some plasma cells, however, develop genetic mutations that allow them to bypass this regulation and grow uncontrollably. As abnormal plasma cells accumulate in the bone marrow, they can lead to various conditions ranging from benign to life-threatening.

When abnormal plasma cells account for less than 10% of cells in a patient’s bone marrow, the patient has a benign condition called monoclonal gammopathy of undetermined significance (MGUS). The abnormal plasma cells produce a protein called M-protein that may be detected through routine blood or urine tests. Most patients with MGUS do not experience any symptoms and have steady levels of M-protein. About 0.5% to 1% of MGUS cases will progress to a form of cancer, such as multiple myeloma, lymphoma, or leukemia. 

When MGUS progresses to multiple myeloma, it first goes through a phase known as smoldering myeloma. Smoldering myeloma is an asymptomatic, early form of multiple myeloma that accounts for roughly 15% of newly diagnosed multiple myeloma cases. 

As an intermediary between MGUS and active multiple myeloma, smoldering myeloma is associated with a plasma-cell concentration that is higher than that seen in MGUS but lower than observed in active multiple myeloma. Because M-protein and plasma-cell levels are lower during smoldering myeloma, patients with this early form of the disease do not experience any of the symptoms that are characteristic of active multiple myeloma. 

Some cases of smoldering myeloma will progress to active multiple myeloma, a symptomatic, advanced form of multiple myeloma in which the dysregulated plasma cells comprise 60% or more of the bone marrow. In active multiple myeloma, plasma cells crowd out normal cells to form tumors in bones throughout the body. These tumors can weaken the patient’s bones, leading to fractures that release calcium into the bloodstream. Plus, the accumulation of antibodies produced by the abundant plasma cells can thicken blood and damage the kidneys. The high blood calcium, kidney (renal) failure, anemia, and bone lesions characteristic of active multiple myeloma are collectively referred to as CRAB features.

How Is Smoldering Myeloma Diagnosed?

Smoldering myeloma may be diagnosed incidentally through routine blood tests or procedures done to address other health conditions, or it may be observed in patients with MGUS who are being closely monitored for progression to smoldering myeloma.

For a diagnosis of smoldering myeloma, a patient must be asymptomatic and have either: high blood/urine levels of M-protein or plasma cells that account for 10% to 60% of their bone marrow. If the patient’s plasma cells make up 60% or more of their bone marrow, or if they experience peripheral nerve failure or myeloma-defining CRAB features, they are considered to have active multiple myeloma instead of smoldering myeloma.

How Often Does Smoldering Myeloma Progress?

According to one pivotal study, patients have a 10% risk per year of progression to active multiple myeloma during the first five years after a smoldering myeloma diagnosis. The risk drops to 3% per year for the next five years, and 1% per year for the following 10 years. The study found that, overall, there is a cumulative 73% chance of progression within the first 15 years after diagnosis.

A patient’s risk of progression to active multiple myeloma depends on several factors, including the amount of M-protein in their blood, the amount of other plasma-cell protein products in their blood, the concentration of plasma cells in their bone marrow, and the presence of certain genetic alterations in abnormal plasma cells.

Patients are considered to have a high risk of progression if they meet at least two of the following criteria: high blood levels of the M-protein, high blood levels of other plasma-cell protein products, and large proportions of plasma cells in the bone marrow. These patients face an estimated 44% risk of progression within two years.

Patients who meet one of these criteria are diagnosed with intermediate-risk disease and have an estimated 18% chance of progression within two years.

Patients who do not meet any of these criteria have low-risk disease and face a 6% risk of progression within the same time frame.

How Is Smoldering Myeloma Treated?

Until recently, the only option available to patients with smoldering myeloma was active monitoring through periodic blood tests, imaging, and/or bone marrow biopsy to check for signs of progression. Although patients could receive experimental treatments by enrolling in clinical trials, there were no approved treatments available to prevent progression of the disease.

This changed in November 2025 when the U.S. Food and Drug Administration (FDA) approved the first treatment for patients with high-risk smoldering myeloma: daratumumab and hyaluronidase (Darzalex Faspro). 

This treatment works by targeting a protein called CD38 that is highly expressed on the surface of abnormal plasma cells to trigger cell death. It was found to reduce the risk of progression among patients with high-risk smoldering myeloma by 51% in a clinical trial. 

The approval of daratumumab and hyaluronidase represents a major step forward in the management of high-risk smoldering myeloma, providing an effective strategy to treat the disease before it progresses to the more advanced, symptomatic form of active multiple myeloma. As with all care decisions, patients and their physicians should consider various factors before undergoing the treatment, including its potential impacts on future clinical trial eligibility. 

Additional treatment approaches for preventing progression of high-risk smoldering myeloma are being evaluated in clinical trials, including immunotherapies like chimeric antigen receptor (CAR) T-cell therapy, cancer vaccines, and T-cell engagers; immune-suppressing therapy; and targeted therapy; among others.

While patients with low-risk and intermediate-risk smoldering myeloma continue to be managed through active monitoring or enrollment in clinical trials, researchers are actively uncovering new insights into the disease and conjuring new strategies to stop it in its tracks, with the ultimate goal of preventing progression of all forms of smoldering myeloma.