Early treatment of smoldering multiple myeloma

Smoldering multiple myeloma (SMM) is a precursor condition associated with multiple myeloma. Because patients with SMM lack symptoms, the condition is typically discovered when M protein is found in blood or urine lab tests. Individuals with SMM are at greater risk for progression to full-blown myeloma, but progression is not guaranteed to occur. For the first five years after diagnosis, about 10% of individuals progress to multiple myeloma each year. The risk then drops to 3% until ten years after diagnosis and further drops to 1% after that time.

Doctors can sometimes predict which patients might face higher risk for earlier progression from SMM to MM. Several different factors play a role in determining the risk for progression:

  • M-protein concentration: individuals with M protein ≥30 g/L are at greater risk for progression
  • Increasing levels of M protein: those with rising levels are at higher risk than those with stable levels
  • M-protein type: plasma cells that are producing M protein of the IgA subtype have a greater risk for progression than those making IgG
  • Genetics of plasma cells: patients with certain cytogenetic abnormalities on the chromosomes of their plasma cells (t[4;14]; del[17p]; 1q+) are at higher risk for early progression
  • Abnormal bone marrow: if magnetic resonance imaging (MRI) scans show lesions, those individuals are at higher risk for progression
  • Bone marrow involvement: patients with greater numbers of plasma cells in the bone marrow are at higher risk of progressing
  • Additional laboratory assessments, such as serum free light chain (FLC) ratio, immunophenotyping by flow cytometry, circulating plasma cells, and other tests, may be performed to assess risk of progression

Historically, physicians have not started treatment for patients with SMM until they progress to multiple myeloma. Instead, the current practice is “watchful waiting”—monitoring patients closely to determine if they progress. Since no more than 10% of SMM patients progress to MM even within the first 5 years after diagnosis, long term treatment of SMM patients with MM therapy could lead to unwanted side effects with no benefit to the patient. But now that SMM patients at high risk for early progression can be identified, researchers are investigating whether those patients might benefit from earlier treatment. The MMRF has been both funding and conducting this research and will continue to do so in order for every patient to receive the best treatment option for his or her disease.

It has long been understood that the earlier any type of cancer is caught, the better chance for treatment success. However, SMM is a precancerous condition. Identifying those individuals with greater odds of progressing to myeloma could potentially prevent that progression from occurring or might help those individuals achieve longer, more durable remissions. Trials are currently being conducted to determine whether these patients do better with earlier treatment and what type of treatment is best.

Early studies have shown that treatment with Revlimid (lenalidomide) and dexamethasone prolonged the amount of time before patients with high-risk SMM progressed to multiple myeloma. The latest efforts are investigating some of the newer immunomodulatory drugs that are given alongside Revlimid and dexamethasone. Other studies are examining whether single-drug therapy will be efficacious in preventing progression or lengthening the time to progression.

The Multiple Myeloma Research Consortium (MMRC) is currently conducting two trials in smoldering myeloma:

  • A phase 2 trial reported results in December 2016—the study evaluated the three-drug combination of Empliciti (elotuzumab), Revlimid, and dexamethasone in high-risk smoldering disease; 71% of patients had a significant response to therapy
  • A phase 2 study of Darzalex (daratumumab) for the treatment of smoldering disease. Results of this trial are pending.

Both of these trials are closed to enrollment. For more information about these and other ongoing trials, visit clinicaltrials.gov or contact an MMRF nurse specialist at 1-888-841-MMRF(6673).