Back Back
Treating SMM
Smoldering Multiple Myeloma: When to Treat?

Released: April 18, 2018

Expiration: April 17, 2019

Activity Information

Activity

Progress
1
Course Completed
Continue

It is clear now that multiple myeloma (MM) is preceded by a prolonged asymptomatic phase, monoclonal gammopathy of undetermined significance (MGUS). A proportion of these patients may go through an intervening phase, smoldering MM (SMM), that is characterized by increased tumor burden but still without any end organ damage. Although the risk of progression to symptomatic MM is significantly higher for patients with SMM than for patients with MGUS (50% vs 5%, respectively, in 5 years), nearly one third will never progress. The conventional approach to SMM, similar to MGUS, has been close observation, initiating treatment only when the patient meets the definition for active MM.

This paradigm is now being questioned due to significant advances in the understanding of disease biology, improved risk stratification approaches, and newer therapies with better efficacy and lower toxicity. Various prognostic factors have been identified, allowing for better assessment of the progression risk. This led to revised IMWG diagnostic criteria, with the incorporation of high free light chain ratio, bone marrow plasmacytosis, and bone marrow lesions on MRI as indicators of active MM requiring therapy. This represents a paradigm shift—for the first time, we started treating asymptomatic patients for their MM, based on the ability to predict a high risk of progression.

The next important question is whether early treatment of patients with SMM, who are at high risk of progression, will alter the natural history of their disease and improve not only the time to progression to active MM, but improve their OS as well. A Spanish phase III trial by Mateos and colleagues compared early treatment with lenalidomide and dexamethasone vs observation in a group of patients with high-risk SMM and demonstrated an improved OS for early intervention without any adverse impact on the benefit of subsequent treatments, allaying concerns of harm. This has led to additional large phase III trials designed to provide confirmation of the benefit for early intervention.

Another important question in MM, which remains incurable with current approaches, is if early intervention can potentially cure the disease. Studies have demonstrated increasing genetic complexity in plasma cells with progression from MGUS to SMM to active MM. In addition, alterations have been identified in the tumor microenvironment and the immune profile during this progression. All these findings suggest that the best possibility of curing the disease may be with early intervention with the most effective therapies available.

However, it is important that these approaches are of limited duration to demonstrate the best value and maintain the best possible quality of life for these patients. This has led to development of several clinical trials examining intense treatment approaches delivered over a defined period, such as the GEM-CESAR trial, which used a combination of carfilzomib, lenalidomide, and dexamethasone with stem cell transplantation, and the upcoming ASCENT trial, evaluating the same combination but using daratumumab instead of transplantation. This fundamental change in our approach to SMM reflects a change in how we view this entity.

In our own practice, we customize the approach to patients with SMM based on the risk of progression. All patients with SMM should be seen in 2-3 months after initial diagnosis to make sure they are not on a trajectory of disease progression missed on a single assessment. Once the stability is ascertained, subsequent follow up would depend on the risk of progression by any of the current risk stratification models. Patients with high risk disease would be either enrolled on a clinical trial or observed every 2-3 months, with closer follow up of renal function in those with elevated serum free light chains. For the patients at lower risk of progression will be observed every 3-6 months. The follow up should include CBC, routine chemistry and monoclonal protein studies, including serum free light chain and imaging studies as indicated. Equivocal findings on imaging at diagnosis should be reevaluated sooner. It is reasonable to screen these patients for bone health and institute anti-resorptive therapy in the presence of osteoporosis. It is also important that routine health maintenance recommendations are followed in these patients.

What has been your experience in treating patients with SMM? Let us know in the comment section below and by answering the question to the right.

Continue

Poll

1.
How do you treat patients with high-risk SMM?
Submit