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Precancerous, or smoldering, multiple myeloma (SMM) is by definition an asymptomatic disease, and about 50% of those diagnosed with this precursor condition will develop full MM .

International Myeloma Working Group's define SMM by a 10% to 60% plasma cell infiltration in bone marrow or a monoclonal (M)-protein concentration in serum in excess of 3 g/dL in the absence of myeloma-defining events.

The condition is usually detected incidentally when a routine check-up shows increased levels of paraprotein or free light chains in the blood or urine. A common primary finding that leads to further work-up is the presence of an elevated total protein level on a routine complete metabolic panel (CMP) or an elevated total protein level on a routine CMP or an elevated protein gap (difference between total protein and albumin), noted Sarah Holstein, MD, PhD, of the University of Nebraska Medical Center in Omaha.

"A variety of specialties might order testing for a monoclonal protein including nephrologists, rheumatologists, and neurologists, which could in turn lead to the diagnosis of SMM," she added.

By the time of clinical manifestation, the disease may have caused debilitating health problems, including peripheral neuropathy, bone fractures, and .

"Since some of the initial presenting features of multiple myeloma, such as anemia and renal failure, can be seen in other medical conditions, this may delay diagnosis and appropriate care for the patient, adding to further complications," said Jessica Caro, MD, of Northwell Health's Zuckerberg Cancer Center in New Hyde Park, New York. "However, there are limited data on the epidemiology of SMM as patients are asymptomatic, and there is no routine screening program to identify patients."

SMM has an estimated prevalence of about 0.5% in persons , with a rate that rises with age and is higher in men than women.

"Laboratory, whole-body imaging, and pathology with bone marrow biopsy evaluation are necessary to differentiate between SMM, MM, as well as other blood conditions such as monoclonal gammopathy of undetermined significance, called MGUS," noted Holstein.

Treatment or Watch and Wait?

Patients with low-risk disease have just a 20% chance of needing treatment for complications in the 5 years after diagnosis, while those at intermediate risk have about a 50% chance of needing treatment, which rises to a 75% to 80% risk for

In the absence of established therapies, doctors have historically adopted a watchful waiting approach, with close monitoring for active disease, such as bone and organ damage and greater frequency of infections. Now, however, drug therapies are beginning to show promise in slowing progression to MM.

"Early treatment is being hotly debated but it only applies to patients at high-risk, or perhaps intermediate risk, who would be eligible to enter clinical trials," said Sandra Mazzoni, DO, of the Cleveland Clinic.

The lack of consensus on the optimal management of SMM is due in large part to the fact that this diagnosis encompasses many different disease phenotypes.

"Definitions that distinguish MGUS from SMM from MM are somewhat arbitrary and focused on plasma cell burden," said Holstein. "It's clear that a subset of patients diagnosed with SMM have disease biology that is much more consistent with MGUS, and to offer them treatment for a process that has a very low likelihood of ever progressing to overt cancer is not appropriate."

On the other hand, a subset have disease that rapidly evolves into overt MM. "In this scenario, if we knew from the beginning how the disease was going to behave, then we would offer the standard-of-care treatment we give for newly diagnosed MM," she said.

Assessing Risk for Progression

While mounting evidence supports the role of the surrounding bone marrow microenvironment and of the immune system in regulating the progression of SMM, this evidence has not yet been translated into existing risk stratification systems.

"And ultimately, previously conducted trials have not shown evidence that early intervention cures the disease," Holstein said. Therefore, outside of clinical trials, watchful waiting remains an important option. "This provides a sense of the rate of change over time in an individual patient's disease metrics, which, in addition to other disease characteristics, can be used to guide the discussion about continued watchful waiting versus intervention."

Experts stress that recommendations to proceed with treatment of this asymptomatic condition must incorporate consideration of disease risk, impact of treatment on quality of life, and patient preferences.

While most current schemes rely heavily on measures of plasma cell burden, will likely include changes in paraprotein levels over time and also consider genetic alterations and immune microenvironment abnormalities.

In the meantime, research is suggesting that some high-risk SMM patients could benefit from early intervention with chemotherapy and perhaps immunotherapy.

Therapy

The thalidomide-analogue lenalidomide (Revlimid), with or without dexamethasone, is an FDA-approved treatment for SMM with demonstrated progression-free survival (PFS) benefits in high-risk patients. In a phase III among 182 SMM patients, 3-year PFS was 91% with lenalidomide versus 66% with careful observation, and no between-group difference in quality of life.

An early of 119 patients from Spain looked at the effect of lenalidomide plus dexamethasone in high-risk SMM. After a median follow-up of 40 months, the median time to disease progression was not reached in the treatment group but was observed at 21 months in the observation-only group. The 3-year survival rate was also higher in the treatment group (94% vs 80%).

Clinical trials have been evaluating other approaches as well, such as single-agent daratumumab (Darzalex) and more intensive combination regimens such as those used in active MM. Mazzoni's group has started a study called , randomly assigning high-risk patients to either standard of care with lenalidomide alone or in combination with daratumumab. Results are not expected for a few years.

As for the addition of immunotherapy, a of 50 high-risk patients combined lenalidomide and dexamethasone with elotuzumab (Empliciti), an immunostimulatory antibody targeting the highly expressed SLAMF7 protein on MM cells. Overall, 84% responded to the triple-drug combination, with no progression to overt disease during 3 years of follow-up.

And in a of 13 SMM patients at intermediate to high risk of progression, treated with the PD-1 inhibitor pembrolizumab (Keytruda), one patient achieved a stringent complete response that was ongoing at 27 months. Eleven patients had stable disease.

Strategies using other immunotherapeutics, such as vaccines have also yielded some success, with results suggesting SMM may be immunogenic in a subset of patients. Hence, therapies that enhance antitumor T-cell responses may be effective in preventing its progression. Trials are evaluating the immunogenicity of neoantigen vaccines such as the multi-peptide PVX-410, which showed some immunogenic activity with or without lenalidomide in a of high-risk SMM patients.

More clinical trials are needed before immunotherapy becomes routine practice in SMM, and the ultra-high-risk population must be better defined before early treatment with its accompanying toxicities is offered.

In the meantime, low-risk patients can be followed by their community primary care doctors for classic signs and symptoms, "but high-risk individuals should definitely be referred to hematologists," said Mazzoni.

Decreased hemoglobin, worsening renal function, increasing protein gap or fatigue, new bone pain, or frequent infections, should raise alarm bells for primary care physicians about the possibility of progression to active MM. "Further evaluation by a composite care team, both primary care and hematology/oncology, is merited," said Holstein.

Mazzoni advises SMM patients to follow a Mediterranean-style diet, avoid excessive alcohol intake, abstain from tobacco, and remain active with cardiovascular and weight-bearing exercise. "There are no specific data on a diet or exercise regimen to delay disease progression, but my recommendation is to remain healthy so that if disease progression occurs, patients will have a better baseline health and in general tolerate treatment better."

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