Smoldering multiple myeloma

In a study of 276 patients by Kyle the overall risk of progression to multiple myeloma of 10% per year for the first five years, approximately 3% per year for the next five years, and 1% per year for the last 10 years.

In a  the study of patients with SMM 59% ultimately developed myeloma: Fast progressors to myeloma were found to have very high monoclonal protein levels for 4 g/dL or greater and the presence of immuno paresis (Kyle RA).

The risk of disease progression increases between 80 and 90% within two years among patients with 60% of great plasma cells or 100 or greater free light chain ratio: these patients should be treated as myeloma patients.

A study showed three separate clinical/biological features can be used to predict the risk of progression: greater than 20% plasma cells in the bone marrow biopsy, a monoclonal protein spike of 2 g/dL, and a free light chain ratio greater than 20 of involved/uninvolved proteins.: When the patient had zero factors the risk of progression was 110 months on average, if they had two or greater of these three features the risk of progression to myeloma was 29 months (Lakshman A).

Approximate 2% of patients will develop myeloma defining events including: the presence of hypercalcemia, renal failure, anemia, or bone disease.

Prior to diagnosing a patient with SMM patient should have advanced imaging including whole body MRI, pelvic/spine MRI, low-dose whole body CT or PET/CT.

One group is characterized by a clinical  compatible with MGUS despite meeting clinical criteria for smoldering multiple myeloma diagnosis.

A more advanced plasma cell disorder then MGUS with 4100 patients diagnosed annually in the US.

In this group the genomics predisposition to acquire new driver events associated with progression is low, the clone is stable, and the clinical course indolent.

 

In general, MGUS and smoldering multiple myeloma share some recurrent genomic aberrations with multiple myeloma, but others such as 13q and 17p deletions are seen at a lower prevalence compared with myeloma.

A recent study looked at over 86,000 people with multiple myeloma and found that 13.7 percent were first diagnosed as having smoldering myeloma, with a median age of 67 years at diagnosis.

Estimated 4,400 people in the U.S. diagnosed with smoldering myeloma each year.

Approximately 50% of patients diagnosed with smoldering multiple myeloma will develop overt disease.

Patients with high risk smoldering myeloma have a proximately 75% risk of developing symptomatic multiple myeloma at five years and the median time to be ration of less than two years.

Smoldering myeloma as a risk progression that is higher than that of MGUS.

The first sign is elevation of the serum total proteins.

Serum protein electrophoresis can detect the presence of a monoclonal component.

When a monoclonal component is higher than 3 g/dL a bone marrow aspirate, with without a biopsy is performed.

Evaluation includes the percentage of bone marrow plasma cells, the presence of anemia, renal function tests, calcium and liver function tests.

The presence of bone lesions suggest a diagnosis of multiple myeloma instead of smoldering multiple myeloma.

Low-dose CT is the new standard for evaluation of lytic lesions.

All patients should be evaluated for serum free light chain ratio.

Active myeloma is diagnosed if serum free light chain ratio is higher than 100 or if two or more focal lesions are identified during bone MRI exams.

With the diagnosis of smoldering multiple myeloma periodic hemogram, biochemistry tests, and proteins should be repeated in approximately 2-3 months to confirm season the stabilization of the monoclonal component, as well absence of anemia, renal impairment and hypercalcemia.

Diagnostics may involve bone marrow plasma cells, monoclonal protein, serum free light chains, flow cytometry, immunoparesis, MRI, and florescence in situ hybridization.

The presence of more than one focal lesion on spine or whole body MRI is associated with a higher risk of progression to symptomatic myeloma.

Markedly elevated serum free like chain ratio of 100 or greater and involved free light chain levels of 100 mg/L are also markers of malignant transformation.

The percentage of monoclonal plasma cells in the bone marrow with 60% or greater is prognostic of disease progression.

Daratuzumab may improve disease free survival.

Lenalidomide can reduce the risk of smoldering myeloma progressing to overt multiple myeloma in high-risk patients, and may also reduce the risk of smoldering myeloma from progressing to cancer in intermediate-risk patients.

Every risk group benefits from intervention.

In half of those diagnosed with smoldering myeloma, the condition progresses to multiple myeloma in the first 5 years.

In the phase II trial, after 3 years, 87 percent of the patients were alive without progressing to multiple myeloma.

In the phase III trial, after 1, 2 and 3 years on the trial, respective progression-free survival rates were 98 percent, 93 percent, and 91 percent for those who received lenalidomide and 89 percent, 76 percent, and 66 percent, respectively, for those who did not receive the treatment.

About 80 percent of patients in the phase II trial and 51 percent of those in phase III trial discontinued lenalidomide due to toxicity: fatigue and non-blood or bone-related side effects.

A 2015 Spanish trial, named PETHEMA, demonstrated that the combination of lenalidomide and dexamethasone lengthened the time before people with smoldering myeloma developed multiple myeloma and extended survival.

Studies suggests that in patients with high-risk smoldering myeloma treated with triple regimen of carfilzomib , lenalidomide, dexamethasone with lenalidomide maintenance therapy alters the natural history of smoldering myeloma by significantly delaying the development of endorgan disease.

The treatment with lenalidomide should be considered for patients who are at higher risk of progression to symptomatic multiple myeloma, to delay or avoid the development of multiple myeloma complications.