Smoldering Multiple Myeloma

Smouldering multiple myeloma is an asymptomatic plasma cell disorder between monoclonal gammopathy of undetermined significance and active myeloma, defined by a serum monoclonal protein of 30 g/L or more (IgG or IgA) or urinary monoclonal protein of 500 mg or more in 24 hours, and/or 10% to 60% clonal plasma cells in the bone marrow, with no myeloma defining events and no amyloidosis. The risk of progression to active myeloma varies widely, so risk stratification decides whether to observe or treat.

It forms about 15% of newly diagnosed myeloma related disorders, with an incidence of about 0.5 to 1 case in 100,000 people each year. Median age at diagnosis is 60 to 65, and the risk is higher in men, Black individuals and people with a family history or obesity.

Pathophysiology. Clonal plasma cells proliferate in the marrow with genetic abnormalities that are also found in myeloma (hyperdiploidy, t(11;14), t(4;14), 1q gain, 17p deletion, MYC rearrangement), and progression depends on changes in the marrow microenvironment and clonal evolution.

Progression risk. About 10% of patients a year progress in the first 5 years, 3% a year in the next 5 years, and 1% a year after that. A common risk model uses three factors: marrow plasma cells over 20%, serum monoclonal protein over 20 g/L, and an involved to uninvolved free light chain ratio over 20. Low risk (no factor) has about 6% progression at 2 years, intermediate risk (1 factor) about 18%, and high risk (2 or 3 factors) about 44% at 2 years.

• Asymptomatic, found by chance on protein electrophoresis or routine blood tests (raised total protein, low albumin ratio).
• No hypercalcaemia, renal impairment, anaemia or bone lesions related to the plasma cell disorder.
• Symptoms suggest progression: bone pain, fatigue, recurrent infections, polyuria and thirst, confusion, neuropathy.

Red flags (progression to active myeloma).

• Hypercalcaemia, renal impairment, anaemia, or new bone lesions.
• Marrow plasma cells 60% or more, free light chain ratio 100 or more (involved light chain at least 100 mg/L), or more than one focal lesion on MRI.

• Serum protein electrophoresis with immunofixation, quantitative immunoglobulins, serum free light chains, and 24-hour urine protein electrophoresis.
• Bone marrow aspirate and biopsy with plasma cell percentage, immunophenotyping, and cytogenetics (FISH for t(4;14), t(14;16), 17p deletion, 1q gain, t(11;14)).
• FBC, creatinine, eGFR, calcium (corrected), albumin, LDH, beta-2 microglobulin and urine protein.
• Whole body low dose CT, FDG-PET-CT or whole body MRI to look for lytic lesions and focal lesions. Plain skeletal survey is less sensitive.
• Exclusion of amyloidosis and POEMS syndrome when clinically suspected.

Differential diagnosis.

• Monoclonal gammopathy of undetermined significance (marrow plasma cells under 10%, protein under 30 g/L)
• Active multiple myeloma and AL amyloidosis
• Waldenström macroglobulinaemia, solitary plasmacytoma and plasma cell leukaemia
• Reactive plasmacytosis (infection, autoimmune disease, liver disease)

Observation (low and intermediate risk). Clinical review and laboratory tests every 3 to 4 months for the first year, every 6 months for the next 2 years if stable, and every 6 to 12 months thereafter, with imaging for new symptoms. Treatment is started at progression to active myeloma, and the patient is advised to report bone pain, fatigue or infections.

Early treatment (high risk disease, in line with specialist assessment, or within clinical studies).

• Daratumumab monotherapy: daratumumab 1800 mg (with hyaluronidase) subcutaneously once weekly in weeks 1 to 8, every 2 weeks in weeks 9 to 24 and then every 4 weeks, for up to 36 months or until progression; maximum 1800 mg in one dose; monitoring: FBC, infusion type reactions (premedicate with paracetamol, an antihistamine and montelukast 10 mg, and dexamethasone 20 mg for the first dose), hepatitis B serology, infection, interference with blood bank cross-matching (inform the blood bank); adjustment: no renal or hepatic adjustment, delay for neutrophils under 1.0 x 10^9/L, give aciclovir 400 mg orally twice daily for shingles prophylaxis
• Lenalidomide with dexamethasone (an alternative): lenalidomide 25 mg orally once daily on days 1 to 21 of each 28-day cycle with dexamethasone 20 mg orally on days 1 to 4 and 12 to 15 for 9 cycles, then lenalidomide 10 mg orally once daily on days 1 to 21 of each 28-day cycle for up to 2 years, with aspirin 75 to 100 mg orally daily for thromboprophylaxis; maximum lenalidomide 25 mg daily; monitoring: FBC every 2 weeks for the first 2 cycles and then monthly, creatinine, liver tests, thyroid function, venous thromboembolism, rash, second primary malignancies, pregnancy prevention programme; adjustment: use 10 mg daily when creatinine clearance is 30 to 60 mL/min and 15 mg on alternate days when under 30 mL/min, hold for neutrophils under 1.0 x 10^9/L or platelets under 50 x 10^9/L and resume at a lower dose, use enoxaparin 40 mg daily instead of aspirin when thrombotic risk is high

Bone and general health. Calcium and vitamin D optimisation, bone density assessment (bisphosphonate or denosumab for osteoporosis, using the dose for osteoporosis rather than the myeloma dose), regular exercise, annual influenza vaccination, pneumococcal and COVID-19 vaccination, and avoidance of nephrotoxins and dehydration.

Treatment on progression. Combination regimens for active myeloma are given by a myeloma team.

Monitoring. Serum protein electrophoresis and free light chains, FBC, calcium and creatinine at each visit. Whole body imaging yearly, or sooner if symptoms or biochemical progression occur, and bone marrow reassessment when the monoclonal protein rises by over 25% or other markers change.

Referral and escalation.

• Referral to haematology on a new monoclonal protein of 30 g/L or more, or marrow plasma cells over 10%.
• Urgent assessment for hypercalcaemia, renal impairment, bone pain or new fractures.

Special groups.

• Renal impairment: investigate for other causes before attributing it to myeloma, and adjust lenalidomide.
• Pregnancy (rare): observation with haematology and obstetric input, and avoidance of lenalidomide.
• Older adults: observation unless high risk, with a preference for monotherapy with daratumumab.