Smouldering multiple myeloma

Smouldering myeloma is defined by a serum M-protein of 30 g/L or more, or urinary M-protein of 500 mg a day or more, or clonal marrow plasma cells of 10 to 60 percent, with none of the myeloma-defining events (the CRAB features of hypercalcaemia, renal failure, anaemia and bone lesions, or the SLiM markers of 60 percent plasma cells, a light chain ratio of 100 or more, or more than one focal lesion on MRI). The Mayo 20/2/20 model, with M-protein above 20 g/L, a free light chain ratio above 20 and marrow plasma cells above 20 percent, separates a high-risk group in which about half progress within two years from a low-risk group that may never need treatment. Whole-body MRI or PET-CT to exclude occult bone disease is part of the work-up.

Active monitoring every three to six months was the only standard until lenalidomide was tested: the ECOG E3A06 trial (2020) showed lenalidomide alone delayed progression in intermediate- and high-risk disease, with three-year progression-free survival of 91 percent against 66 percent under observation, at the price of side effects that most patients on a watch-and-wait footing found hard to accept. AQUILA, reported in 2024, randomised 390 patients with high-risk smouldering myeloma to subcutaneous daratumumab monotherapy for up to three years or active monitoring: five-year progression-free survival 63.1 percent versus 40.8 percent (hazard ratio 0.49), with a survival signal, and daratumumab was approved for high-risk smouldering myeloma in the United States in late 2025, the first drug licensed before myeloma becomes active.

Whether to treat at all remains argued: many high-risk patients would have lived years without symptoms, no trial has yet shown that early treatment lengthens life, and intensive curative-intent regimens (carfilzomib-lenalidomide-dexamethasone and transplant in the Spanish GEM-CESAR and US ASCENT studies) trade heavy therapy for deep remissions of uncertain meaning. Bispecific antibodies such as linvoseltamab and quadruplets are being tested in the same population, and population screening for M-protein (iStopMM in Iceland) is asking whether finding the disease earlier helps anyone.