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Smouldering myeloma is myeloma that has not yet damaged bones, kidneys or blood counts. Most people are watched, but those at high risk of progressing can now be treated: the AQUILA trial showed daratumumab alone delays active myeloma, and it was approved for this use in 2025.
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.
Found in about one in seven people diagnosed with a plasma cell cancer, usually by chance on a blood test; about one in ten progress to active myeloma each year for the first five years, and the high-risk half progress much faster.
Leukaemias, myeloma and MDS live in the marrow and blood; lymphomas grow in lymph nodes and spleen. The node stations are the disease map, not a route of spread, and staging counts them.
In lymphoma the node stations are the disease itself; staging (Ann Arbor / Lugano) counts how many regions and sides of the diaphragm are involved.
Same organ: High-grade B-cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma), Mediastinal grey zone lymphoma, Primary effusion lymphoma, Plasmablastic lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, EBV-positive diffuse large B-cell lymphoma, Primary large B-cell lymphoma of the testis, Gastric MALT lymphoma, Ocular adnexal MALT lymphoma, Extranodal NK/T-cell lymphoma, Adult T-cell leukaemia/lymphoma, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, Breast implant-associated anaplastic large cell lymphoma, Primary cutaneous anaplastic large cell lymphoma, Lymphomatoid papulosis, Mycosis fungoides, Enteropathy-associated T-cell lymphoma, Monomorphic epitheliotropic intestinal T-cell lymphoma, Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), Splenic marginal zone lymphoma, Nodal marginal zone lymphoma, Primary cutaneous marginal zone lymphoma, Primary cutaneous follicle centre lymphoma, Sezary syndrome, Nodal T-follicular helper cell lymphoma, angioimmunoblastic type (angioimmunoblastic T-cell lymphoma), Hepatosplenic T-cell lymphoma, Intravascular large B-cell lymphoma, Lymphomatoid granulomatosis, T-cell prolymphocytic leukaemia, Splenic B-cell lymphoma/leukaemia with prominent nucleoli (formerly B-cell prolymphocytic leukaemia and hairy cell leukaemia variant), T-cell large granular lymphocytic leukaemia, Mixed-phenotype acute leukaemia, Myeloid leukaemia of Down syndrome, Burkitt leukaemia, Marginal zone lymphoma, Cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome), Primary mediastinal (thymic) large B-cell lymphoma, Leukaemia (all types), Acute myeloid leukaemia, Acute lymphoblastic leukaemia, Chronic lymphocytic leukaemia, Chronic myeloid leukaemia (CML), Diffuse large B-cell lymphoma, Follicular lymphoma, Hodgkin lymphoma, Mantle cell lymphoma, Multiple myeloma, Non-Hodgkin lymphoma (all types), Myelodysplastic syndromes / neoplasms (MDS), Myeloproliferative neoplasms (PV, ET, myelofibrosis), Polycythaemia vera (PV), Essential thrombocythaemia (ET), Waldenström macroglobulinaemia, Hairy cell leukaemia, Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma), Blastic plasmacytoid dendritic cell neoplasm (BPDCN), Burkitt lymphoma, HIV-associated (AIDS-related) lymphomas, Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms, Systemic mastocytosis, Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms, Langerhans cell histiocytosis (LCH), Post-transplant lymphoproliferative disorder (PTLD), FLT3-mutated acute myeloid leukaemia, IDH1- and IDH2-mutated acute myeloid leukaemia, NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia, Secondary and therapy-related acute myeloid leukaemia, Acute promyelocytic leukaemia, Acute myeloid leukaemia in older or unfit patients, Newly diagnosed multiple myeloma, transplant-eligible, Newly diagnosed multiple myeloma, transplant-ineligible, Relapsed or refractory multiple myeloma, Plasma cell leukaemia, Lower-risk myelodysplastic syndromes, Higher-risk myelodysplastic syndromes, Chronic lymphocytic leukaemia, first treatment, Relapsed or refractory chronic lymphocytic leukaemia, Richter transformation of chronic lymphocytic leukaemia, Chronic myeloid leukaemia, chronic phase, Chronic myeloid leukaemia, accelerated and blast phase, Primary myelofibrosis, Standard-risk B-cell acute lymphoblastic leukaemia in children, High-risk acute lymphoblastic leukaemia in children (high-risk B-ALL and T-ALL), Philadelphia chromosome-positive acute lymphoblastic leukaemia in children (Ph-positive ALL), Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like or BCR::ABL1-like ALL), Infant acute lymphoblastic leukaemia (KMT2A-rearranged, under one year), Relapsed and refractory acute lymphoblastic leukaemia in children, Acute myeloid leukaemia in children, Erdheim-Chester disease, Rosai-Dorfman-Destombes disease, Single-system Langerhans cell histiocytosis (bone, skin or one other organ), Multisystem Langerhans cell histiocytosis (with or without risk-organ involvement), Indolent and smouldering systemic mastocytosis, Advanced systemic mastocytosis (aggressive SM, SM with an associated haematological neoplasm, mast cell leukaemia), Early-stage classical Hodgkin lymphoma (stage I to II), Advanced-stage classical Hodgkin lymphoma (stage III to IV), Nodular lymphocyte-predominant Hodgkin lymphoma (nodular lymphocyte-predominant B-cell lymphoma), Relapsed and refractory classical Hodgkin lymphoma
Active monitoring with blood tests every three to six months and imaging when the M-protein or light chains rise; no treatment.
Daratumumab monotherapy for up to three years (AQUILA), or lenalidomide with or without dexamethasone (E3A06), or a clinical trial; monitoring remains acceptable after shared decision-making.
Bispecific antibodies (linvoseltamab), isatuximab-lenalidomide-dexamethasone and curative-intent quadruplets in high-risk disease; population screening studies.
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Early single-agent treatment of high-risk smouldering myeloma is now an option with regulatory approval, though monitoring remains acceptable and the definition of high risk matters.
Lenalidomide showed that intervening before symptoms can delay end-organ damage, supporting later trials such as AQUILA, but tolerability limits its use as a single agent.
The 20/2/20 model defines high-risk smouldering myeloma in current guidelines and trial eligibility, including in AQUILA-informed practice.
Whether a patient is labelled smouldering or active myeloma, and therefore whether treatment starts, depends on these criteria.
Query for this cancer: (TITLE:"Smouldering multiple myeloma" OR ABSTRACT:"Smouldering multiple myeloma" OR TITLE:"Smoldering multiple myeloma" OR ABSTRACT:"Smoldering multiple myeloma" OR TITLE:"SMM" OR ABSTRACT:"SMM" OR TITLE:"High-risk smouldering myeloma" OR ABSTRACT:"High-risk smouldering myeloma" OR TITLE:"Asymptomatic myeloma" OR ABSTRACT:"Asymptomatic myeloma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Smouldering multiple myeloma, not a curated reading list.
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A swollen painful calf, or sudden breathlessness with chest pain; venous and arterial thromboembolism is a boxed warning and blood-thinning prophylaxis is recommended.
Fever of 38 C or higher, chills, low blood pressure, fast heartbeat or breathlessness, especially after a step-up dose. Boxed warning on teclistamab, epcoritamab, glofitamab, tarlatamab and blinatumomab.
Venous and arterial thromboembolism risk rises markedly with lenalidomide plus dexamethasone (and further with erythropoietin or oestrogens).. Thromboprophylaxis (aspirin, LMWH or a DOAC by risk) is standard.
Dose by creatinine clearance: 10 mg daily for CrCl 30-60, 15 mg every other day below 30, 5 mg daily on dialysis.
When engineered T cells or a bispecific antibody switch on, the immune system can overshoot. The first sign is a fever, and the treatment is a drug that blocks the main signal, given early. A smaller number of people become confused or drowsy, which is graded and treated separately.
Reactions around the moment a drug is given: chills, fever or breathlessness from antibodies (infusion reactions), true allergy (hypersensitivity, rarely anaphylaxis), and leakage of a damaging drug into tissue around the vein (extravasation).
See all on the product pages:DaratumumabDexamethasoneLenalidomideLinvoseltamab·Printable cards in the navigator
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