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Smouldering myeloma

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Smouldering myeloma
Other namesSmoldering myeloma, Smoldering multiple myeloma, Indolent myeloma or Asymptomatic myeloma

Smouldering myeloma is a disease classified as intermediate in a spectrum of step-wise progressive diseases termed plasma cell dyscrasias. In this spectrum of diseases, a clone of plasma cells secreting monoclonal paraprotein (also termed myeloma protein or M protein) causes the relatively benign disease of monoclonal gammopathy of undetermined significance. This clone proliferates and may slowly evolve into more aggressive sub-clones that cause smouldering multiple myeloma. Further and more rapid evolution causes the overtly malignant stage of multiple myeloma and can subsequently lead to the extremely malignant stage of secondary plasma cell leukemia.[1][2][3] Thus, some patients with smouldering myeloma progress to multiple myeloma and plasma cell leukemia. Smouldering myeloma, however, is not a malignant disease. It is characterised as a pre-malignant disease that lacks symptoms but is associated with bone marrow biopsy showing the presence of an abnormal number of clonal myeloma cells, blood and/or urine containing a myeloma protein, and a significant risk of developing into a malignant disease.[2]


Smouldering myeloma is characterised by:[4]

  • Serum paraprotein >30 g/L or urinary monoclonal protein ≥500 mg per 24 h AND/OR
  • Clonal plasma cells >10% and <60% on bone marrow biopsy AND
  • No evidence of end organ damage that can be attributed to plasma cell disorder AND
  • No myeloma-defining event (>60% plasma cells in bone marrow OR Involved/Uninvolved light chain ratio>100)


Treatment for multiple myeloma is focused on therapies that decrease the clonal plasma cell population and consequently decrease the signs and symptoms of disease. If the disease is completely asymptomatic (i.e. there is a paraprotein and an abnormal bone marrow population but no end-organ damage), as in smouldering myeloma, treatment is typically deferred, or restricted to clinical trials.[5]

They are generally responsive to IL-1β neutralisation.[6]

Treatment for smoldering multiple myeloma (SMM) has changed significantly in the recent years. The current treatment of SMM depends on whether or not the patient has high or low risk of SMM.

The method to distinguish between high risk and low risk patients come from the MAYO 2008, PETHEMA, and SWOG models. The PETHEMA group characterizes between risk categories using immunoparesis and aberrant plasma cell percentages with high risk patients exhibiting short time to progression towards symptomatic multiple myeloma. The MAYO 2008 model also incorporates parameters such as bone marrow and plasma cell percentage, M-protein levels, and sFLC ratios.

In 2019, the 20/2/20 model emerged from the International Myeloma Foundation (IMF). This model states that if all three of the following are true: the percentage of plasma cells in the bone marrow is 20% or more, M-Protein level is 2g/dL or greater, or the sFLC ratio is greater than 20, then the patient is classified as high risk.[7]

Patients classified as low risk SMM are cared for by being given active surveillance. Doctors would closely monitor the serum M protein, serum free light chain (FLC) levels, complete blood count, serum calcium, and serum creatinine of the patient every 3 to 4 months for 5 years. If any changes indicative of disease progression is detected, then the patient would be classified as a high risk and will be diagnosed as such. If the patient does not show any signs of change, additional visits after the initial 5 years will separated by 6 months instead.

High risk patients require early intervention to prevent or delay the progression towards symptomatic multiple myeloma and other complications. Lenalidomide or lenalidomide plus dexamethasone (Rd) is a common treatment for high risk SMM. Many clinical trials have shown that a lenalidomide based therapy can significantly lengthen the time before the patient progresses to symptomatic multiple myeloma. The duration and intensity of lenalidomide based therapy may vary based on factors of the patient as well as the response to the treatment. Other treatments include bisphosphonates or monoclonal antibodies. These may be used in selecting high risk patients, specifically, bisphosphonates may be used to reduce the risk of skeletal related events in high risk patients with osteopenia or osteoporosis.

The purpose of using lenalidomide based therapy instead of myeloma like therapy for high risk SMM is based on randomized trials that ultimately show that lenalidomide based therapy has a clear increase in survival rate. The reason as to not immediately go straight to myeloma like therapy is due to the high amount of regulation required. Tests must be made to check if using a certain drug is actually beneficial to the patient before it may be administered, however lenalidomide based therapy can be administered regularly.[8]


Smouldering myeloma with an increasingly abnormal serum free light chain (FLC) ratio is associated with a higher risk for progression to active multiple myeloma.[9]


  1. ^ Agarwal, Amit; Ghobrial, Irene M. (1 March 2013). "Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma: A Review of the Current Understanding of Epidemiology, Biology, Risk Stratification, and Management of Myeloma Precursor Disease". Clinical Cancer Research. 19 (5): 985–994. doi:10.1158/1078-0432.ccr-12-2922. PMC 3593941. PMID 23224402.
  2. ^ a b Dutta, Ankit K.; Hewett, Duncan R.; Fink, J. Lynn; Grady, John P.; Zannettino, Andrew C. W. (July 2017). "Cutting edge genomics reveal new insights into tumour development, disease progression and therapeutic impacts in multiple myeloma". British Journal of Haematology. 178 (2): 196–208. doi:10.1111/bjh.14649. PMID 28466550.
  3. ^ van de Donk, Niels W. C. J.; Palumbo, Antonio; Johnsen, Hans Erik; Engelhardt, Monika; Gay, Francesca; Gregersen, Henrik; Hajek, Roman; Kleber, Martina; Ludwig, Heinz; Morgan, Gareth; Musto, Pellegrino; Plesner, Torben; Sezer, Orhan; Terpos, Evangelos; Waage, Anders; Zweegman, Sonja; Einsele, Hermann; Sonneveld, Pieter; Lokhorst, Henk M. (1 June 2014). "The clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma Network". Haematologica. 99 (6): 984–996. doi:10.3324/haematol.2013.100552. PMC 4040895. PMID 24658815.
  4. ^ Rajkumar, S Vincent; Dimopoulos, Meletios A; Palumbo, Antonio; Blade, Joan; Merlini, Giampaolo; Mateos, María-Victoria; Kumar, Shaji; Hillengass, Jens; Kastritis, Efstathios; Richardson, Paul; Landgren, Ola; Paiva, Bruno; Dispenzieri, Angela; Weiss, Brendan; LeLeu, Xavier; Zweegman, Sonja; Lonial, Sagar; Rosinol, Laura; Zamagni, Elena; Jagannath, Sundar; Sezer, Orhan; Kristinsson, Sigurdur Y; Caers, Jo; Usmani, Saad Z; Lahuerta, Juan José; Johnsen, Hans Erik; Beksac, Meral; Cavo, Michele; Goldschmidt, Hartmut; Terpos, Evangelos; Kyle, Robert A; Anderson, Kenneth C; Durie, Brian G M; Miguel, Jesus F San (November 2014). "International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma". The Lancet Oncology. 15 (12): e538–e548. doi:10.1016/S1470-2045(14)70442-5. hdl:2268/174646. PMID 25439696. S2CID 36384542.
  5. ^ Korde, Neha; Kristinsson, Sigurdur Y.; Landgren, Ola (26 May 2011). "Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies". Blood. 117 (21): 5573–5581. doi:10.1182/blood-2011-01-270140. PMC 3316455. PMID 21441462.
  6. ^ Dinarello, Charles A. (7 April 2011). "Interleukin-1 in the pathogenesis and treatment of inflammatory diseases". Blood. 117 (14): 3720–3732. doi:10.1182/blood-2010-07-273417. PMC 3083294. PMID 21304099.
  7. ^ Kunacheewa, Chutima; Manasanch, Elisabet (March 2020). "High-risk smoldering myeloma versus early detection of multiple myeloma: Current models, goals of therapy, and clinical implications". Best Practice & Research Clinical Haematology. 33 (1) – via Elsevier Science Direct.
  8. ^ Rajkumar, S. Vincent; Kumar, Shaji; Lonial, Sagar; Mateos, Maria Victoria (2022-09-05). "Smoldering multiple myeloma current treatment algorithms". Blood Cancer Journal. 12 (9): 1–7. doi:10.1038/s41408-022-00719-0. ISSN 2044-5385. PMC 9445066.
  9. ^ Ballew, Carol; Liu, Kiang; Savage, Peter; Oberman, Albert; Smoak, Carey (January 1990). "The utility of indirect measures of obesity in racial comparisons of blood pressure". Journal of Clinical Epidemiology. 43 (8): 799–804. doi:10.1016/0895-4356(90)90240-p. PMID 2200851.

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