Smouldering 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
Other names	Smoldering myeloma, Smoldering multiple myeloma, Indolent myeloma or Asymptomatic myeloma
Specialty	Hematology/oncology

Diagnosis

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

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]

Prognosis

Smouldering myeloma with an increasingly abnormal serum free light chain (FLC) ratio is associated with a higher risk for progression to active multiple myeloma.^[7]

References

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. 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. 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.

Further reading

• Barlogie B, van Rhee F, Shaughnessy JD, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB (Oct 15, 2008). "Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease". Blood. 112 (8): 3122–5. doi:10.1182/blood-2008-06-164228. PMC 2569167. PMID 18669874.
• Pérez-Persona E, Vidriales MB, Mateo G, García-Sanz R, Mateos MV, de Coca AG, Galende J, Martín-Nuñez G, Alonso JM, de Las Heras N, Hernández JM, Martín A, López-Berges C, Orfao A, San Miguel JF (Oct 1, 2007). "New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells". Blood. 110 (7): 2586–92. doi:10.1182/blood-2007-05-088443. PMID 17576818.
• Kyle RA, Durie BG, Rajkumar SV, Landgren O, Blade J, Merlini G, Kröger N, Einsele H, Vesole DH, Dimopoulos M, San Miguel J, Avet-Loiseau H, Hajek R, Chen WM, Anderson KC, Ludwig H, Sonneveld P, Pavlovsky S, Palumbo A, Richardson PG, Barlogie B, Greipp P, Vescio R, Turesson I, Westin J, Boccadoro M (Jun 2010). "Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management". Leukemia. 24 (6): 1121–7. doi:10.1038/leu.2010.60. PMC 7020664. PMID 20410922.
• Dispenzieri, A; Kumar, S (Oct 31, 2013). "Treatment for high-risk smoldering myeloma". The New England Journal of Medicine. 369 (18): 1764. doi:10.1056/NEJMc1310911. PMID 24171529.
• Dispenzieri A, Kumar S (31 October 2013). "Treatment for High-Risk Smoldering Myeloma". New England Journal of Medicine. 369 (18): 1762–1765. doi:10.1056/NEJMc1310911. PMID 24171529.