Abstract:

Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder and bridges monoclonal gammo- pathyof undetermined significance to multiple myeloma (MM), based on higher levels of circulating monoclonal immunoglobulin and bone marrow plasmocytosis without end-organ damage. Until a Spanish study reported fewer MM-related events and better overall survival among patients with high- risk SMM treated with lenalidomide and dexamethasone, prior studies had failed to show improved survival with earlier intervention,although a reduction in skeletal-related events (without any impact on disease progression) has been described with bisphosphonate use. Risk factors have now been defined, and a subset of ultra-high-risk patients have been reclassified by the International Myeloma Working Group as MM, and thus will require optimal MM treatment, based on biomarkers that identify patients with a >80% risk of progression. The number of these redefined patients is small (~10%), but important to unravel, because theirriskof progression to overt MM is substantial ($80% within 2 years). Patients with a high-risk cytogenetic profile are not yet considered for early treatment, because groups are heterogeneous and risk factors other than cytogenetics are deemed to weight higher. Because patients with ultra-high- risk SMM are now considered as MM and may be treated as such, concerns exist that earlier therapy may increase the risk of selecting resistant clones and induce side effects and costs. Therefore, an even more accurate identification of patients who would benefit from interventions needs to be performed, and clinical judgment and careful discussion of pros and cons of treatment initiation need to be undertaken. For the majority of SMM patients, the standard of care remains observation until development of symptomatic MM occurs, encouraging participation in ongoing and upcoming SMM/early MM clinical trials, as well as consideration of bisphosphonate use in patients with early bone loss. © AlphaMed Press 2016.

Notes:

Cited By :3Export Date: 18 February 2017References: Engelhardt, M., Terpos, E., Kleber, M., European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma (2014) Haematologica, 99, pp. 232-242;Rollig, C., Knop, S., Bornhauser, M., Multiple myeloma (2015) Lancet, 385, pp. 2197-2208; Kyle, R.A., Greipp, P.R., Smoldering multiple myeloma (1980) N Engljmed, 302, pp. 1347-1349; Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: A report of the International Myeloma Working Group (2003) Br J Haematol, 121, pp. 749-757; Caers, J., Vekemans, M.-C., Bries, G., Diagnosis and follow-up of monoclonal gammopathies of undetermined significance; information for referring physicians (2013) Ann Med, 45, pp. 413-422; Rajkumar, S.V., Dimopoulos, M.A., Palumbo, A., International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma (2014) Lancet Oncol, 15, pp. e538-e548; Kyle, R.A., Remstein, E.D., Therneau, T.M., Clinical course and prognosis ofsmoldering (Asymptomatic) multiple myeloma (2007) N Engl J Med, 356, pp. 2582-2590; Neben, K., Jauch, A., Hielscher, T., Progression in smoldering myeloma is independently determined bythe chromosomal abnormalities del(17p), t(4;14),gain 1q, hyperdiploidy, andtumorload (2013) J Clin Oncol, 31, pp. 4325-4332; Dhodapkar, M.V., Sexton, R., Waheed, S., Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120) (2014) Blood, 123, pp. 78-85; Rajkumar, S.V., Landgren, O., Mateos, M.-V., Smoldering multiple myeloma (2015) Blood, 125, pp. 3069-3075; Rajkumar, S.V., Larson, D., Kyle, R.A., Diagnosis of smoldering multiple myeloma (2011) N Engl J Med, 365, pp. 474-475; Kastritis, E., Terpos, E., Moulopoulos, L., Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease (2013) Leukemia, 27, pp. 947-953; Rago, A., Grammatico, S., Za, T., Prognostic factors associated with progression of smoldering multiple myeloma to symptomatic form (2012) Cancer, 118, pp. 5544-5549; Dispenzieri, A., Stewart, A.K., Chanan-Khan, A., Smoldering multiple myeloma requiring treatment: Time for a new definition? (2013) Blood, 122, pp. 4172-4181; Rajkumar, S.V., Kyle, R.A., Therneau, T.M., Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance (2005) Blood, 106, pp. 812-817; Dispenzieri, A., Kyle, R.A., Katzmann, J.A., Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (Asymptomatic) multiple myeloma (2008) Blood, 111, pp. 785-789; Larsen, J.T., Kumar, S.K., Dispenzieri, A., Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma (2013) Leukemia, 27, pp. 941-946; Caers, J., Withofs, N., Hillengass, J., The roleof positron emission tomography-computed tomography and magnetic resonance imaging in diagnosis and follow up of multiple myeloma (2014) Haematologica, 99, pp. 629-637; Moulopoulos, L.A., Dimopoulos, M.A., Smith, T.L., Prognostic significance of magnetic resonance imaging in patients with asymptomatic multiple myeloma (1995) J Clin Oncol, 13, pp. 251-256; Hillengass, J., Fechtner, K., Weber, M.A., Prognostic significance of focal lesions in whole- body magnetic resonance imaging in patients with asymptomatic multiple myeloma (2010) J Clin Oncol, 28, pp. 1606-1610; Kastritis, E., Moulopoulos, L.A., Terpos, E., The prognostic importance of the presence of more than one focal lesion in spine MRI of patients with asymptomatic (Smoldering) multiple myeloma (2014) Leukemia, 28, pp. 2402-2403; Merz, M., Hielscher, T., Wagner, B., Predictive value of longitudinal whole-body magnetic resonance imaging in patients with smoldering multiple myeloma (2014) Leukemia, 28, pp. 1902-1908; Zamagni, E., Nanni, C., Gay, F., 18F-FDG PET/ CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease (2015) Leukemia, , Epub ahead of print; Siontis, B., Kumar, S., Dispenzieri, A., Positron emission tomography-computed tomographyin the diagnostic evaluation of smoldering multiple myeloma: Identification of patients needing therapy (2015) Blood Cancer J, p. 5; Ocqueteau, M., Orfao, A., Almeida, J., Immunophenotypiccharacterization ofplasmacells from monoclonal gammopathy of undetermined significance patients. Implications for the differential diagnosis between MGUS and multiple myeloma (1998) Am J Pathol, 152, pp. 1655-1665; Perez-Persona, E., Vidriales, M.-B., Mateo, G., New criteria to identify riskof progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells (2007) Blood, 110, pp. 2586-2592; Rosinol, L., Blade, J., Esteve, J., Smoldering multiplemyeloma:Naturalhistoryandrecognitionofan evolvingtype (2003) Brj Haematol, 123, pp. 631-636; Landgren, O., Kyle, R.A., Pfeiffer, R.M., Monoclonal gammopathy of undetermined significance (MGUS) consistentlyprecedes multiple myeloma: A prospective study (2009) Blood, 113, pp. 5412-5417; Rajkumar, S.V., Gupta, V., Fonseca, R., Impact ofprimary molecularcytogeneticabnormalitiesand riskofprogression in smoldering multiple myeloma (2013) Leukemia, 27, pp. 1738-1744; Khan, R., Dhodapkar, M., Rosenthal, A., Four genes predict high risk of progression from smoldering to symptomatic multiple myeloma (SWOG S0120) (2015) Haematologica, 100, pp. 1214-1221; Paiva, B., Paino, T., Sayagues, J.-M., Detailed characterization of multiple myeloma circulating tumor cells shows unique phenotypic, cytogenetic, functional, and circadian distribution profile (2013) Blood, 122, pp. 3591-3598; Bianchi, G., Kyle, R.A., Larson, D.R., High levels of peripheral blood circulating plasma cells as a specific risk factor for progression of smoldering multiple myeloma (2013) Leukemia, 27, pp. 680-685; Billadeau, D., Van Ness, B., Kimlinger, T., Clonal circulating cells are common in plasma cell proliferative disorders: A comparison of monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and active myeloma (1996) Blood, 88, pp. 289-296; Cherry, B.M., Korde, N., Kwok, M., Modeling progression risk for smoldering multiple myeloma: Results from a prospective clinical study (2013) Leuk Lymphoma, 54, pp. 2215-2218; Kyle, R.A., Durie, B.G., Rajkumar, S.V., Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management (2010) Leukemia, 24, pp. 1121-1127; Rajkumar, S.V., Merlini, G., San Miguel, J.F., Haematological cancer: Redefining myeloma (2012) Nat Rev Clin Oncol, 9, pp. 494-496; Hjorth, M., Hellquist, L., Holmberg, E., Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I—a randomized study (1993) Eur J Haematol, 50, pp. 95-102; Riccardi, A., Mora, O., Tinelli, C., Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: A multicentre randomized study (2000) Br J Cancer, 82, pp. 1254-1260; Detweiler-Short, K., Hayman, S., Gertz, M.A., Long-term results of single-agent thalidomide as initial therapy for asymptomatic (Smoldering or indolent) myeloma (2010) Am J Hematol, 85, pp. 737-740; Barlogie, B., Van Rhee, F., Shaughnessy, J.D., Jr., Seven-year median time to progression with thalidomide for smoldering myeloma: Partial response identifies subset requiring earlier salvage therapy for symptomatic disease (2008) Blood, 112, pp. 3122-3125; Witzig, T.E., Laumann, K.M., Lacy, M.Q., A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma (2013) Leukemia, 27, pp. 220-225; D'arena, G., Gobbi, P.G., Broglia, C., Pamidr- onate versus observation in asymptomatic myeloma: Final results with long-term follow-up of a randomized study (2011) Leuk Lymphoma, 52, pp. 771-775; Martin, A., Garcia-Sanz, R., Hernandez, J., Pamidronate induces bone formation in patients with smouldering or indolent myeloma, with no significant anti-tumour effect (2002) Br J Haematol, 118, pp. 239-242; Musto, P., Falcone, A., Sanpaolo, G., Pamidr- onate for early-stage, untreated myeloma (2003) J Clin Oncol, 21, pp. 3177-3178. , author reply 3178; Musto, P., Petrucci, M.T., Bringhen, S., A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma (2008) Cancer, 113, pp. 1588-1595; Terpos, E., Morgan, G., Dimopoulos, M.A., InternationalMyeloma Working Group recommendations for the treatment of multiple myeloma- related bone disease (2013) J Clin Oncol, 31, pp. 2347-2357; Lust, J.A., Lacy, M.Q., Zeldenrust, S.R., Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1b-induced interleukin 6 production and the myeloma proliferative component (2009) Mayo Clin Proc, 84, pp. 114-122; Mateos, M.-V., Hernandez, M.-T., Giraldo, P., Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma (2013) N Engl J Med, 369, pp. 438-447; Korde, N., Roschewski, M., Zingone, A., Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma (2015) JAMA Oncol, 1, pp. 746-754; Selder, R., Pandurevic, M., Moller, M.-D., (2014) First Results of the Interdisciplinary Comprehensive Cancer Center Freiburg Tumor Board Multiple Myeloma Assessing Questions, Advice Adherence, Satisfaction of Patients, Participants and Reffering Physicians, Inclusion of Difficult-To-Treat-Mm Pts in Clinical Trials (CT) and Patient Outcome. Paper Presented at 56Th American Society of Hematology Annual Meeting and Exposition; December 6-9, , San Francisco, CA

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