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Prognostic Factors for Malignant Transformation in Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma

From the Department of Hematology, Bone Marrow Transplantation Centre, and Laboratory of Clinical Biochemistry and Hematology, Niguarda Cà Granda Hospital, Milan; Department of Biometry and Clinical Epidemiology, Scientific Direction, Istituto di Ricovero e Cura a Carattere Scientifico San Matteo General Hospital, Pavia; and Department of Hematology, University of Parma, Parma, Italy.

Address reprint requests to Enrica Morra, MD, Divisione di Ematologia, Centro Trapianti di Midollo Osseo, Ospedale Maggiore Niguarda Cà Granda, Piazza Ospedale Maggiore 3, 20162 Milano, Italy; email: morraenrica{at}hotmail.com

PURPOSE: To evaluate the natural history of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), identify early predictors of evolution, and assess whether associated conditions correlate with disease progression.

PATIENTS AND METHODS: A total of 1,231 consecutive patients with either MGUS (n = 1,104) or SMM (n = 127) diagnosed from July 1975 to March 1998 were included in the study. Cumulative survival probability and cumulative probability of transformation into lymphoproliferative disease were calculated by means of the Kaplan-Meier estimator. Univariate and multivariate Cox models were used to identify possible predictors of malignant evolution.

RESULTS: Cumulative transformation probability at 10 and 15 years was 14% and 30%, respectively. At a median follow-up of 65 months (range, 12 to 239 months), 64 MGUS cases (5.8%) evolved to multiple myeloma (MM) (n = 43), extramedullary plasmacytoma (n = 1), primary amyloidosis (n = 1), Waldenström’s macroglobulinemia (n = 12), non-Hodgkin’s lymphoma (n = 6), and B-chronic lymphocytic leukemia (n = 1). At a median follow-up of 72 months (range, 12 to 247 months), 25 SMMs (19.7%) evolved to overt MM. A lower evolution risk was observed in MGUS than in SMM (P < .0001). Greater than 5% marrow plasmacytosis, detectable Bence Jones proteinuria, polyclonal serum immunoglobulin reduction, and high erythrocyte sedimentation rate (ESR) were independent factors influencing MGUS transformation. SMM progression correlated with greater than 10% marrow plasma cells, detectable Bence Jones proteinuria, and immunoglobulin (Ig) A isotype. Neither concomitant diseases nor immunosuppression correlated with progression.

CONCLUSION: Careful evaluation of marrow plasmacytosis, urinary paraprotein, background immunoglobulins, ESR, and paraprotein isotype might help identify at presentation patients with benign monoclonal gammopathies requiring stricter monitoring.

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