Natural History Of Smoldering Monoclonal Gammopathy-Associated Malignancies: A Population-Based Study

We performed a population-based study to determine the natural history of monoclonal gammopathy-associated malignancies (MGAM) including multiple myeloma, lymphoplasmacytic lymphoma, and Waldenstrom's macroglobulinemia that were considered smoldering at the time of cancer diagnosis. We compared the clinical outcomes among those with and without a prior monoclonal gammopathy of undetermined significance (MGUS) follow-up.

Data were obtained from the Surveillance Epidemiology and End Results (SEER) database linked to Medicare claims. We considered patients age ≥ 67 years with MGAM diagnosed from 1994-2005. We excluded those who were diagnosed by autopsy or death certificate only, had invasive cancers within 5 years prior to MGAM diagnosis, prior diagnosis of MGAM, lacked date of either diagnosis or death, lacked complete Medicare parts A/B coverage 15 months prior to or 3 months after MGAM diagnosis (or to date of death, if death was within 3 months), and receiving dialysis more than 3 months before MGAM diagnosis. Major complications including acute kidney injury, cord compression, dialysis-requirement, fracture, and hypercalcemia at time of disease progression were obtained from diagnosis and procedure claims. MGUS follow-up was defined as having a diagnosis claim 4-15 months prior to smoldering MGAM diagnosis. Smoldering MGAM was defined as absence of all of the following criteria: any major complication claims, any treatment claims, and death because of MGAM within 12 months of MGAM diagnosis, while progression to active MGAM was defined by the presence of any of these criteria.

At the time of MGAM diagnosis 2,189 had smoldering disease. Of these, 1,753 (80.1%) progressed to active MGAM with a median time-to-progression of 17 months. Progression to active MGAM were identified by claims reflecting the development of major cancer complications (34.9%), administration of cancer therapy (59.5%), both (0.7%), or report of death from MGAM without major complication or treatment claims (4.9%). The cumulative probability of progression by Kaplan-Meier analysis was 40.2%, 72.9%, 85.7%, and 96.1%, at years 1, 3, 5, and 10, respectively. Among those who progressed, 35.6% developed one or more major complications including acute kidney injury (13.0%), cord compression (1.8%), dialysis-requirement (2.0%), fracture (15.6%), and hypercalcemia (5.6%). A prior MGUS follow-up occurred in 199 (9.1%) smoldering MGAM patients. The time to progression for smoldering MGAM patients with a prior MGUS follow-up was similar to those without MGUS follow-up (P = 0.52). Multivariable analysis factoring in year of smoldering MGAM diagnosis, type of cancer, age, sex, race, place of residence, SEER site, median annual household income, Charlson co-morbidity index, and prior MGUS follow-up showed that older age, higher Charlson co-morbidity scores, and diagnosis of multiple myeloma as independent predictors of progression (Table).

Our population-based study shows that most patients with smoldering MGAM diagnosed at age ≥ 67 years progress to active disease within the first three years. Those with a prior history of MGUS follow-up progress at a similar rate compared to those without such a history. The determinants of progression at diagnosis are age, number of co-morbidities, and type of MGAM.

No relevant conflicts of interest to declare.