Does Rheumatic Disease Increase Risk of MGUS Progression to Hematologic Malignancies?

Patients with monoclonal gammopathy of undetermined significance (MGUS) and concomitant non-antibody (Ab)–mediated inflammatory rheumatic diseases are at increased risk of progression to overt multiple myeloma (MM), compared with patients who have MGUS without associated rheumatic diseases. This is according to results from a retrospective study published in Blood Advances.

MGUS is a premalignant, clonal plasma cell disorder characterized by the presence of a monoclonal protein, <10% clonal plasma cells in the bone marrow, and the absence of lymphoplasmacytic malignancy (LPM), according to study authors, led by Normann Steiner, MD, from the Medical University of Innsbruck in Austria. An MGUS diagnosis is considered a requisite precursor to several LPMs, including MM, immunoglobulin light-chain amyloidosis, and Waldenström macroglobulinemia.

Patients with MGUS face a risk for transformation to MM or other hematologic malignancies that increases at a rate of 1% per year. Myeloma protein concentration of ≥15 g/L and an abnormal serum free light chain (FLC) ratio are primary risk factors for disease progression of non−immunoglobulin G (IgG) isotype MGUS.

Previous reports have shown that chronic inflammatory diseases can increase the risk of cancer, but studies exploring a possible link between inflammation and MGUS progression to hematologic malignancies are limited.

In this study, researchers retrospectively identified 2,935 patients with MGUS who were screened for chronic inflammatory rheumatic diseases between 2000 and 2016. A total of 2,680 patients had MGUS only, while 255 patients had MGUS plus concomitant rheumatic diseases.

“Future studies are necessary to further elucidate the impact of proinflammatory processes and immunosuppressive therapies on how MGUS evolves and its risk of progression.”

—Normann Steiner, MD

Patients with rheumatic diseases were stratified by Ab-mediated disease and non–Ab-mediated disease. In this study, Ab-mediated rheumatic diseases included:

  • rheumatoid arthritis, n=68
  • connective tissue diseases (CTDs) including systemic lupus erythematosus, Sjogren syndrome, mixed CTD, systemic sclerosis, and antineutrophil cytoplasmic antibody–associated vasculitis, n=86

Non–Ab-mediated rheumatic diseases included:

  • polymyalgia rheumatica or large-vessel giant cell arteritis, n=47
  • spondylarthritis, n=22
  • gout, n=32

Approximately 62% of patients with MGUS and rheumatic diseases had an IgG MGUS. In contrast, approximately 19%, 11%, 0.4%, and 3% had an IgM, IgA, IgD, and light-chain–only MGUS, respectively.

The investigators compared outcomes in patients with MGUS and associated rheumatic diseases against those in patients with MGUS only, including overall survival, progression-free survival (PFS), and risk factors for disease progression.

During the median follow-up period of 3.2 years, 19% of patients with MGUS and concomitant rheumatic disease and 23% of patients with MGUS and no rheumatic disease died. Progression was observed in 4.5% of all patients (n=132).

Patients with MGUS and non–Ab-mediated rheumatic diseases had a significantly higher risk of disease progression compared with patients without accompanying rheumatic diseases (hazard ratio [HR] = 2.1; 95% CI 1.1-3.9; p=0.02). According to the investigators, the five-year risk of progression among patients with MGUS and concomitant non–Ab-mediated rheumatic diseases was 10%. In contrast, this risk was significantly lower among patients with MGUS without rheumatologic comorbidity (4%) and patients with Ab-mediated rheumatologic comorbidity (2%).

The presence of non–Ab-mediated rheumatic diseases was associated with the highest risk for disease progression, according to a risk stratification model that incorporated clinical variables such as myeloma protein concentration, immunoglobulin type, and FLC ratio (HR=6.8; 95% CI 1.5-30.7; p=0.01).

According to MGUS risk status and concomitant rheumatic disease, disease progression was more frequently observed among those with intermediate- and high-risk MGUS than those with low-risk MGUS (HR=9.6; 95% CI 1.2-73.3; p=0.03). The cohorts of patients with intermediate- and high-risk MGUS and rheumatic disease also had a higher risk for progression if they had non–Ab-mediated versus Ab-mediated rheumatic diseases (HR=6.8; 95% CI 1.5-30.7; p=0.01).

Additionally, a subgroup of patients who did not receive any treatment (n=13) had significantly worse PFS compared with a larger group of patients (n=88) who received therapy (p<0.02).

“Future studies are necessary to further elucidate the impact of proinflammatory processes and immunosuppressive therapies on how MGUS evolves and its risk of progression,” the authors wrote.

These findings were limited by the study’s retrospective nature, as well as the incomplete characterization of patients with MGUS and rheumatic diseases.


Steiner N, Göbel G, Michaeler D, et al. Rheumatologic diseases impact the risk of progression of MGUS to overt multiple myeloma. Blood Adv. 2021;5:1746-1754.