MGUS and Disease Development

But evidence also exists that MGUS may act as a precursor to other diseases.

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“MGUS patients,” Dr Dhodapkar wrote, “are also at an increased risk of morbidity related to several conditions such as skeletal morbidity, infections, other malignancies, neuropathies, thrombosis, and renal disease. If we were to apply emerging technologies to diagnose gammopathies earlier, we are likely to further increase the estimated prevalence of these disorders.”

Two years after naming MGUS, Dr Kyle identified the closely related condition of smoldering multiple myeloma, with “an M protein level of 3 g/dL or higher and/or 10% or more monoclonal plasma cells in the bone marrow but no evidence of end-organ damage.”

Although it is also asymptomatic, SMM carries a much higher risk of progression to malignancy: 10% per year for the first 5 years, about 3% per year for the next 5 years, and 1% to 2% per year for the following 10 years.

“A more important question is what to do with those patients that have smoldering myeloma, said Dr Aron Berkman, chief of medical oncology at Florida International University’s Herbert Wertheim College of Medicine in Miami. “They have more significant bone marrow infiltration by malignant cells. We know those patients almost always are going to progress to myeloma. And with many malignancies, not all but many, if we can diagnose those patients early and treat them early, when their tumors are even smaller, then survival and possible cure is more feasible.”

As Dr Ola Landgren and colleagues pointed out in a 2011 report, recent years have seen improvements in risk stratification models involving molecular markers of both MGUS and SMM. But the challenge of “developing individualized risk profiles for patients” continues.4

“Vincent Rajkumar developed criteria for patients who have actually smoldering multiple myeloma but, quote, have ‘ultra-high risk’ of developing myeloma,” noted Dr Kyle.

“We know that treating those patients with our anti-myeloma agents today will reduce the protein, decrease the number of plasma cells in the bone marrow, give them a remission—even a complete remission. But, we don’t know yet whether these patients will go on and develop symptomatic multiple myeloma at the same time or in the future.”

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Unlocking the mysteries of MGUS could also yield benefits in yet-unrecognized realms.

“Further studies are therefore needed to understand the potential implication of the diagnosis of an expanded plasma cell clone in selected clinical settings wherein they might similarly affect pathogenesis and, ultimately, management,” Dr Dhodapkar wrote. “Fully exploring the biology of MGUS may have broader implications for human health beyond MM.” 


  1. Dhodapkar MV. MGUS to myeloma: a mysterious gammopathy of underexplored significance. Blood. 2016;128(23):2599-606.
  2. Kyle RA. Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med. 1978;64(5):814-26.
  3. Kyle RA1, Buadi F, Rajkumar SV. Management of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Oncology (Williston Park). 2011;25(7):578-86.
  4. Korde N, Kristinsson SY, Landgren O. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies. Blood. 2011;117(21):5573-81. doi: 10.1182/blood-2011-01-270140