Risk of progression to MM: a long-term follow-up of MGUS patients

Statistics suggest that 3.2% of people aged 50 years or older and 5.3% of those aged 70 years or older have monoclonal gammopathy of undetermined significance (MGUS), the precursor disease to Multiple Myeloma (MM). Understanding the risk factors that determine progression to MM is a key area of research, as many physicians are now keen to move on from the ‘watch and wait’ philosophy, with the aim that earlier intervention in patients where high of progression can be identified will prevent MM taking hold in the first place. Due to the short follow-up times in many previous studies, it has been difficult to establish the risk of progression from MGUS to MM. There is also a paucity of data related to the prognosis and risk stratification in MGUS patients who are classified either with IgM or non-IgM biological subtypes. 

Robert A. Kyle, and a team of highly esteemed colleagues from the Mayo Clinic, Rochester, Minnesota, US, conducted a long-term follow-up in which they assessed the rate of progression and survival in MGUS patients, who were classified as either IgM or non-IgM subtypes. The primary end-point of the study was progression to either MM, or any other plasma cell (PC) or lymphoid disorder (non-hodgkin’s lymphoma, AL amyloidosis, waldenstrom’s macroglobulinemia, chronic lymphocytic leukemia or plasmacytoma). The results were published in the New England Journal of Medicine in January 2018.

Study design:

• Patient (pt) numbers: Entire cohort = 1,384; IgM = 210; Non-IgM = 1,129
• Pts from southeastern Minnesota, were assessed from 1 January 1960–31 December 1994
• M proteins were identified and quantitated in each of the patients
• Follow-up included reviewing inpatient and outpatient records, and death certificates
• Median Follow-up (years): Entire cohort = 34.1 (0.0–43.6) ; IgM = 29.3 (0.0–37.2) ; Non-IgM = 34.1 (0.0–43.6)
• Median age at MGUS diagnosis (years) = Entire cohort = 72 ; IgM = 74 ; Non-IgM = 72
• Median M protein level (g/dl): Entire cohort = 1.2 ; IgM = 1.1 ; Non-IgM = 1.2
• Abnormal free-light chain ratio (%): Entire cohort = 33 ; IgM = 34 ; Non-IgM = 33

Key Findings:

• Pt deaths during study period = 1,300 (94%)
• Risk and type of MGUS progression:
  • Entire cohort: any progression = 147 pts (11%), relative risk (RR) compared to control population = 6.5 times (95% CI, 5.5–7.7); progression to MM = 97 pts, RR = 23.8 (95% CI, 19.3–29.1)
  • IgM MGUS: any progression = 34 pts, RR = 10.8 (7.5–15.0); MM = 0 pt, RR = 0.0 (0.0–6.5)
  • Non-IgM MGUS: any progression = 107 pts, RR = 5.7 (4.7–6.9); MM = 93 pts, RR = 27.5 (22.2–33.7)
• Cumulative risk of progression: 10 years = 10%; 20 years = 18%; 30 years = 28%; 35 years = 36%; at 40 years = 36%
• Higher risk of progression among IgM MGUS pts vs non-IgM MGUS pts: RR = 10.8 (95% CI, 7.5–15.0) vs 5.7 (95% CI, 4.7–6.9)
• Most important univariate risk factors for progression to a PC disorder (for MGUS patients with IgM or non-IgM) were initial concentration of the serum M protein and serum free light-chain ratio
• Percentage risk of progression at 20 years among IgM pts vs non-IgM pts:
  • Presence of two risk factors (abnormal serum free light-chain ratio and high serum M protein level ≥1.5 g per deciliter) = 55% vs 30%
  • Presence of one risk factor = 41% vs 20%
  • Absence of either risk factor = 19% vs 7%
• Rate of progression per 100 person-years (IgM vs non-IgM) (95% CI):
  • Overall = 1.8 (1.3–2.5) vs 0.9 (0.7–1.1)
• Rate of progression per 100 person-years in MGUS pts with IgM:
  • M-protein < 1.5 g/dL & normal FLC ratio = 1.1 (0.6–2.0)
  • M-protein > 1.5 g/dL & abnormal FLC ratio = 3.6 (1.8–7.2)
• Pt age at diagnosis and duration of follow-up were not risk factors for progression, although when age at follow-up was taken into account there was an increasing annual risk of progression with older age
• A low concentration of two uninvolved immunoglobulins was associated with a higher risk of progression: HR = 2.0; (95% CI, 1.1–3.7); P = 0.03
• Death rate at 40 years owing to : PC disorders = 11%, non-PC disorders = 87%
• Observed survival rates in MGUS pts:
  • 10-years = 42%; 20-years = 18%; 30-years = 6%; 35-years = 4% and 40-years = 2%
• Shorter median survival in MGUS pts vs matched controls: 8.1 vs 12.4 years, P < 0.001
• Overall survival rate at 30-years (IgM MGUS pts vs non-IgM MGUS pts) = 4% (2–9) vs 7% (6–9); P = 0.12

Significant differences were observed between both the IgM and non-IgM subtype of MGUS patients and the risk of progression, suggesting that identifying the biological subtype could help with monitoring and therapeutic strategy. Another key finding was the shorter survival rate in MGUS patients in comparison with the age- and sex-matched control population. However, a much lower risk of progression to MM and other related conditions was found in MGUS patients, in comparison to the risk of death due to other causes. This, therefore, strengthens the case for continuing with a 'watch and wait' approach for MGUS patients, at least until clearer genetic links and risk factors can be identified. The ongoing Icelandic study (iSTOPMM), which has recruited a large number of MGUS patients, should generate insightful data on ways to monitor and manage MGUS patients, in terms of progression to MM.