In December 2024, we had the opportunity to sit down with Dr. Ola Landgren at the ASH conference to discuss multiple myeloma and MGUS. This blog includes insights and opinions shared during that interview, supplemented with additional information and commentary.
What is MGUS?
In 1978, Dr. Robert Kyle at the Mayo Clinic continued ongoing work of Dr. Jan Waldenstrom, who initially found that there was a subset of healthy patients with abnormal protein in their serum. Dr. Waldenstrom believed that the presence of abnormal protein without any symptoms was considered a benign condition. Dr. Kyle followed several of those patients and discovered that some of them did, in fact, develop myeloma or other malignancies.1 Thus, Dr. Kyle published the term “MGUS” or, monoclonal gammopathy of undetermined significance, from those findings. He defined MGUS as the presence of monoclonal protein (M protein) less than 3.0 g/dL, less than 10% plasma cells in the bone marrow, little or no M protein in the urine, and the absence of lytic bone lesions, anemia, hypercalcemia or renal insufficiency.2
Prevalence and incidence of MGUS
It's important to note that MGUS is a pre-malignant condition and normally asymptomatic. Most individuals with MGUS are unaware of their condition because it is rarely tested for during routine health checks and is usually found incidentally. Although not all MGUS patients will progress to myeloma, all myeloma patients will have previously had MGUS, whether it was known or not.3 Various screening studies have been conducted to better understand the prevalence of MGUS, and the potential value of identifying MGUS patients to allow for early intervention for myeloma. One notable study is the iStopMM study, a population-based screening trial currently being conducted in Iceland. The study aims to identify individuals over the age of 40 with MGUS and assess the effects of screening, not only on their physical health, but also on their psychological wellbeing.4 In the study, the control arm is receiving no further workup, the second arm is receiving workup based on guidelines, and the third arm is receiving a more intensive follow-up.4 This study is providing valuable insights into how different levels of intervention impact the overall health and psychological state of individuals diagnosed with MGUS.
In African Americans/Blacks, the MGUS incidence can be almost 2x higher than in Caucasians, suggesting that care should be taken if trying to extrapolate the results from iStopMM study to other populations.5
It's also important to recognize that individuals with a family history of MGUS are more likely to develop MGUS.6
Research has shown that monoclonal gammopathies tend to present 5 to 10 years earlier in African Americans/Blacks and people of African descent, compared to their Caucasian counterparts. However, despite this earlier onset and increased prevalence, the prognosis for patients with multiple myeloma is not significantly different based on race.7
The prognosis is no different in African Americans or Black patients than Caucasian patients for myeloma, if anything, they respond better to treatments based on study data.
What do the guidelines recommend for initial diagnosis of MGUS?
Currently, there are no established screening guidelines for MGUS. The condition is often discovered incidentally when trying to rule out myeloma or when abnormalities, such as elevated total protein levels, are detected during routine diagnostic workups. Both national and international guidelines suggest certain tests for the initial diagnostic work-up for multiple myeloma.8-11 These include:
- Serum protein electrophoresis (SPEP)
- Immunofixation electrophoresis (IFE)
- Serum free light chains (sFLC)
Depending on a patient’s results and clinical symptoms, additional diagnostic testing may be recommended, such as10:
- PET/CT scans or whole-body MRI
- Bone marrow biopsy for establishing a baseline diagnosis
What about urine testing for MGUS patients?
Research indicates that SPEP, sFLC, and IFE have over 99% sensitivity for detecting myeloma and can identify 97% of MGUS patients, helping negate the need for urine testing in patients.12
There is no indication for testing light chains in the urine, light chains should be tested in the serum.
Follow-up evaluation of MGUS patients
It is important to note that 20% of patients will have light chain only MGUS which will only release light chains, thus it is important to check for kappa and lambda free light chains along with the SPEP and IFE
There is a 1% annual risk of progression from MGUS and light chain-MGUS to a malignancy, such as multiple myeloma, IgM lymphoma, primary amyloidosis, macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma.10,13 In a study from 2009, every patient diagnosed with myeloma had MGUS prior to developing myeloma; therefore, those who have known MGUS, sFLC results can sometimes be the first indication of progression to myeloma.14 In the PLCO study, which was a population-based prospective Prostate, Lunch, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, the study identified patients who developed multiple myeloma through pre-diagnostic lab work that was obtained two to ten years prior to the multiple myeloma diagnosis. In these patients, the sFLC studies were followed year after year, and what they found was that the light chains increased from low stable numbers into abnormal numbers that indicated myeloma over the period of five years.14
How often should MGUS patients be evaluated?
Since the majority of MGUS patients will never progress to malignant disease, when considering whether a patient may benefit from additional follow-up or assessing the frequency of that follow-up, many factors are considered, including whether any relevant clinical symptoms are present or developing, the amount and type of monoclonal protein present, and whether the monoclonal protein concentration appears to be increasing.10
Patients should only have serum testing with SPEP, IFE and sFLC, annually, unless clinically indicated for more frequent or invasive procedures.
The bottom line
Although there are no screening guidelines for myeloma, identifying patients who may benefit from testing and ordering the appropriate tests, is critical for early myeloma detection and timely referral. Primary care providers play a vital role in bridging the gap between initial presentation and time to referral, as well as in the ongoing evaluation of MGUS patients.
Patients diagnosed with MGUS should be evaluated carefully for any new symptoms and concerning laboratory results; however, frequent and invasive workups are generally not necessary. Collaboration between primary care providers and hematology-oncology specialists is key in ensuring the development of an appropriate care plan for MGUS patients.
References
- Kyle RA. Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med. 1978;64(5):814-826
- Kyle R. A. "Benign" monoclonal gammopathy--after 20 to 35 years of follow-up. Mayo Clinic proceedings 1993, 68(1), 26–36.
- Kumar SK, et al. Multiple myeloma. Nat Rev Dis Primers 3, 17046 (2017).
- Kristinsson, SY et. al. Screening for Monoclonal Gammopathy of Undetermined Significance: A Population-Based Randomized Clinical Trial. First Results from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) Study, Blood (2021) 138, (Supplement 1): 156.
- Landgren O, et al. Racial disparities in the prevalence of monoclonal gammopathies: a population-based study of 12 482 persons from the National Health and Nutritional Examination Survey. Leukemia 2014; 28:1537-1542
- Landgren O, et al. Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden. Blood. 2009 Jul 23;114(4):791-5
- Mikhael et al. Multiple Myeloma for the Primary Care Provider: A Practical Review to Promote Earlier Diagnosis Among Diverse Populations. Am J Med. 2023 Jan;136(1):33-41.
- 8. Keren et al. Laboratory Detection and Initial Diagnosis of Monoclonal Gammopathies Arch Pathol Lab Med 2021;146:575-90
- 9. Dispenzieri et al. International Myeloma Working Group Guidelines for serum free light chains in multiple myeloma and other related disorders, Leukemia 2009;23:215-24
- 10. Rajkumar SV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014; 15:e538-e548
- 11. Kumar SK, Callander NS, Adekola K, et al. Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2023 Dec;21(12):1281-1301
- 12. Katzmann et al. Screening panels for detection of monoclonal gammopathies. Clin Chem. 2009 Aug;55(8):1517-22.
- 13. Kyle RA, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002; 346:564-569
- 14. Landgren O, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 2009; 113:5412-5417