While I enjoy writing this column for The Jewish Link, I also spend the bulk of my time seeing patients, doing research and writing articles for more scholarly journals. Not long ago, I wrote an editorial for the journal Cancer Epidemiology Biomarkers and Prevention on the question of screening for monoclonal gammopathy of undetermined significance (MGUS).

MGUS is the only well-established precursor condition for a hematologic malignancy, multiple myeloma. In other words, all cases of multiple myeloma start out as MGUS and are derived from it, similar to adenomatous polyps of the colon and colon cancer. Multiple myeloma is a malignancy of plasma cells, a type of lymphocyte which produces antibodies or immunoglobulins. The diagnosis of multiple myeloma is usually based on a triad of factors (other abnormalities may be present as well): a unique elevation of a single antibody which appears as a peak or spike (called an M-spike) in an immunoglobulin on a test called the serum protein electrophoresis (SPEP); a significant increase in plasma cells in the bone marrow; and holes in the bones (lytic lesions) from plasma cell tumors seen on scans (the bone lesions are called myeloma and give the disease its name).

The SPEP is a blood test that spreads out the proteins in the serum in a band so they can be visualized. Most prominent among the serum proteins are the antibodies that an individual has accumulated over the course of his/her life from exposure to organisms or vaccines, etc. In multiple myeloma, there is a malignant plasma cell which has abnormally proliferated and is producing a specific antibody to excess; this antibody will show up as a peak or “spike” on the SPEP. It is the hallmark of the malignancy.

In a previous article I highlighted the high prevalence of MGUS in the general population. If you were to do SPEPs on asymptomatic Whites over the age of 50 years, approximately 1% would have an abnormal M-spike on their SPEP (the rate would be significantly higher among Blacks), but without the accompanying bone abnormalities and increased bone marrow plasma cells that are characteristic of myeloma. MGUS alone is clinically unimportant, but its significance lies in the fact that a population of individuals with MGUS progresses to multiple myeloma at a rate of approximately 1% a year.

My editorial commented that the SPEP is a cheap test, so would it be worthwhile to screen the population with this test to identify those who have MGUS? My conclusion was that it would not be worthwhile at the present time because there does not exist a treatment for MGUS that would prevent its progression, and that, until such a treatment were developed, we would need to wait. But we should introduce one more entity to make this discussion complete. While MGUS represents solely an abnormality in the M-spike on SPEP and multiple myeloma is the full-blown malignant form of the plasma cell cancer with the abnormal M-spike, bone lesions and an increased number of plasma cells in the bone marrow, smoldering myeloma (SMM) represents a third intermediate condition between the two. It is a still benign condition, generally asymptomatic, but in which there is an M-spike on the SPEP and an increase in the plasma cells on bone marrow but no bone lesions. Like MGUS, there is no treatment for it at the present time and SMM patients are simply observed.

SMM can be classified as low, intermediate or high-risk for progression to multiple myeloma depending on the level of the M-spike on SPEP and the percentage of plasma cells in the bone marrow, as well as other factors. For those with high-risk SMM, the risk of progression to multiple myeloma is as high as 50% at two years. SMM, like MGUS, is not generally treated because previous attempts at treatment have been unavailing in preventing progression to myeloma.

Now comes a new randomized trial, the AQUILA Study, published in the New England Journal of Medicine in December 2024, led by investigators from the University of Athens in Greece and including institutions and patients in 23 countries. They randomized 390 patients with high-risk smoldering multiple myeloma to receive subcutaneous daratumumab, a drug used in the treatment of multiple myeloma, every four weeks for 36 months, or to be simply observed. With a median follow-up time of 65 months (over five years), 67 patients (34.5%) in the daratumumab group versus 99 patients (50.5%) in the active surveillance group had progressed to multiple myeloma or died; this represented a 51% reduction in the progression rate (95% confidence interval 0.36-0.67). Overall, 41 patients died—15 (7.7%) in the daratumumab group and 26 (13.3%) in the surveillance group (hazard ratio 0.52, 95% confidence interval 0.27-0.98). The side effect profile was very tolerable.

This was the first demonstration of a clear-cut benefit to treatment for a precursor of multiple myeloma. Its benefits were obviously quite substantial and at a reasonable toxicity. It suggests that the day may not be far off when we will be using SPEPs to screen for those with precursor abnormalities of plasma cell malignancies. A true advance for this disease.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York. Email: [email protected].

 This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.