Precursors to multiple myeloma were identified by population screening in two studies reported at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition. The prevalence of monoclonal gammopathies was determined in the PROMISE trial using cutting-edge technology in a high-risk U.S. population,1 and the iStopMM study screened more than 80,000 unselected adults in Iceland.2 Both studies showed that screening is possible and that individuals at risk for myeloma can be identified before full-blown disease is diagnosed.
Irene M. Ghobrial, MD
Habib El-Khoury, MD
Sigurdur Y. Kristinsson, MD, PhD
“We know that in cancers such as breast cancer and lung cancer, screening, early detection, and early intervention can make a difference in patient survival,” said senior investigator of the PROMISE trial, Irene M. Ghobrial, MD, Professor of Medicine at Harvard Medical School and Attending Physician in Medical Oncology at Dana-Farber Cancer Institute, Boston, where she is also Director of the Clinical Investigator Research Program and the Michele & Stephen Kirsch Laboratory. “We have shown for the first time that with highly sensitive screening techniques, it may eventually be possible to make a difference in the survival of people at elevated risk for multiple myeloma.”
Interim screening findings from the PROMISE trial were reported at the ASH meeting by Habib El-Khoury, MD, of Dana-Farber Cancer Institute, and by Dr. Ghobrial at a press briefing.
Results from the prospective iStopMM trial were reported at the ASH meeting by Sigurdur Y. Kristinsson, MD, PhD, Professor of Hematology at the University of Iceland. The study showed that “intensive” screening going beyond conventional blood work not only identifies more patients with monoclonal gammopathy of undetermined significance (MGUS), but also detects a sizable number of individuals with smoldering disease, full-blown malignancy, and other lymphoproliferative cancers.
“Our findings illustrate the fact that early detection and intervention are achievable,” Dr. Kristinsson said.
First Results of PROMISE
The general estimate is that 3% of the general population aged 50 years and older have MGUS. Although studies have shown that people of African descent and those with a family history of blood cancers are at increased risk for multiple myeloma, none have looked prospectively for MGUS in a high-risk population. The PROMISE trial endeavored to do so, screening individuals who were 40 to 75 years old, African American/Black, or with a first-degree relative diagnosed with a hematologic malignancy or myeloma precursor. The study ultimately will enroll 30,000 individuals.
To date, 7,622 people have been screened, including 2,211 deemed the PROMISE cohort and—to enrich for African American/Black participation—5,411 from the Mass General Brigham Biobank. The early data set reported at the ASH meeting comprises the initial screening population of 2,439 Black and 3,866 non-Black participants with a family history.
Blood from all participants was analyzed conventionally via serum protein electrophoresis/immunofixation (SPEP/IFX) with serum free light-chain analysis and analysis of IgG, IgA, and IgM. In a subset, investigators also used the higher-sensitivity matrix-assisted laser desorption/ionization–time of flight mass spectrometry (MALDI-TOF MS) for detection.
With the conventional SPEP/IFX method, the analysis revealed significantly higher rates of MGUS in high-risk individuals older than age 50 (6%) than has been previously reported (3%). By MALDI-TOF MS, the detection rate was even higher (13% in individuals at high risk of disease), including rates of 17% among Black and 13% among non-Black individuals without a family history, compared with 10% of non-Black individuals without a family history (the control group). Multivariate analysis found significant predictors of MGUS to be increasing age (odds ratio [OR] = 1.93; P < .001), male gender (OR = 1.18; P = .034), and Black ancestry (OR = 1.64; P = .003).
“Our data show that the use of mass spectrometry is capable of capturing a new and larger pool of patients with MGUS,” Dr. El-Khoury commented.
MALDI-TOF MS detected even minute amounts of M-protein in 42% of the high-risk population older than age 50. Furthermore, it detected lower-level monoclonal gammopathies (ie, monoclonal gammopathies of indeterminate potential [MGIP]), at levels lower than the limit of detection used for conventional methods (< 0.2 g/L). MGIP increased with age and was detected in about 28% of individuals aged 50 and older.
For patients with M-protein below the threshold of 0.2 g/L, IgM was the most common isotype, followed by IgA and IgG. For M-protein above 0.2 g/L, IgG was the most common, followed by IgA and IgM. Moreover, participants whose samples came from the Biobank had a median follow-up of 4.5 years, and those with any level of M-protein had a slightly higher all-cause mortality rate as compared with persons lacking M-protein.
Dr. Ghobrial cautioned that she is “not advocating to start cancer screening yet, before we understand more of the implications…. But we are getting there.” Meanwhile, all PROMISE study participants testing positive for MGUS are further monitored or referred to an outside hematologist.
First Results of iStopMM
Iceland’s population-based screening iStopMM trial also included a randomized component of follow-up and treatment strategies. The study was open to all Iceland residents born before 1976 (almost 150,000 individuals), of whom 80,759 (54%) agreed to participate; 75,422 (93%) have been screened, with 3,725 testing positive for MGUS (by M-protein and free light chain analysis) and therefore being randomly assigned to one of three arms: not contacted (arm 1); followed based on current guidelines (arm 2); or followed with a more intensive diagnostic and monitoring strategy (arm 3). The intensive arm received extensive blood work, bone marrow evaluations, low-dose computed tomography, and annual follow-up. All participants who experienced disease progression were offered early treatment.
Screening revealed a 4.9% overall prevalence of MGUS that varied by age: 2.3% among persons diagnosed between the ages of 40 and 59, 6.2% for those diagnosed between the ages of 60 and 79, and 12.9% for those diagnosed between the ages of 80 and 103, Dr. Kristinsson reported. Prevalence of MGUS was higher in men, 5.9% vs 4.1% (P < .0001). MGUS was classified as low risk (38%), low-intermediate risk (36%), high-intermediate risk (26%) or high risk (0.2%). Half the isotopes were IgG. Median M-protein concentration was 0.34 g/dL.
Intensive workup and follow-up resulted in significantly more diagnoses of lymphoproliferative disorders after 3 years of follow-up: 9 diagnoses in arm 1 (no contact), 92 diagnoses in arm 2 (conventional follow-up), and 133 diagnoses in arm 3 (intensive follow-up; P < .001). Excluding indolent (smoldering) myeloma that was detected, these numbers were 6, 16, and 24, respectively (P = .0046). Most diagnoses were smoldering myeloma, but patients were also diagnosed with frank myeloma, amyloidosis, (smoldering) Waldenström’s macroglobulinemia, non-Hodgkin lymphoma, and chronic lymphocytic leukemia.
“If you do more bone marrows, more aggressive imaging, and more aggressive biopsies, you get more cases. This was highly statistically significant,” Dr. Kristinsson said.
“Although our findings are encouraging, until final results of the iStopMM study become available, including data on survival and quality of life, we advise against systematic MGUS screening in healthy individuals,” he said.
DISCLOSURE: Dr. Ghobrial has received honoraria from Celgene, Bristol Myers Squibb, Takeda, Amgen, and Janssen; has served as a consultant or advisor for Bristol Myers Squibb, Novartis, Amgen, Takeda, Celgene, Cellectar, Sanofi, Janssen, Pfizer, Menarini Silicon Biosystems, Oncopeptides, The Binding Site, GlaxoSmithKline, AbbVie, and Adaptive; has received reimbursement for travel accomodations or expenses from Bristol Myers Squibb, Novartis, Celgene, Takeda, and Janssen Oncology; and her spouse is Chief Medical Officer at Disc Medicine and holds equity in the company. Dr. El-Khoury reported no conflicts of interest. Dr. Kristinsson has received research funding from Amgen and Celgene.
1. El-Khoury H, Alberge J, Barr H, et al: High prevalence of monoclonal gammopathy in a population at risk: The first results of the Promise Study. 2021 ASH Annual Meeting & Exposition. Abstract 152. Presented December 11, 2021.
2. Kristinsson SY, Rögnvaldsson S, Thorsteinsdottir S, et al: Screening for monoclonal gammopathy of undetermined significance. 2021 ASH Annual Meeting & Exposition. Abstract 156. Presented December 11, 2021.
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