Absolute Risk of Multiple Myeloma Is Quite Modest in Individuals with Incidentally Discovered Vertebral Fractures: A Prospective Cohort Study of 9,065 CT-Scanned Danish General Population Individuals with Independent Validation in a UK General Population Cohort

Background:

Incidentally discovered vertebral fractures are a very common finding on CT scans or dual-energy X-ray absorptiometry (DXA) scans in individuals without symptoms of multiple myeloma. Risk of multiple myeloma in individuals with incidentally discovered vertebral fractures is unknown. Currently, some clinical guidelines recommend that all individuals with incidentally discovered vertebral fractures should be evaluated for underlying myeloma (including measuring serum M-protein and free light chains), while other guidelines recommend that clinicians should decide based on clinical judgement whether or not to evaluate for myeloma. To lay ground for an evidence-based clinical approach, we studied relative and absolute risks of being diagnosed with multiple myeloma in individuals with incidentally discovered vertebral fractures.

Methods:

We studied 9,065 Danish general population individuals aged 33-94 years (median 62 years) from the Copenhagen General Population Study, all of whom attended a health examination and had a CT scan performed as part of study procedures. All 9,065 individuals’ CT scans were reviewed by trained medical students for presence and grade of vertebral fractures in the lumbar and lower thoracic spine. During a median prospective follow-up of 5.5 years (range 0-10 years) after the CT scan, 13 individuals were diagnosed with myeloma. To validate our findings in an independent cohort, we conducted a case-cohort study based on 56,159 general population individuals aged 45-85 years (median 66 years) from the United Kingdom (UK) Biobank who all had a DXA scan performed as part of study procedures. In the UK case-cohort validation study, median follow up after the DXA scan was 4.0 years (range 0-9 years) and DXA images were reviewed by a medical doctor for all 49 individuals diagnosed with myeloma during follow-up who had DXA images available, and for 245 randomly chosen general population individuals never diagnosed with myeloma. In both cohorts, diagnoses of multiple myeloma were from national registries, covering all hospitals in Denmark and the UK. Individuals were excluded from the study if they had been diagnosed with myeloma and/or vertebral fractures before their CT or DXA scan was performed. This research has been conducted using the UK Biobank Resource under application number 99692.

Results:

Among the 9,065 Danish individuals, 1,574 (17.4%) had one or more incidentally discovered vertebral fractures on the CT scan, of which 875 (9.7%) had one or more grade 1 fractures (defined as a vertebra with 20-25% loss of vertebral height) and 699 (7.7%) had one or more grade 2-3 fractures (>25% loss of vertebral height). Relative risk of being diagnosed with multiple myeloma was increased for individuals with grade 1 vertebral fractures (age and sex adjusted hazard ratio 2.39;95%CI 0.49-11.50) and was even higher for individuals with grade 2-3 fractures (hazard ratio 5.54;95%CI 1.60-19.18). Absolute 5-year risks of multiple myeloma were 0.07% and 0.10% in women and men without vertebral fractures, respectively. Although relative risk of myeloma was increased in individuals with vertebral fractures, absolute risk was quite modest with absolute 5-year risks for myeloma of 0.17% in women with grade 1 fractures, 0.24% in men with grade 1 fractures, 0.43% in women with grade 2-3 fractures and 0.63% in men with grade 2-3 fractures.

In the independent UK validation cohort, absolute 5-year risk of myeloma were 0.06% in women with incidentally discovered grade 1 fractures, 0.12% in men with grade 1 fractures, 0.14% in women with grade 2-3 fractures, and 0.26% in men with grade 2-3 fractures.

Conclusion:

In our primary Danish general population cohort, relative risk of myeloma was increased in individuals with incidentally discovered vertebral fractures on CT scans, but absolute risk was quite modest, as the highest 5-year absolute risks for myeloma were 0.43% and 0.63% in women and men with grade 2-3 fractures, respectively. Absolute risk estimates were even lower in the UK validation cohort. These findings indicate that there is little benefit in evaluating asymptomatic individuals with incidentally discovered vertebral fractures on CT or DXA scans for underlying multiple myeloma, and that such evaluation is probably only indicated in individuals with symptoms or other clinical findings giving suspicion of underlying myeloma.