The presence of large focal lesions is a strong independent prognostic factor in multiple myeloma

Abstract

Spatial intratumor heterogeneity is frequently seen in multiple myeloma (MM) and poses a significant challenge for risk classifiers, which rely on tumor samples from the iliac crest. Because biopsy-based assessment of multiple skeletal sites is difficult, alternative strategies for risk stratification are required. Recently, the size of focal lesions (FLs) was shown to be a surrogate marker for spatial heterogeneity, suggesting that data from medical imaging could be used to improve risk stratification approaches. Here, we investigated the prognostic value of FL size in 404 transplant-eligible, newly diagnosed MM patients. Using diffusion-weighted magnetic resonance imaging with background suppression, we identified the presence of multiple large FLs as a strong prognostic factor. Patients with at least 3 large FLs with a product of the perpendicular diameters >5 cm² were associated with poor progression-free survival (PFS) and overall survival (OS; median, 2.3 and 3.6 years, respectively). This pattern, seen in 13.8% of patients, was independent of the Revised International Staging System (RISS), gene expression profiling (GEP)-based risk score, gain(1q), or extramedullary disease (hazard ratio, 2.7 and 2.2 for PFS and OS in multivariate analysis, respectively). The number of FLs lost its negative impact on outcome after adjusting for FL size. In conclusion, the presence of at least 3 large FL is a feature of high risk, which can be used to refine the diagnosis of this type of disease behavior and as an entry criterion for risk-stratified trials.

Graphical abstract

Figure 1.

The impact of focal lesion size on outcome. (A) The FL-HiR pattern as seen in whole-body diffusion-weighted MRI scan with background suppression. It consists of ≥3 large FLs, each with a PPD ≥5 cm². (B) Outcome of 404 NDMM patients enrolled into Total Therapy trials stratified by this pattern. Log-rank test was used to perform the group comparison.

Figure 2.

Association test and multivariate analysis including the FL-HiR pattern. (A) Association between the FL-HiR pattern and disease features. Statistical significance was determined by Fisher’s exact test. (B) Forrest plot illustrating the results of a Cox regression model including the depicted variables. Hazard ratios and 95% confidence intervals are indicated by squares and crossing horizontal lines, respectively. *P < .05; **P < .01; ***P < .001. AIC, Akaike information criterion.

Figure 3.

Combination of FL-HiR with established risk stratifiers. Progression-free survival for newly diagnosed MM patients stratified by the combination of the FL-HiR pattern with R-ISS (left) and GEP70 (right), respectively. The log-rank test was used to calculate P values.