Strategies to assess and improve prognostication of plasma cell disorders

Abstract: Plasma cell dyscrasias (PCD) are a group of disorders, most of which have the overproduction of monoclonal immunoglobulins (M-protein) in common. Included in the group of PCDs are both benign and treatment demanding disorders. Multiple myeloma (MM) is one of the treatment demanding PCDs and also the second most common hematological malignancy. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are both PCD disorders currently not thought to require treatment. Although, in the case of SMM, recent trials have shown the time to progress to symptomatic MM was prolonged with treatment. Biomarkers are an essential key for diagnosing, risk prediction, and monitoring diseases. An essential biomarker in PCDs is the assessment of M-protein in serum/plasma and urine used to detect and monitor. In the past decades, new research findings and technical development of biomarkers have improved the ability to diagnose and monitor PCDs. Particularly, serum free light chain (FLC) assessment has shown an important role in diagnosing and risk prediction in MGUS, SMM, and MM and for assigning stringent complete response in MM. Research has shown that MGUS or SMM consistently precedes MM. This observation has lead to a growing interest in the dynamic evaluation of biomarkers to predict patients at risk. However, the kinetics of biomarkers in PCDs is still a developing research field. In study I, we aimed to identify dynamic changes of M-protein and FLC associated with increased risk of progression from MGUS to symptomatic MM. We observed that dynamic increases of involved FLC (iFLC) above 100mg/L were a consistent risk factor during follow-up, while M-protein elevations above 5g/L were associated with increased risk of progression at only a few time-points. Furthermore, we identified several independent predictors of progression at the time of MGUS diagnosis, age >65 years, M-protein >15g/L, and iFLC >100mg/L. We observed that the 5-year cumulative probability of progression was higher in patients with two or three risk factors at diagnosis (31%) than patients with no risk factors (2%). In study II, we attempt to define cut-offs for temporal biomarkers in individuals with SMM, associated with progression to symptomatic MM. We found that increases of M-protein and iFLC ratio (iFLCr) were significant predictors of progression, with the optimal cut-offs at >5g/L and >4.5, respectively. Moreover, we could confirm that clonal bone marrow plasma cells >20% and M-protein >20g/L, at diagnosis, were independent risk factors of progression. Interestingly, while increases in iFLCr during follow-up were associated with increased risk of progression, iFLCr at diagnosis were not an independent risk factor. In study III, we investigated whether response and progression in patients with MM were detected earlier by iFLC or M-protein. We observed that at least partial response, or better, was overall observed significantly earlier when assessed with iFLC than M-protein, while no overall significant differences were detected between the two biomarkers when detecting biochemical progression. Subgroup analysis included heavy chain type, measurable disease groups, and early and late progression. In these subgroup analyses, iFLC appears to be non-inferior in response detection compared to M-protein. The subgroup analyses of the time to progression showed that M-protein detected biochemical progression significantly earlier than iFLC in patients with iFLC <100mg/L and a detectable M-protein, >10g/L. In study IV, we investigated the causes of death and risk factors for overall survival in patients with MGUS that had not progressed to hematological malignancy. Light chain MGUS (versus IgG MGUS) was associated with inferior survival. Additionally, independent predictors for overall survival were male gender, hypoalbuminemia, and renal insufficiency. In conclusion, with these studies, we have increased the knowledge of temporal FLC and M-protein assessments in MGUS, SMM, and MM, potentially improving these patients’ follow-up. Furthermore, this dissertation may open up further research efforts, especially in excess mortality in individuals with light chain MGUS.