Prognostic factors for smoldering multiple myeloma progression

Smoldering multiple myeloma (SMM) is a precursor form of multiple myeloma (MM). Most SMM patients (pts) are asymptomatic and do not require any form of treatment. However, SMM pts need to be monitored at regular time intervals as there is a 10% probability each year of developing MM in the first five years after diagnosis. This is reduced to 3% per year in the next five years and to 1% per year thereafter. Identifying clear biomarkers which can predict high-risk SMM pts can help treat these pts timely, before they develop any end-of-organ damage. It can also help to limit treatment in SMM pts whose disease may never progress, avoiding cumulative side-effects of long-term treatment.

In 2014 the International Myeloma Working Group (IMWG) identified a set of criteria, which included bone marrow plasma cell (BMPC) percentage > 60, free light chain ratio (FLCr) ≥ 100 and more than one focal lesion detected by magnetic resonance imaging (MRI), that were associated with higher-risk of SMM pts to develop MM.

Vernon Wu from the Stony Brook University School of Medicine, Stony Brook, US, Ajai Chari from Icahn School of Medicine at Mount Sinai, New York, US and colleagues studied collectively a set of biomarkers to determine their predictive value in identifying high-risk SMM pts. In addition to serum FLCr ≥100 and BMPC ≥ 60%, the authors used a group-based trajectory modeling (GBTM) to include evolving (e) biomarkers, the levels of which can change during time. The GBTM identified high-risk groups of pts taking into account changes in the values of hemoglobin (Hb), monoclonal (M-) protein (MP), FLCr and the difference in the concentration between the involved and uninvolved FLC (dFLC) a year after SMM diagnosis.

Key Data:

• Number of pts = 273
• Median age = 60 (range: 20-90)
• Male participants = 52% (143/273)
• FLCr < 100 = 156 pts; ≥ 100 = 27 pts
• BMPC < 60% = 251 pts; ≥ 60% = 22 pts
• Median BMPC = 20% (range: 10-95)
• Isotype = IgG, 71%; IgA, 21%; LC only, 5%; other, 3%
• Involved light chains = κ, 70%; λ, 29%; biclonal, 1%
• Median M-protein = 1.9 g/dL (range: 0-3)
• Serum M-protein < 3 g/dL = 86% (189/220 pts); ≥ 3 g/dL = 14% (31/220 pts)
• Median follow-up = 67 months
• Median time to progression (TTP) = 74 months
• Number of pts progressing to MM = 123/273 (45%)
• Progression events: hypercalcemia, n = 4; renal insufficiency, n = 11; anemia, n = 62; bone disease, n = 64
• Symptoms of progression in the FLCr and BMPC stratification groups were similar to those of the overall population (predominantly anemia and bone disease)
• Median TTP for FLCr group < 100 vs FLCr group ≥ 100 = 93 months vs 40 months (P = 0.0019)
• Median TTP for BMPC group < 60% vs BMPC group ≥ 60% = 79 months vs 31 months (P = 0.0006)
• 2-year PD rate for FLCr group ≥ 100 = 44%
• 2-year PD rate for BMPC group ≥ 60% = 41%
• FLCr group ≥ 100 = 90% specificity and 28% sensitivity for predicting progression at 24 months; 44% of pts did not progress during follow-up period
• BMPC group ≥ 60% = 94% specificity and 15% sensitivity for predicting progression at 24 months; 60% did not progress during follow-up period
• Analysis of a subgroup of pts with dFLC ≥ 100 mg/L revealed a high-risk cohort with a median TTP = 71 months and a 2-year PD rate = 36%
• High-risk eHb group = average decrease of Hb at year one, 1.57 g/dL (95% confidence interval [CI], 1.29-84); TTP, 26 months; 2-year PD rate, 43%
• High-risk eMP group = average increase of M-protein at year one, 64% (95% CI, 44-84); TTP, 40 months; 2-year PD rate, 36%
• High-risk eFLCr group = average increase in FLCr at year one, 188% (95% CI, 183-193); TTP, 37 months; 2-year PD rate, 32%
• High-risk edFLC group = average increase in dFLC at year one, 169% (95% CI, 143-195); TTP, 45 months; 2-year PD rate, 30%
• Most significant predictors of a 2-year PD using a multivariable model = immunoparesis, eMP, eHb, edFLC; number of pts analyzed = 90
• The multivariable model (≥ 3 risk factors) identified a group of ultra-high-risk pts with a median TTP = 13 months and 2-year PF = 88%

Conclusions

This study identifies SMM pts with FLCr ≥ 100 and BMPC ≥ 60% as high-risk group, similar to previous studies, but with a better prognosis in terms of TTP and 2-year PD rate to that previously described. A GBTM identified four evolving biomarkers, immunoparesis, eMP, eHb and edFLC, as significant predictors of an ultra-high-risk group of pts. These evolving biomarkers can be validated further in future studies or in a meta-analysis of previously collected data.