Evidence for cytogenetic and fluorescence in situ hybridization risk stratification of newly diagnosed multiple myeloma in the era of novel therapie

Abstract

Overall survival (OS) has improved with increasing use of novel agents in multiple myeloma (MM). However, the disease course remains highly variable, and the heterogeneity largely reflects different genetic abnormalities. We studied the impact of the Mayo risk-stratification model of MM on patient outcome in the era of novel therapies, evaluating each individual component of the model-fluorescence in situ hybridization (FISH), conventional cytogenetics (CG), and the plasma cell labeling index-that segregates patients into high- and standard-risk categories. This report consists of 290 patients with newly diagnosed MM, predominantly treated with novel agents, who were risk-stratified at diagnosis and were followed up for OS. Of these patients, 81% had received primarily thalidomide (n=50), lenalidomide (n=199), or bortezomib (n=79) as frontline or salvage therapies. Our retrospective analysis validates the currently proposed Mayo risk-stratification model (median OS, 37 months vs not reached for high- and standard-risk patients, respectively; P=.003). Although the FISH or CG test identifies a high-risk cohort with hazard ratios of 2.1 (P=.006) and 2.5 (P=.006), respectively, the plasma cell labeling index cutoff of 3% fails to independently prognosticate patient risk (hazard ratio, 1.4; P=.41). In those stratified as standard-risk by one of the 2 tests (FISH or CG), the other test appears to be of additional prognostic significance. This study validates the high-risk features defined by FISH and CG in the Mayo risk-stratification model for patients with MM predominantly treated with novel therapies based on immunomodulatory agents.

Figures

FIGURE 1.

Overall survival (OS) of high-risk vs standard (std)-risk patients with newly diagnosed multiple myeloma. A, Patients classified by Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) criteria: median OS of high-risk patients (n=80) is 37 months vs not reached (NR) for std-risk patients (n=210). B, Patients classified by fluorescence in situ hybridization (FISH) alone: median OS of high-risk (n=51) vs std-risk (n=239) patients is 30 months vs NR, respectively. C, Patients classified by metaphase cytogenetics (CG) alone: median OS of high-risk (n=22) vs std-risk (n=268) patients is 29 months vs 65 months, respectively. D, Patients classified by plasma cell labeling index (PCLI) alone: median OS of high-risk (n=27) vs std-risk (n=263) patients is 37 months vs 65 months, respectively. Rx = therapy.

FIGURE 2.

A, Cytogenetics (CG)-based risk stratification of patients with high-risk features by fluorescence in situ hybridization (FISH). When FISH-detected high-risk patients (n=51) are further subdivided into 2 groups based on presence (n=6) or absence (n=45) of high-risk features on CG, median overall survival (OS) is 16 months vs 35 months, respectively. B, CG-based risk stratification of patients with standard (std)-risk features by FISH. When std-risk patients by FISH (n=239) are further subdivided into 2 groups based on presence (n=16) or absence (n=223) of high-risk features on CG, median OS is 37 months vs not reached (NR), respectively. C, FISH-based risk stratification of patients with high-risk features by CG. When high-risk patients by CG (n=22) are further subdivided into 2 groups based on presence (n=6) or absence (n=16) of high-risk features on FISH, median OS is 16 months vs 37 months, respectively. D, FISH-based risk stratification of patients with std-risk features by CG. When std-risk patients by CG (n=268) are further subdivided into 2 groups based on presence (n=45) or absence (n=223) of high-risk features on FISH, median OS is 35 months vs NR, respectively. Rx = therapy.

FIGURE 3.

Risk stratification based on presence of high-risk features on fluorescence in situ hybridization (FISH) or cytogenetics (CG) or both. A, Median overall survival (OS) is 16 months vs 35 months vs not reached (NR) for patients with high-risk features on both FISH and CG (n=6), either (n=61), or neither (standard [std]-risk; n=223), respectively; P=.0002. No difference in survival was noted between patients stratified as high-risk by either vs both, which likely reflects the small number of patients in the group with high-risk features on both FISH and CG. B, Median OS is 16 months vs 35 months vs 37 months vs NR for patients stratified as high-risk by both FISH and CG (n=6), high-risk by CG only (n=16), high-risk by FISH only (n=45), and std-risk (n=223), respectively. Note that the survival curves of patients stratified as high-risk by either FISH or CG are intertwined. Rx = therapy.