Evidence for Cytogenetic and Fluorescence In Situ Hybridization Risk Stratification of Newly Diagnosed Multiple Myeloma in the Era of Novel Therapies

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.CG = cytogenetics; CI = confidence interval; FISH = fluorescence in situ hybridization; HR = hazard ratio; IgH = immunoglobulin heavy chain; MM = multiple myeloma; mSMART = Mayo Stratification of Myeloma and Risk-Adapted Therapy; NR = not reached; PCLI = plasma cell labeling index; SCT = stem cell transplantationMultiple myeloma (MM) is a clonal plasma cell disorder that has witnessed considerable therapeutic advances in recent times. This progress can be attributed to improved antimyeloma therapy along with a better understanding of the tumor biology and heterogeneity.^1,2 Although a wide variation in overall survival (OS) of patients has been observed in studies analyzing the natural history of MM,³ only now are we beginning to associate the disparity in clinical outcomes with specific genetic abnormalities. Such chromosomal abnormalities are almost universally prevalent in the neoplastic plasma cells, typically occurring early in the disease process and dictating its course.⁴ Both cytogenetics (CG) and interphase fluorescence in situ hybridization (FISH) assays have played pivotal roles in the risk stratification of patients with newly diagnosed MM. Although still useful, conventional prognostic factors (β₂-microglobulin, lactate dehydrogenase, serum albumin, C-reactive protein, etc)⁵ appear to be somewhat less discerning of the outcome compared with the genetic aberrations that drive the tumor biology.^6-10The Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) criteria use a combination of metaphase CG, FISH, and plasma cell labeling index (PCLI; a measure of the percentage of plasma cells in the S phase of the cell cycle)¹¹ results to derive 2 composite risk categories (high-risk vs standard-risk) for prognostication of patients with newly diagnosed MM.¹² Although the initial prognostication criteria were based on the evidence predominantly garnered from patients treated with conventional chemotherapy and/or stem cell transplantation (SCT), the recommendations are periodically revised as new data emerge. Less than a decade ago, melphalan-prednisone or combination chemotherapies along with SCT were the mainstays of treatment of MM. The introduction of newer therapies, immunomodulatory drugs (thalidomide and lenalidomide), and the first-in-class proteasome inhibitor bortezomib ushered in a period of remarkable progress as the profound impact of such novel agents became evident early in the disease course.^1,13 Therefore, the Mayo prognostic model needed a formal assessment in the current era of expanded use of novel therapies. The objectives of our study were to evaluate the significance of the Mayo risk-stratification criteria since the integration of novel agents in the management of MM and to assess the independent prognostic value of each of the components (CG, FISH, and PCLI) in the model.