Metaphase cytogenetics and plasma cell proliferation index for risk stratification in newly diagnosed multiple myeloma

Abstract

Metaphase cytogenetic abnormalities, plasma cell proliferation index (PCPro), and gain 1q by fluorescence in situ hybridization (FISH) are associated with inferior survival in newly diagnosed multiple myeloma (MM) treated with novel agents; however, their role in risk stratification is unclear in the era of the revised International Staging System (R-ISS). The objective of this study was to determine if these predictors improve risk stratification in newly diagnosed MM when accounting for R-ISS and age. We studied a retrospective cohort of 483 patients with newly diagnosed MM treated with proteasome inhibitors and/or immunomodulators. On multivariable analysis, R-ISS, age, metaphase cytogenetic abnormalities (both in aggregate and for specific abnormalities), PCPro, and FISH gain 1q were associated with inferior progression-free (PFS) and overall survival (OS). We devised a risk scoring system based on hazard ratios from multivariable analyses and assigned patients to low-, intermediate-, and high-risk groups based on their cumulative scores. The addition of metaphase cytogenetic abnormalities, PCPro, and FISH gain 1q to a risk scoring system accounting for R-ISS and age did not improve risk discrimination of Kaplan-Meier estimates for PFS or OS. Moreover, they did not improve prognostic performance when evaluated by Uno’s censoring-adjusted C-statistic. Lastly, we performed a paired analysis of metaphase cytogenetic and interphase FISH abnormalities, which revealed the former to be insensitive for the detection of prognostic chromosomal abnormalities. Ultimately, metaphase cytogenetics lack sensitivity for important chromosomal aberrations and, along with PCPro and FISH gain 1q, do not improve risk stratification in MM when accounting for R-ISS and age.

Clonal heterogeneity by fluorescence in situ hybridization in multiple myeloma: enhanced cytogenetic risk stratification

“…Similarly in a recent study on 292 newly diagnosed MM patients by Barilà et al, 2020, concomitant trisomies 9/11/15 were the most powerful prognostic factor ( P < 0.01), followed by IGH rearrangement ( P < 0.04), although in the opposite direction [ 20 ]. Also Mellors et al in 2020 revealed that R-ISS stage and age 70 years were associated with inferior OS in the base model [ 21 ].…”

Perspectives on the Risk-Stratified Treatment of Multiple Myeloma

“…Initial studies used metaphase cytogenetics and discovered that in many multiple myeloma cases, it was not possible to obtain metaphase spreads for examination. The ability, therefore, to generate abnormal metaphase spreads per se is considered a poor prognostic factor ( 22 ). The presence of a complex karyotype and detection of monosomy 13 on metaphase analysis are also poor prognostic factors; however, many characteristic myeloma markers initially identified by Southern blot are karyotypically silent [e.g., t(4;14)], leading to CD138-selected interphase FISH (iFISH) being the preferred test.…”

High-risk disease in newly diagnosed multiple myeloma: beyond the R-ISS and IMWG definitions

“… * Large FLs (diameter >2.5 cm) associated with site-specific enrichment of HiR driver mutations consistent with them being key mediators of drug resistance and treatment failure [ 86 – 100 ]. ** Certain EME sites seemed to carry worse prognosis with 3-year PFS differing according to involved organs: kidney (59.5%), skin (20.1%), lymph nodes (37.6%), CNS (47.9%), lung/respiratory tract (44.4%), GI/liver (22.5%), and spleen, ovaries, and testes (60.0%).…”