## High-Risk Cytogenetics in Multiple Myeloma **Key Point:** del(17p) with TP53 loss is the single most important adverse cytogenetic finding in multiple myeloma, conferring significantly shortened overall survival (median ~2 years vs. 5–10 years in standard-risk disease). ### Cytogenetic Risk Stratification in MM | Abnormality | Frequency | Prognosis | Mechanism | | --- | --- | --- | --- | | del(17p) TP53 loss | 5–10% | **High-risk** | Loss of p53 tumor suppressor; impaired apoptosis | | t(4;14) FGFR3-MMSET | 15–20% | **High-risk** | FGFR3 activation; MMSET overexpression | | t(14;16) MAF | 5% | **High-risk** | MAF transcription factor activation | | t(11;14) CCND1 | 15–20% | Standard-risk | Cyclin D1 overexpression; variable outcome | | Hyperdiploidy | 40–50% | Standard-risk | Generally favorable | | Normal karyotype | 20% | Standard-risk | Intermediate prognosis | **High-Yield:** The **International Myeloma Working Group (IMWG)** revised cytogenetic risk classification in 2015 defines high-risk disease as: (1) del(17p), (2) t(4;14), or (3) t(14;16). del(17p) is the single worst prognostic marker. **Clinical Pearl:** del(17p) is often detected by fluorescence in situ hybridization (FISH) rather than conventional karyotyping, which may miss it. This is why FISH is now standard-of-care at diagnosis. **Mnemonic:** **"TP53 = Terrible Prognosis"** — del(17p) removes the p53 gene, eliminating the cell's "guardian of the genome," allowing unchecked proliferation and resistance to therapy.
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