What is the defining cytogenetic abnormality most commonly associated with poor prognosis in multiple myeloma?

Question

Accepted Answer

D. del(17p) with TP53 loss. ## 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.

Answer

A. t(9;22) Philadelphia chromosome

Answer

B. t(15;17) PML-RARA

Answer

C. Trisomy 8

What is the defining cytogenetic abnormality most commonly associated with poor prognosis in multiple myeloma?

Explanation

High-Risk Cytogenetics in Multiple Myeloma

Cytogenetic Risk Stratification in MM

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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