A 58-year-old Indian woman with newly diagnosed multiple myeloma (IgG-kappa, 35% bone marrow plasma cells, serum M-spike 3.8 g/dL, serum creatinine 1.2 mg/dL, hemoglobin 10.5 g/dL, serum calcium 9.5 mg/dL) is being evaluated for treatment initiation. Cytogenetic analysis by FISH shows deletion 17p (TP53 loss) in 25% of plasma cells. Serum beta-2 microglobulin is 4.2 mg/L and LDH is 450 IU/L. According to current NEET PG / international guidelines, what is her revised International Staging System (R-ISS) risk category, and what is the most appropriate first-line induction therapy?

Explanation

## Revised International Staging System (R-ISS) and Risk-Adapted Induction Therapy ### R-ISS Risk Stratification The **Revised International Staging System (R-ISS)** incorporates three key prognostic factors: | Factor | Stage I (Standard) | Stage II (Intermediate) | Stage III (High) | |---|---|---|---| | **ISS Stage** | I | II | III | | **Cytogenetics (FISH)** | No del(17p), no t(4;14) | No del(17p), no t(4;14) | **del(17p) OR t(4;14) OR t(14;16)** | | **LDH** | Normal | Normal | **Elevated (>250 IU/L)** | | **Median OS** | ~10 years | ~7 years | **~3–4 years** | ### This Patient's Risk Category **Key Point:** This patient has **R-ISS Stage III (high-risk)** disease because she meets **two high-risk criteria**: 1. **del(17p)** (TP53 loss in 25% of plasma cells) — **most aggressive cytogenetic abnormality** 2. **Elevated LDH** (450 IU/L, normal <250 IU/L) Note: ISS Stage I (serum beta-2 microglobulin ≤3.5 mg/L AND serum albumin ≥3.5 g/dL) is met, but the presence of del(17p) or t(4;14) **overrides** ISS stage and defines R-ISS Stage III. ### Treatment Approach for R-ISS Stage III **High-Yield:** High-risk myeloma (del(17p), t(4;14), t(14;16)) **requires proteasome inhibitor (PI)-based induction** because: - **Bortezomib (Velcade)** has demonstrated superior efficacy in del(17p) disease - PI-based regimens overcome the poor prognosis associated with TP53 loss - Standard IMiD-based therapy (lenalidomide, thalidomide) alone is insufficient ### Recommended First-Line Induction Regimens for High-Risk MM | Regimen | Components | Rationale | |---|---|---| | **VRd (Velcade-Revlimid-dexamethasone)** | Bortezomib + Lenalidomide + Dexamethasone | **PI + IMiD + corticosteroid; standard for high-risk** | | **VTd (Velcade-Thalidomide-dexamethasone)** | Bortezomib + Thalidomide + Dexamethasone | PI + IMiD + corticosteroid; alternative | | **RVd (Revlimid-Velcade-dexamethasone)** | Lenalidomide + Bortezomib + Dexamethasone | Same as VRd (different order) | | **Daratumumab-based** (e.g., D-VRd) | Anti-CD38 mAb + VRd | Emerging option; enhanced efficacy | | ~~Rd (Lenalidomide-dexamethasone)~~ | IMiD-based only | **Insufficient for del(17p); not recommended** | | ~~Td (Thalidomide-dexamethasone)~~ | IMiD-based only | **Insufficient for high-risk; not recommended** | **Clinical Pearl:** The presence of **del(17p)** is a **contraindication to IMiD-only therapy** because TP53 loss confers intrinsic resistance to lenalidomide and thalidomide. Proteasome inhibitors work through a different mechanism and are effective even in del(17p) disease. ### Why Option 0 is Correct **Mnemonic:** **HiRISS = PI-based** = High-Risk R-ISS Stage III requires Proteasome Inhibitor-based induction Option 0 correctly identifies: 1. **R-ISS Stage III** (del(17p) + elevated LDH) 2. **Bortezomib-based induction** (VRd or VTd) as the standard of care Bortezomib is the **preferred proteasome inhibitor** for newly diagnosed myeloma induction because of extensive clinical trial data (VISTA, CREST, EFFORT trials) demonstrating superior outcomes in high-risk disease.