## Salvage Therapy in Bortezomib-Refractory Relapsed Multiple Myeloma **Key Point:** Carfilzomib (second-generation proteasome inhibitor) with lenalidomide and dexamethasone (KRd) is the preferred salvage regimen for patients with bortezomib-refractory relapsed myeloma, as it overcomes proteasome inhibitor resistance. ### Why KRd in Bortezomib-Refractory Disease 1. **Second-generation proteasome inhibitor**: Carfilzomib is a next-generation proteasome inhibitor with a different binding mechanism than bortezomib, allowing activity in bortezomib-resistant disease. 2. **Irreversible proteasome binding**: Carfilzomib binds irreversibly to the proteasome, whereas bortezomib binding is reversible, potentially explaining resistance. 3. **Maintained IMiD backbone**: Lenalidomide continues to provide immunomodulatory and anti-angiogenic effects. 4. **Evidence-based**: KRd has demonstrated superior progression-free survival in relapsed/refractory MM compared to bortezomib-based regimens in bortezomib-refractory patients. ### Management Algorithm for Relapsed/Refractory MM ```mermaid flowchart TD A[Relapsed/Refractory MM]:::outcome --> B{Prior bortezomib response?}:::decision B -->|Bortezomib-sensitive| C[Repeat VRd or VTd]:::action B -->|Bortezomib-refractory| D[Switch to 2nd-gen PI]:::action D --> E[Carfilzomib-based KRd]:::action B -->|IMiD-refractory| F[Consider pomalidomide + PI]:::action E --> G[Assess response at 2-3 months]:::decision G -->|Good response| H[Continue KRd]:::action G -->|Progression| I[Add daratumumab or switch regimen]:::action ``` **High-Yield:** Carfilzomib (irreversible proteasome inhibitor) is the standard choice for bortezomib-refractory relapsed MM because it overcomes resistance through a different mechanism of proteasome inhibition. **Clinical Pearl:** Carfilzomib carries a higher risk of cardiac toxicity and hypertension compared to bortezomib; baseline echocardiography and blood pressure monitoring are essential. **Mnemonic:** **CARE** — **C**arfilzomib for **A**dvanced/bortezomib-**R**efractory **E**scalation. [cite:Harrison 21e Ch 191]
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