116.3 🩺 內科專科考前版
116.3.0.1 📌 一頁重點
- 22E 重大進展:
- 4-drug induction (Dara-VRd / Isa-KRd)：GRIFFIN, IsKia, GMMG-HD7 → 4-drug 已成 transplant-eligible 標準；MRD− 率 50%+
- MAIA: DRd 在 transplant-ineligible PFS 60+ mo, OS benefit → 取代舊 Rd
- DETERMINATION: 早 ASCT vs 延遲 → PFS 早 ASCT 較好但 OS 同 → ASCT timing 可彈性（但仍 standard）
- CARTITUDE-4: Cilta-cel 在 R/R MM 從三線推 second-line（取代多種 trad regimens）
- MajesTEC-3 / MagnetisMM-7: 21E ongoing — bispecific 進 second-line
- Talquetamab (GPRC5D): 第一個 non-BCMA target，避 BCMA escape
- Cevostamab (FcRH5 × CD3): 第三 target；trials advancing
- Iberdomide (next-gen IMiD), mezigdomide (CELMoD): phase 2/3
- WM: zanubrutinib (ASPEN trial) head-to-head 勝 ibrutinib in CXCR4 wt；BTK degraders trials emerging
- Taiwan: 健保 lenalidomide / bortezomib / pomalidomide / carfilzomib / daratumumab / isatuximab 條件給付；ASCT 健保條件給付；CAR-T (cilta-cel) 自費（cytopiq 自費 ~ NT 1500 萬）；bispecific 自費；POEMS 治療同 MM 條件適用
116.3.0.2 🌟 Pearls (15)
- MM driver mutations: KRAS (~ 23%), NRAS (~ 20%), BRAF (~ 10%, V600E targetable)；高 risk 病人多 TP53 + 1q gain
- Cytogenetic dependency: t(11;14) → venetoclax 高度敏感（BELLINI study, 但 OS concern → 限 t(11;14) 使用）
- DETERMINATION 詳解: VRd × 3 induction → ASCT vs no ASCT → maintenance；ASCT 組 PFS 67 vs 46 mo, OS 同 → 早 ASCT 仍是 standard 但可延遲
- MRD 重要性: NGS / NGF 檢測，10⁻⁵ or 10⁻⁶ sensitivity；MRD− 強烈 predictor of long-term PFS + OS；可指導 maintenance duration（trials）
- CARTITUDE-1 5-yr update: Cilta-cel median PFS 35 mo（heavily pretreated），depth + duration 是目前 R/R MM 最高
- MajesTEC-1 vs MagnetisMM-3: teclistamab vs elranatamab — 兩者 ORR 60–70% in 4+ lines；choice 多由 access / SC convenience / step-up 容易度決定
- GPRC5D vs BCMA: GPRC5D 表達於 plasma cells but not normal B cells；talquetamab 有獨特 SE：dysgeusia, weight loss, skin/nail changes（GPRC5D 表達於皮膚 + 味蕾）
- Cevostamab (FcRH5): phase 2 ORR 50%+ in heavily pretreated post-BCMA → 可作 BCMA escape rescue
- Anti-CD38 mAb 干擾：daratumumab + isatuximab 干擾 indirect Coombs (anti-CD38 抑制 reagent RBC) + serum protein electrophoresis (M-spike)；建議：blood bank 用 DTT-treated red cells；SPEP 監測 IgG kappa M-spike with IFE/MASS-FIX/QIP-MS 區別 dara from disease
- Renal failure in MM: cast nephropathy 病理特徵（PAS+ 巨大 cast + 多核 macrophage）；bortezomib-based regimen 是 first choice（> 50% 腎功能改善），可 reverse 部分 dialysis dependence
- Light chain only myeloma (~ 15%): 無 serum M-spike，要靠 24-hr urine + serum FLC ratio 診斷；多腎損
- POEMS 治療反應: VEGF 下降為 surrogate；神經症狀多在治療後 6–12 個月才改善；ASCT 仍可考慮
- WM treatment selection: MYD88+/CXCR4 wt → ibrutinib best；MYD88+/CXCR4 mut → ibrutinib 反應較差；MYD88 wt → 不適 BTK i，多選 BR / VR；ASPEN trial: zanubrutinib > ibrutinib in CXCR4 wt + 較好 toxicity
- WM 預後 (rIPSSWM): age, sex, β2M, hemoglobin, platelet, LDH, IgM；5-yr survival 74–94% by score
- Heavy chain diseases: gamma (Franklin’s) — palatal edema, autoimmune；alpha (Seligmann’s, IPSID) — small bowel + Campylobacter jejuni → 抗生素治療 30–70% CR；mu — CLL 變體
116.3.0.3 📍 Taiwan + 健保
116.3.0.3.1 診斷
- 健保：CBC + Cr + Ca + albumin + LDH + β2M
- 健保：SPEP + IFE + serum FLC + 24-hr urine
- 健保：BMA + biopsy + 流式 + cytogenetics + FISH panel (del 17p, t(4;14), t(14;16), +1q, t(11;14))
- 健保條件：NGS panel
- 健保：WBLDCT for MM staging（取代 plain x-ray）
- 健保：MRI 必要 indication（spine cord compression, solitary plasmacytoma）
- 健保：PET-CT — 部分 indication
116.3.0.3.2 治療
- Bortezomib (Velcade / 學名 Bortezomib): 健保條件給付 frontline + R/R
- Lenalidomide (Revlimid): 健保條件給付 R/R + maintenance；frontline 條件給付逐步擴大
- Thalidomide: 健保條件給付（仍 used for some elderly cohorts）
- Pomalidomide (Imnovid): 健保條件給付 ≥ 2 prior lines
- Carfilzomib (Kyprolis): 健保條件給付 R/R
- Ixazomib (Ninlaro): 健保條件給付 R/R + maintenance
- Daratumumab (Darzalex SC): 健保條件給付 frontline transplant-ineligible (DRd, MAIA-based) + R/R 條件
- Isatuximab (Sarclisa): 健保條件給付 R/R combo
- Elotuzumab: 健保條件給付 R/R combo
- Belantamab mafodotin: 自費（眼毒監測）
- Selinexor (Xpovio): 自費
- Panobinostat: 條件給付（罕用）
- CAR-T (Cilta-cel / Ide-cel): 自費 (~ NT 1500 萬)；台大 / 林口長庚 / 北榮 / 中國醫等中心可執行
- Bispecific (teclistamab, elranatamab, talquetamab): 自費；多 IND / clinical trial available
- HSCT (auto / allo): 健保條件給付
116.3.0.3.3 在地分布特點
- MM 在台: 年發病率 ~ 3/100K（西方 6–7/100K）
- 亞裔 MM 特徵:
- t(11;14) 比例較高（亞洲 ~ 30%, 西方 ~ 15%）→ venetoclax 試驗 cohort 有意義
- Hyperdiploidy 比例較低
- Waldenström’s macroglobulinemia 在台少見（西方 4–6/百萬）
- POEMS syndrome 在亞洲（中、日、台）相對較常
- 學會：TSH（台灣血液學會）+ 台灣骨髓瘤工作小組 共識；NCCN / IMWG / EHA 為國際 reference
116.3.0.3.4 病人衛教重點（Taiwan）
- Bortezomib SC 改善 PN，可繼續長期治療
- Lenalidomide DVT prophylaxis（aspirin or DOAC）
- Pneumococcal conjugate vaccine > polysaccharide
- HSV/Zoster prophylaxis（acyclovir）during anti-CD38 / bortezomib
- CAR-T post-treatment: prolonged hypogamma → IVIg + 避活毒疫苗
- Anti-CD38 干擾 type-and-screen → 醫療警示牌 / 卡片（重要！）
- 腎功能: 避免 NSAID + 顯影劑 + 脫水
- 骨健康: 月一 zoledronate / denosumab + Ca + Vit D + 牙科 evaluate before bisphosphonate (ONJ risk)
116.3.0.4 🎓 內專必懂 (15)
- MGUS / SMM / MM / SP / WM / POEMS 鑑別診斷 + criteria
- IMWG 2014 MDE + R-ISS staging + Mayo SMM 2/20/20 model
- Cytogenetics + risk stratification + treatment selection based on FISH
- Frontline 4-drug induction trials: GRIFFIN, IsKia, GMMG-HD7 + Dara-VRd vs Isa-KRd choice
- DETERMINATION + ASCT timing decision + transplant-eligible criteria
- Maintenance therapy: lenalidomide vs ixazomib vs daratumumab + duration + 2nd cancer concern
- R/R sequencing: PI ↔︎ IMiD ↔︎ anti-CD38 ↔︎ cellular ↔︎ bispecific
- CAR-T (Ide-cel, Cilta-cel): trials, CRS/ICANS management, pre-CAR-T optimization
- Bispecific (teclistamab, elranatamab, talquetamab) + step-up dosing + infection prophy
- GPRC5D 與 BCMA 兩 target 比較 + sequence (post-BCMA → talquetamab data)
- Renal failure in MM: cast nephropathy + bortezomib-based reversal data + dialysis-dependent patient management
- Anti-CD38 干擾 lab tests + workaround (DTT, IFE, mass spec)
- Waldenström’s: MYD88 + CXCR4 mutational dependency on BTK inhibitor response (ASPEN trial)
- POEMS / Castleman’s overlap + VEGF mechanism + IL-6 in Castleman’s
- MM survivorship: 心血管 / 第二癌症 (lenalidomide t-MN) / bone health / fertility / quality of life
116.3.0.5 🔬 進階機轉 / 試驗
116.3.0.5.1 Frontline trials timeline
| 年 | 試驗 | 結論 |
|---|---|---|
| 2008 | VAD vs MP | VAD 較深 response |
| 2017 | Cassiopeia | Dara-VTd > VTd induction transplant-eligible |
| 2020 GRIFFIN | Dara-VRd vs VRd transplant-eligible | Dara-VRd 較深 response, MRD− ↑ |
| 2019 MAIA | DRd vs Rd transplant-ineligible | DRd PFS > 60 mo, OS benefit |
| 2022 DETERMINATION | VRd ± ASCT | ASCT PFS 67 vs 46 mo, OS 同 |
| 2023 IsKia | Isa-KRd | High MRD− rate transplant-eligible |
| 2024 GMMG-HD7 | Isa-VRd | Confirm Isa-based 4-drug |
116.3.0.5.2 R/R trials
| 試驗 | Regimen | 結論 |
|---|---|---|
| POLLUX | DRd vs Rd | DRd > |
| CASTOR | DVd vs Vd | DVd > |
| CANDOR | DKd vs Kd | DKd > |
| APOLLO | DPd vs Pd | DPd > |
| CARTITUDE-1 | Cilta-cel R/R | ORR 98%, CR 82% (heavily pretreated) |
| CARTITUDE-4 | Cilta-cel ≥ 2 lines | Cilta-cel > standard regimens (PVd / DPd) |
| KarMMa-3 | Ide-cel ≥ 2 lines | Ide-cel > standard |
| MajesTEC-1 | Teclistamab ≥ 4 lines | ORR 63% |
| MagnetisMM-3 | Elranatamab | ORR 61% |
| MonumenTAL-1 | Talquetamab GPRC5D | ORR 70% |
| DREAMM-7 | Belamaf + Vd | Eye AE; vs DVd +/- |
116.3.0.5.3 MRD assessment
| Method | Sensitivity | Notes |
|---|---|---|
| Conventional flow (4-color) | 10⁻³ | Outdated |
| NGF (next-gen flow, EuroFlow 8-color) | 10⁻⁵ – 10⁻⁶ | Standardized |
| NGS (clonoSEQ) | 10⁻⁵ – 10⁻⁶ | FDA approved |
| Imaging (PET-CT) | Functional MRD | Complementary to marrow MRD |
→ MRD− at 10⁻⁵ 是 strong predictor of long PFS + OS；sustained MRD− 更強
116.3.0.5.4 WM trials
| 試驗 | Regimen | 結論 |
|---|---|---|
| iNNOVATE | Ibrutinib + R vs placebo + R | Ibrutinib + R PFS > |
| ASPEN | Zanubrutinib vs ibrutinib | Zanu noninferior PFS, less AF / hypertension / bleeding, wt CXCR4 better response |
| iLLUMINATE | Acalabrutinib | Single arm, ORR > 90% |
116.3.0.5.5 22E new drugs in pipeline
- Mezigdomide (CELMoD): cereblon-modulating, more potent than IMiD
- Iberdomide: next-gen IMiD
- Cevostamab (FcRH5 × CD3): third bispecific target
- GPRC5D ADC + various combinations
- Allogeneic CAR-T: avoid leukapheresis + waiting time
- Dual-target CAR-T (BCMA + GPRC5D): avoid antigen escape
- CAR-NK: lower toxicity
116.3.0.6 ⚠️ 內專易錯點
- 不查 24-hr urine + FLC → 漏 light chain only myeloma
- plain x-ray skeletal survey 取代 WBLDCT → 漏 lytic lesions（敏感度 30%）
- CRAB 缺一就排除 MM → MDE 也算
- Lenalidomide 不 DVT prophy → VTE rate ↑↑
- Bortezomib IV 而非 SC → ↑ PN
- Bortezomib + 抗 CD38 不給 acyclovir → zoster reactivation
- Anti-CD38 不警告 type-and-screen 干擾 → 急輸血困難
- t(11;14) 病人不考慮 venetoclax（在 R/R 場景特別敏感）
- High-risk SMM 仍 W&W → 早期介入可延緩進展（CENTAURUS, ASCENT）
- 腎不全 MM 用 lenalidomide 不 dose adjust → toxicity ↑
- Cast nephropathy 不立即 bortezomib-based → 失去 reverse 機會
- WM 高 IgM 直接給 rituximab → IgM flare
- WM CXCR4 mutated 病人選 ibrutinib alone → 反應差，應 + chemo
- POEMS 直接化療不評估 sclerotic 局部 RT → 失去 RT 治療機會
- CAR-T post-treatment 不警告 prolonged hypogamma → 反覆感染未補 IVIg
- Bispecific step-up dosing 不嚴守 → CRS 嚴重
- Belantamab mafodotin 不眼科 baseline + monitoring → keratopathy 漏監測
- BCMA-targeting 連續使用未間隔 → BCMA escape；應考慮 GPRC5D 換 target
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