Ohio State's ASH Review 2017 - Update in Myeloma
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The document reviews advancements in multiple myeloma treatment, highlighting recent data on approved therapies such as daratumumab and the role of stem cell transplantation. It also discusses investigational agents like venetoclax, nelfinavir, and selinexor, presenting clinical trial findings and their implications for practice guidelines. Key takeaways include evidence supporting the efficacy of daratumumab combinations and updated treatment protocols for various risk profiles in myeloma patients.
Ohio State's ASH Review 2017 - Update in Myeloma
- 2. Objectives • 1. Review new data with approved therapies • Daratumumab • Role of stem cell transplantation • 2. Review data on investigational agents • Venatoclax • Nelfinavir • Selinexor • 3. Integrate new evidence to practice guidelines
- 3. Daratumumab Demographics POLLUX (n=569) Len/dex ± dara CASTOR (n=498) Bort/dex ± dara Patient information: Median age (years) 65 64 ISS stage 3 (%) 20 22 High risk cyto/FISH (%) 20 27 Treatment history: 1 prior line (%) 52 47 > 3 prior lines (%) 6 10 ‐ Prior SCT (%) 63 61 ‐ Prior PI & IMID 44 50 ‐ Refractory to IMID (%) n/a 33 ‐ Refractory to bortezomib (%) 21 n/a POLLUX New Eng J Med 2016; 375: 1319‐31 & CASTOR New Eng J Med 2016; 375: 754‐66
- 8. Daratumumab Abstract 489 POLLUX (New Eng J Med 2016; 375: 1319‐31) ‐ len / dex vs. len / dex / daratumumab ‐ 1‐3 prior lines lenalidomide‐naïve results (n=219 v 226) Outcome Len/dex + dara p value PFS (mo) 18.4 N/R < 0.0001 1‐yr PFS (%) 59 83 ORR (%) 79 96 < 0.0001 ≥ VGPR (%) 47 76 < 0.0001 ≥ CR (%) 21 44 < 0.0001 Prior lenalidomide results (n=45 v 46) Outcome Len/dex + dara p value PFS (mo) N/R N/R 1‐yr PFS (%) 63 81 ORR (%) 71 87 0.0729 ≥ VGPR (%) 38 78 0.0001 ≥ CR (%) 12 44 0.0011 bortezomib‐naïve results (n=45 v 44) Outcome Len/dex + dara p value PFS (mo) 15.8 N/R 0.017 1‐yr PFS (%) 69.2 85.4 ORR (%) 82 98 0.0158 ≥ VGPR (%) 55 74 0.0544 ≥ CR (%) 23 42 0.0576 Bortezomib‐refractory results (n=49 v 54) Outcome Len/dex + dara p value PFS (mo) 10.3 N/R 0.0117 1‐yr PFS (%) 44.4 70.8 ORR (%) 68 92 0.0024 ≥ VGPR (%) 36 75 0.0001 ≥ CR (%) 13 46 0.0003
- 9. Daratumumab Abstract 1149 “PAVO”: Phase 1b study of SQ daratumumab with rHuPH20 ‐ co‐formulate approved in Europe for trastuzumab and rituximab • Eligibility: – ≥ 3 prior lines • PI & IMID • 1200mg (n=8) – In 60mL / 20min • 1800mg (n=45) – In 90mL / 30 min TEAE 1200mg 1800mg AE profile of DARA‐PH20 consistent with IV daratumumab Any drug‐related (%) 63 62 Anemia (%) 13 13 Low platelets (%) 13 7 Neutropenia (%) 13 7 Hypertension (%) 25 4 Fatigue (%) 25 2 Device‐related infection (%) 0 4 Infusion related (%) 13 24 (all Gr 1 or 2)
- 10. Daratumumab Abstract 1149 “PAVO”: Phase 1b study of SQ daratumumab with rHuPH20 ‐ co‐formulate approved in Europe for trastuzumab and rituximab
- 11. STaMINA trial Abstract LBA‐1 Melphalan autoSCT Len maintenance VRD x 4 cycles Len maintenance Mel autoSCT Len maintenancen=754: ‐ SOC n = 257 ‐ VRD n = 254 ‐ tandem n= 247 High risk cyto/FISH = 24%
- 12. STaMINA trial Abstract LBA‐1 Melphalan autoSCT Len maintenance VRD x 4 cycles Len maintenance Mel autoSCT Len maintenancen=754: ‐ SOC n = 257 ‐ VRD n = 254 ‐ tandem n= 247 High risk cyto/FISH = 24% Adherence: 95% Adherence: 88% Adherence: 68%
- 13. STaMINA trial Abstract LBA‐1 Melphalan autoSCT Len maintenance VRD x 4 cycles Len maintenance Mel autoSCT Len maintenancen=754: ‐ SOC n = 257 ‐ VRD n = 254 ‐ tandem n= 247 High risk cyto/FISH = 24% PFS (%) HR PFS OS SPM 52 40 83 4 PFS (%) HR PFS OS SPM 56 38 82 5.9 All p‐values = n/s PFS (%) HR PFS OS SPM 57 48 86 6 Median follow up 38 months
- 14. Investigational agents • Venetoclax • Nelfinavir • Selinexor
- 15. Venetoclax Abstract 488 Patients N=66 Cytogenetics/FISH (n): ‐ t(11;14) ‐ Other: t(4;14), del17p, del13q 30 36 Prior lines: median (range) 5 (1‐15) Prior SCT (%) 75 Bort and len refractory (%) 61 Refractory to last line (%) 79
- 18. Nelfinavir
- 19. Nelfinavir – SAKK 39/13 trial Patient population (n=34) Age, med 67 (42‐82) Prior therapy, med 5 (2‐10) Prior SCT (%) 76 Poor risk cyto (%) 38 Bort refractory (%) 100 Len refractory (%) 79 Pom refractory (%) 44 Abstract 487 Response rates: (%) Overall RR (≥ PR) 65 ‐ high risk FISH 77 ‐ bort + len refractory 70 ‐ bort + len + pom ref 60 A phase II study of Bort/Dex + Nelfinavir in Bort‐refractory myeloma
- 20. Selinexor • “STORM” trial: phase II of CRM1/XPO1 SINE – n=79 patients enrolled: • Quad‐refractory (len, pom, bort, carfil) n=48 • Penta‐refractory (quad + anti‐CD38) n=31 – Median prior lines of therapy = 7 – Baseline ≥ grade 3 anemia 13%, thrombocytopenia 8% – Common TRAE’s: cytopenias (21‐58%), GI (3‐5%), fatigue Abstract 491
- 21. Selinexor Abstract 491 Outcomes • Median OS = 9.3 months – Responders = N/R (> 11 months) – Non responders = 5.7 months • DOR 5 months • High risk FISH = 33% ORR – Responses observed despite: • Del17p, t(14;16), t (4;14)
- 22. Standard risk Intermediate risk High risk Trisomies t(4;14) del17p t(11;14) 1q gain t(14;16) t(6;14) t(14;20) All others GEP signature Updated practice guidelines
- 23. Standard risk Intermediate risk High risk Transplant ineligible VRD x ~ 12 months (len/dex if ≥ 75 / frail) VRD x ~ 12 months VRD x ~ 12 months Len/dex x 1 year or to progression Bortezomib maintenance x 1 year Bortezomib maintenance x 1 year Transplant eligible VRD x 4 cycles VRD x 4 cycles KRD x 4 cycles SCT Collect cells SCT SCT (tandem?) Len x at least 2 years Len/dex to progression Bortezomib maintenance x 2 years Bortezomib or Carfilzomib maintenance x 2 years First line
- 24. First relapse On maintenance Off therapy* Fit patient* Indolent relapse* or frail patient Fit patient* Indolent relapse* or frail patient Len: ‐ KPD ‐ Dara/bort/dex Bort: ‐ Dara/len/dex Len: ‐Dara/bort/dex ‐Ixa/cytox/dex Bort: ‐Dara/len/dex ‐Ixa/len/dex ‐ KRD ‐ Dara/len/dex ‐Ixa/len/dex ‐Elo/len/dex * SCT if not already performed; 2nd SCT if > 18 months PFS or > 36 months PFS
- 25. Second or later relapse No plasma cell leukemia / extramedullary disease Single refractory* Dual refractory* Triple refractory* Triple refractory* Refractory to IMID: ‐ Dara/bort/dex Refractory to PI: ‐ Dara/len/dex** Refractory to len and bort/ixa: ‐ KPD / KRD ‐ Pom‐based regimen + dara** Refractory to len, bort/ixa, carfil: ‐Pom‐based + dara** Refractory to len, pom, bort/ixa: ‐dara‐based** ‐Alkylator‐based ‐Bort/dex/pano * SCT if not already performed; 2nd SCT if > 18 months PFS or > 36 months PFS ** if daratumumab‐refractory, use elotuzumab Quadruple refractory (len, pom, bort/ixa, carfil) OR Secondary plasma cell leukemia / extramedullary disease VDT‐PACE x 2 cycles (or CVAD if older / poor PS) ‐‐‐‐ SCT (if candidate), other options include: dara‐based, pano‐ containing, alkylator combination, anthracycline combination
- 26. Summary • Daratumumab combinations • SCT len • On the radar: – Venetoclax for t(11;14) – Nelfinavir – Selinexor • Guideline updates: • VRD induction • Class switching at relapse • Daratumumab combinations