Multiple Myeloma 9th Annual Living with Myeloma Conference 25 Years of Progress in Myeloma Therapy Scottsdale, AZ March 21, 2015 Robert A. Kyle, MD Mayo Clinic, Rochester, MN Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida CP1123175-1 Disclosures for Robert A. Kyle Johnson & Johnson Disease Monitoring Committee Celgene Disease Monitoring Committees Novartis Disease Monitoring Boards Merck Data Monitoring Committee Bristol-Myers Squibb Independent Monitoring Committee Aeterna Zentaris (Keryx) Data & Safety Monitoring Board Onyx Data Monitoring Committee Binding Site Honoraria Pharmacyclics Data Safety Monitoring Board Treatment of Multiple Myeloma L-sarcolysin (L-phenylalanine mustard) (Melphalan) (Alkeran) Blokhin et al, 1958 Bersagel et al, 1962 Multiple Myeloma Single (M/P) vs Combination Chemotherapy (CCT) n=4,930 (20 trials) Therapy Response (%) M/P 53 CCT 60 P<0.00001 No difference in survival No subsets with benefit CP1123175-33 Autologous Stem Cell Transplant • Plasma cell leukemia • Melphalan 140 mg/m2 IV with good response • Collected stem cells • Relapsed and given Melphalan 140 mg/m2 IV plus stem cells • Treated 8 myeloma patients McElwain TJ, Powles RL. Lancet 1983 Oct 8;2(8354):822-4. Novel Agents • Thalidomide • Bortezomib (Velcade) • Lenalidomide (Revlimid) mSMART 2.0: Classification of Active MM High-Risk  FISHc  Del 17p  t(14;16)  t(14;20)  GEP High risk signature Intermediate-Riska  FISH  t(4;14)d  1q gain  Complex karyotype  Metaphase Deletion 13 or hypodiploidy Standard-Riska,b All others including:  Trisomies  t(11;14)e  t(6;14)  High PC S-phasef a Note that a subset of patients with these factors will be classified as high-risk by GEP b LDH >ULN and beta-2 M > 5.5 may indicate worse prognosis; cTrisomies may ameliorate d Prognosis is worse when associated with high beta-2 M and anemia e t(11;14) may be associated with plasma cell leukemia; f Cut-offs vary Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin Proc 2013;88:360-376. v12 //last reviewed March 2014 Multiple Myeloma Autologous Transplant Eligibility • Diagnosis of Multiple Myeloma with CRAB • Age (physiologic) < 70 • Performance status (0-2) • Bilirubin ≤ 2.0 mg/dL, creatinine ≤ 2.5 mg/dL & New York Heart Class I or II • Adequate stem cells • Concomitant diseases (heart, stroke, etc.) mSMART – Off-Study Transplant Eligible Standard-Risk Intermediate-Risk High-Risk Trisomies only t 11;14, t 6;14, Trisomies + IgH t 4;14 4 cycles of Rda 4 cycles CyBorD 4 cycles of CyBorD 4 cycles of VRd Autologous stem cell transplant Autologous stem cell transplant, especially if not in CR Del 17p, t14;16, t14;20 Collect Stem Cellsb Autologous stem cell transplant Continue c Rd 2 cycles of Rd consolidation; then Len maintenance if not in VGPR but Len responsive* Bor based therapy for minimum of 1 year a Bortezomib containing regimens preferred in renal failure or if rapid response b If age >65 or > 4 cycles of Rd Consider G-CSF plus cytoxan or plerixafor Bor or CyBorD for minimum of 1 year needed c Continuing Rd for patients responding to Rd and with low toxicities; Dex is usually discontinued after first year * Consider risks and benefits; If used, consider limited duration 12-24 months Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin Proc 2013;88:360-376. v12 //last reviewed March 2014 Multiple Myeloma Is maintenance therapy necessary after autologous stem cell transplant (high dose therapy)? Treatment of Multiple Myeloma Transplant Eligible < 65 years N=273 Induction (4 mos) N=399 Lenalidomide 25 mg days 1-21 plus dex 40, day 1, 8, 15, 22 Consolidation N=273 PFS mos OS 4 yr % Transplant vs MPR (6 mos) 43 82 22 65 P = < 0.001 P=0.02 Palumbo et al., NEJM 371:895, 2014 Treatment of Multiple Myeloma Maintenance After Transplant N=141 Maintenance (Revlimid) No maintenance PFS* mos OS** 3 yr % 42 88 22 79 *P = < 0.001 **P = 0.14 Palumbo et al., NEJM 371: 895, 2014 mSMART – Off-Study Transplant Ineligible Standard-Risk Intermediate-Risk High-Risk Trisomies only t 11;14, t 6;14, Trisomies + IgH t 4;14 Del 17p, t14;16, t14;20 Rd a, b Weekly CyBorD for ~12 months c Weekly CyBorD for ~12 months c VRd* for ~12 months Until progression d Followed by observation Bor-based therapy maintenance for minimum of 1 year Bor as maintenance for minimum of 1 year a In patients treated with Rd, continuing treatment is an option for patients responding well with low toxicities; Dex is usually discontinued after first year b Bortezomib containing regimens preferred in renal failure or if rapid response needed c CyBorD is considered a less toxic variation of VMP; VMP can be used as alternative d Continuing Rd for patients responding to Rd and with low toxicities; Dex is usually discontinued after first year *Clinical trials strongly recommended as the first option Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin Proc 2013;88:360-376. v12 //last reviewed March 2014 Multiple Myeloma Transplant Ineligible Maintenance Therapy MM015 N=459 PFS MOS OS 3 yr % Second Primary malignancies % MPR-R 31 70 7 MPR (9 mos) 14 62 7 MP (9 mos) 13 66 3 Palumbo et al., N. Engl. J Med 366:1759, 2012 Treatment of Multiple Myeloma Newly Diagnosed and > age 65 MM-015 N=459 MPR-R MPR MP MPR-R vs MPR MPR-R vs MP PFS2 mos OS mos 40 54 52 55 29 HR .78 HR .70 Dimopoulos M. A., et al., Blood (ASH Annual Meeting Abstracts): 2013:122(21): Abstract 405 Multiple Myeloma Transplant Ineligible 020 N=1623 PFS Mos OS 4 yrs % MPR-R 25.5 59 MPR (18 mos) MPT (18 mos) 20.7 21.2 56 51 Benboubker L. , Facon T., et al., NEJM 371:906, 2014. Multiple Myeloma Novel Agents Pomalidomide (Pomalyst) CC-4047 Carfilzomib (Kyprolis) PR-171 Patients Refractory to LEN, and LEN + BORT Best Overall Response LEN and BORT refractory* POM (n = 64) POM + LoDEX (n = 69) ORR (≥ PR) % 16 30 CR % 2 0 VGPR 2 6 PR % 14 30 Median time to response, months 2.0 1.8 Median duration of response, months 8.3 6.5 *Refractory defined as progression while on the last LEN- or BORT containing regimen, or within 60 days after the last dose of that therapy Richardson et al., ASH 2011 Treatment of Multiple Myeloma MM-003 – Rel/Ref N=455 Pom + Dex vs 302 ≥ PR % 31 Hi-Dex 153 10 N PFS mos 4.0 OS mos 13 1.9 8 San Miguel J. F., et al., Blood (ASH Annual Meeting Abstracts): 2013:122(21): Abstract 686 Carfilzomib Bortezomib-naïve Cohort 1 20 mg/m2 (n=59) Cohort 2 20/27 mg/m2 Bortezomib-naïve (n=67)* % % CR 3 2 VGPR 14 27 PR 25 24 42 52 12 16 Best Response ORR (CR+VGPR+PR) PD *3 patients were not included as they did not have either baseline or post-baseline assessment. Vij et al., ASH 2011 Treatment of Relapsed Multiple Myeloma Carfilzomib, lenalidomide and dexamethasone N=792 ≥ PR CR 26.3 2 year survival % 73 87 32 17.6 65 67 9 PFS (mos) Carfilzomib Plus Lenalidomide Plus Dex vs Lenalidomide Plus Dex Stewart AK et al., NEJM 372:142, 2015 Multiple Myeloma Novel Agents Monoclonal Antibodies (Daratumumab, SAR 650984) Proteosome inhibitor (oral/IV) MLN-9708 (Ixazomib) Proteosome inhibitor (oral) NPI-0052 Elotuzumab Bendamustine Histone deacetylase inhibitor Vorinostat (SAHA) Histone deacetylase inhibitor Panobinostat Measles Virotherapy Treatment of Multiple Myeloma Relapsed and/or Refractory N=20 Daratumumab plus Lenalidomide plus Dexamethasone ≥ PR % ≥ VGPR % 75 40 Plesner T. et al., Blood 124: #84, 2014 Treatment of Multiple Myeloma Relapsed/Refractory N=31 SAR 650984 Plus Lenalidomide Plus Dexamethasone ≥ PR % ≥ VGPR % CR % 65 26 26 Martin III TG, Blood 124, #83, 2014 Treatment of Multiple Myeloma Untreated Ixazomib Maintenance N=50 Ixazomib d. 1, 8, 15 Plus Lenalidomide d. 121 Plus Dexamethasone d. 1, 8, 15 Ixazomib d. 1, 8, 15 q. 28 d. (maintenance) N=21 ≥ PR % ≥ VGPR % 90 59 71% CR % 52% Kumar S et al., Blood 124, #82, 2014 Treatment of Multiple Myeloma Untreated N=65 Ixazomib (MLN9708) Ixazomib d 1, 8, 15 Plus Lenalidomide d 1-21 Plus Dexamethasone d 1, 8, 15, 22 ≥ PR ≥ VGPR 1 yr OS 92% 58% 94% Kumar SK, et al., Lancet Oncol 15:1503, 2014 [email protected]