Approaches for Relapsed & Refractory Multiple Myeloma Robert Z. Orlowski, M.D., Ph.D. Florence Maude Thomas Cancer Research Professor Chair, ad interim , Department of Lymphoma/Myeloma Chair, SWOG Myeloma Committee Principal Investigator, LLS SCOR in High-risk Plasma Cell Dyscrasias Twitter handle: @Myeloma_Doc Zinc Co de : E M/ I XZ/ 1218/ 0032 Da te o f Pre pa ra tio n: No ve mb e r 2018
Definition of Relapsed/Refractory • Progression on therapy in patients who achieve minor response (MR) or better, or who progress within 60 days of their last therapy. • Patients who never achieve at least an MR to initial induction therapy and progress while on therapy are de fi ned as “ primary refractory. ” Rajkumar, SV et al. Blood 117: 4691, 2011. Zinc Co de : E M/ I XZ/ 1218/ 0032
Options for Relapsed/Refractory Disease NCCN Guidelines V 2.2019; www.nccn.org Zinc Co de : E M/ I XZ/ 1218/ 0032
APEX (1-3 Priors) : Bortezomib vs. Dex 1.0 78% improvement in median time-to-progression 0.9 0.8 Proportion of patients Median TTP All Pts Post-1st relapse 0.7 6.2 mos 7.0 mos Bortezomib 0.6 3.5 mos 5.6 mos Dexamethasone 0.5 0.4 P = .0001 0.3 Bortezomib 0.2 Dexamethasone 0.1 0.0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 Time (days) Richardson, PG et al. N Engl J Med. 352:2487, 2005. Zinc Co de : E M/ I XZ/ 1218/ 0032
DOXIL-MMY- 3001 : (≥1 Priors) 100 Percent of Patients Progression-Free PLD + Bortezomib 80 9.3 months 60 Bortezomib 40 6.5 months Statistical analysis: 20 HR (95% CI) 1.82 (1.41-2.35) p = 0.000004 0 0 100 200 300 400 500 Orlowski, RZ et al. J Clin Oncol. 25:3892, 2007. Zinc Co de : E M/ I XZ/ 1218/ 0032
Len/Dex vs. Dex (≥1 Priors) Weber, DM et al. N. Engl. J. Med. 357:2133, 2007. Zinc Co de : E M/ I XZ/ 1218/ 0032
PANORAMA (≥2 Priors) : PFS • Clinically relevant increase in PFS of 3.9 months San Miguel, JF et al. Lancet Oncol. 15:1195, 2014. Zinc Co de : E M/ I XZ/ 1218/ 0032
Carfilzomib (≥2 Priors) • Results from PX-171- 003-A1 study of carfilzomib in patients with relapsed and refractory myeloma • ORR of 23.7% Siegel, DS et al. Blood 120:2817, 2012. Zinc Co de : E M/ I XZ/ 1218/ 0032
ASPIRE (1-3 Priors) : Response Rates Stewart, AK et al. N Engl J Med. 372:142, 2015. Zinc Co de : E M/ I XZ/ 1218/ 0032
Pomalidomide (≥2 Priors) Richardson, PG et al. Blood 123:1826, 2014. Zinc Co de : E M/ I XZ/ 1218/ 0032
ENDEAVOR (1-3 Priors) : PFS by ITT Dimopoulos, MA et al. Lancet Oncol. 17:27, 2016. Zinc Co de : E M/ I XZ/ 1218/ 0032
TOURMALINE1 (≥1 Priors) : Key Data Moreau, P et al. N Engl J Med. 374:1621, 2016. Zinc Co de : E M/ I XZ/ 1218/ 0032
Safety Profile Moreau, P et al. N Engl J Med. 374:1621, 2016. Zinc Co de : E M/ I XZ/ 1218/ 0032
Impact on High-risk Patients Avet-Loiseau, H et al. Blood 130: 2610, 2017. Zinc Co de : E M/ I XZ/ 1218/ 0032
SIRIUS (≥3 Priors) : Response Data Lonial, S et al. Lancet 387:1551, 2016. Zinc Co de : E M/ I XZ/ 1218/ 0032
Daratumumab + Bortez/Dex (≥1 Priors) Palumbo, A et al. N Engl J Med. 375:754, 2016. Zinc Co de : E M/ I XZ/ 1218/ 0032
Daratumumab + Len/Dex (≥1 Priors) Dimopoulos, MA et al. N Engl J Med. 375 :1319, 2016. Zinc Co de : E M/ I XZ/ 1218/ 0032
ELOQUENT2 (1-3 Priors) : PFS Curves Lonial, S et al. N Engl J Med. 373:621, 2015. Zinc Co de : E M/ I XZ/ 1218/ 0032
Daratumumab/ Pomalidomide/ Dexamethasone (≥2 Priors) • ORR was 58% in double refractory patients Chari, A et al. Blood 130:974, 2017. Zinc Co de : E M/ I XZ/ 1218/ 0032
ARROW Trial (2 or 3 Priors) Mateos, MV et al. 2018 ASCO Abstract # 8000. Zinc Co de : E M/ I XZ/ 1218/ 0032
PFS Data Mateos, MV et al. 2018 ASCO Abstract # 8000. Zinc Co de : E M/ I XZ/ 1218/ 0032
Selected AEs Mateos, MV et al. 2018 ASCO Abstract # 8000. Zinc Co de : E M/ I XZ/ 1218/ 0032
OPTIMISMM Trial (1-3 Priors) Richardson, P et al. 2018 ASCO Abstract # 8001. Zinc Co de : E M/ I XZ/ 1218/ 0032
PFS Data Richardson, P et al. 2018 ASCO Abstract # 8001. Zinc Co de : E M/ I XZ/ 1218/ 0032
Selected AEs Richardson, P et al. 2018 ASCO Abstract # 8001. Zinc Co de : E M/ I XZ/ 1218/ 0032
Elotuzumab/Pomalidomide/dex 10.3 months 4.7 months Richardson, P et al. 2018 ASCO Abstract # 8001. Zinc Co de : E M/ I XZ/ 1218/ 0032
Other Approaches • CAR T-cells – bb2121, LCAR-B38M • Novel small molecules – Selinexor, venetoclax • Novel immunotherapies – Isatuximab, GSK2857916, BiTEs Zinc Co de : E M/ I XZ/ 1218/ 0032
Options Overview : Relapsed Kunacheewa C & Orlowski RZ. Annu Rev Med., 2019, in press. Zinc Co de : E M/ I XZ/ 1218/ 0032
Options : Bortez & Len Refractory Kunacheewa C & Orlowski RZ. Annu Rev Med., 2019, in press. Zinc Co de : E M/ I XZ/ 1218/ 0032
Options : Dual Refractory Kunacheewa C & Orlowski RZ. Annu Rev Med., 2019, in press. Zinc Co de : E M/ I XZ/ 1218/ 0032
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