Disclosures for Palumbo Antonio, MD Research Support/P.I. No relevant conflicts of interest to declare Employee No relevant conflicts of interest to declare Amgen, Bristol-Myers Squibb, Celgene, Janssen, Consultant Millenium, Onyx Major Stockholder No relevant conflicts of interest to declare No relevant conflicts of interest to declare Speakers Bureau Amgen, Bristol-Myers Squibb, Celgene, Janssen, Honoraria Millenium, Onyx No relevant conflicts of interest to declare Scientific Advisory Board Presentation includes discussion of the off-label use of a drug or drugs
Status of the art of treatment Antonio Palumbo, MD University of Torino Torino, Italy
Biological events Clinical Phase Normal Precursor Multiple Extramedullary Pregerminal B cells disease myeloma myeloma Primary IgH translocations Hyperdiploidy Cyclin D gene dysregulation Deletion of chromosome 13 NRAS mutation KRAS and FGFR3 mutations MYC up-regulation MYC rearrangement p18, p53 and Rb gene inactivation NDMM: 5286 substitutions RRMM: 12581 substitutions Korde N, et al. Blood. 2011;117: 5573-81.
Early or late intervention Increasing genetic and epigenetic abnormalities 1 Normal Precursor Multiple Extramedullary pre-germinal B cells disease myeloma myeloma Sensitive disease Resistant disease • 5-year PFS: 67% • Median PFS: 5 mo • 5-year OS: 73% • Median OS: 9 mo • 1 st Tx 100; - 2 nd Tx 60; - 3 rd Tx 35; - 4 th Tx 20; - 5 th Tx 10
Progenitors Cells - Antigen Escape CDxx?? CDxx?? CDxx
Early vs Late ASCT 791 patients PFS MEL200 High Risk CC Standard Risk Gay F. et al manuscript in preparation
Clonal evolution 1.00 1.00 Spontaneous clonal evolution 0.75 0.75 Patients (%) 0.50 0.50 0.25 0.25 Drug-related clonal evolution 0.00 0.00 0 0 5 5 10 10 15 15 20 20 25 25 Time
Continuous vs Fix duration Meta-analysis of 3 studies: 1218 patients 1-year Landmark analysis N= 1218 PFS2 PFS1 O P P Ind. Maintenance Ind. Maintenance S F F Median Median S S 100 100 CT 32 mos CT 55 mos FDT 16 mos FDT 40 mos 2 1 75 75 % of patients 50 50 N= 687 25 25 2 nd P F HR 0.61, 95% CI 0.50-0.75, P <.001 HR 0.47, 95% CI 0.40-0.56, P <.001 0 S 0 0 12 24 36 48 60 0 12 24 36 48 60 Months Months CT, continuous therapy; FDT, fixed duration of therapy; PFS, progression-free survival; mos, months. Palumbo A, et al. JCO 2015 in Press
Maintenance vs no Maintenance in 1964 CR patients Progression-free survial 12-months landmark analysis • • Young patients treated with ASCT Young patients treated with CC 1.00 1.00 Probability 0.75 Probability 0.75 Maint Maint 0.50 0.50 No maint No maint 0.25 0.25 No maint No maint P 0.02 P < 0.001 P < 0.001 HR 0.22 HR 0.19 HR 0.19 0.00 0.00 0 10 20 30 40 50 0 10 20 30 40 50 Months Months Months MEDIAN PFS: NA vs 13.2 months MEDIAN PFS: NA vs 30.8 months Cerrato C et al AH 2015
Tumor load during maintenance according to mainteneance (no relapsed patients included) Absolute PC in maint in CRD (no relapsed pz) (assessed by flow cytometry) 10000 1000 100 PC/uL 10 1 0.1 s e e e e e i c c c c c s n n n n n o a a a a a n n n n n n g e e e e e a t t t t t n n n i n i D a i i i i a a a a m m m m m 8 - 3 6 2 1 e + r + + 1 p +
Complete Response
MRD sensitivity 1 10 -1 Serum tools 10 -2 10 -3 Immunophenotype 10 -4 RQ- PCR 10 -5 NEXT-GENERATION SEQUENCE 10 -6 10 -7 “cure” 0 1 2 3 4 5
MRD: bone marrow only? NO • CT/PET positive in 29% of CR patients PFS: VRD vs MEL200 negative PET-CT and MRD (47.7% of patients) • PET/CT sensitivity of 50.0 % specificity of 85.7 %, 89.6% overall accuracy of 74.2 %. p = 0.02 54.5% • MRI sensitivity of 80.0 %, specificity of 38.1 %, overall accuracy of 51.6 %. Moreau et al – ASH2015 Zamagni E. et al, Clin Cancer Res. 2015;21(19):4384
Young patients
Three Drug Regimens Induction regimen Schedule 28-day cycles Bortezomib-Cylophosphamide- Bor: 1.3 mg/m 2 d 1-4-8-11 Cycl: 300 mg/m 2 d 1-8-15-(22) Dexamethasone 2 Dex: 40 mg d 1, 8, 15, 22 28-day cycles Bortezomib-Doxorubicin- Bor: 1.3 mg/m 2 d 1-4-8-11 Dox: 9 mg/m2 d 1-4 Dexamethasone 3 Dex. 40 mg d 1, 8, 15, 22 21-day cycles Bortezomib-Thalidomide- Bor: 1.3 mg/m 2 d 1-4-8-11 Dexamethasone 4 Thal: 100 - 200 mg/d Dex: 40 mg, d 1-4, 9-12 28-day cycles Bortezomib-Lenalidomide- Bor: 1.3 or 1 mg/m 2 d 1-4-8-11 Dexamethasone 5 Len: 15 or 25 mg d 1-21 Dex: 40 mg d 1, 8, 15, 22 2 Khan ML, et al. Br J Haematol. 2012;156(3):326-333; 3 Sonneveld P, et al. J Clin Oncol. 2012;30(24):2946-5295; 4 Cavo M, et al. Lancet. 2010;376(9758):2075-2085; 5 Richardson PG, et al. Blood 2010; 116(5):679-686.
Consolidation Improves Response before after VTD 1 CR: 15% 49% before after TD 2 CR: 40% 47% before after VTD 2 CR: 49% 61% before after V:Bortezomib V 3 (n)CR: 20% 45% T:Thalidomide D:Dexamethasone before after R:Lenalidomide VTD 4 CR: 33% 52% before after 1 1 2 3 R 5 ≥VGPR : 58% 69% 0 10 20 30 40 50 60 70 80 Percentage 1 Ladetto M, et al. J Clin Oncol. 2010;28(12):2077-2084. 2 Cavo M, et al. Blood. 2012;120(1):9-19. 3. Mellqvist UH, et al. Blood. 2013;121(23):4647-4651; 4. Leleu X, et al. Leukemia. 2013;27(11):2242-2244 5 Attal M, et al. N Eng J Med 2012;366(19):1782-1791
Sequential treatment T R C A O M VRD N N A VCD R S MEL200 S I Four 28-day Four 21-day courses P O N course Two courses L L Maintenance T V: 1.3 mg/m 2 d M: 200 mg/m 2 A I E V: 1.3g/m 2 , d 1,4,8,11 L: 10 mg/day on 1,4,8,11 N D day -2 N C: 500 mg/m 2 , d 1,8 days 1-21 R: 25 mg/day, d 1- T A A Stem cell D: 40 mg, d 1,4,8,11 A T 21 N support day 0 T I C D: 40 mg, d I O E 1,4,8,11 O N N V, bortezomib; C, cyclophosphamide; D, dexamethasone; MEL200, melphalan 200 mg/m 2 ; R, lenalidomide
Italian KRd study design Study Schema: Induction (4 cycles) Consolidation (4 cycles) Maintenance One cycle = 28 days One cycle = 28 days One cycle = 28 days Arm A: CRd Arm A: CRd • • Carfilzomib 36 mg/m2 IV Days 1, 2, 8, 9, Carfilzomib 36 mg/m2 IV Days 1, 2, 8, 9, 15, 15, 16 16 • • Lenalidomide 25mg/day Days 1 - 21 Lenalidomide 25mg/day Days 1 - 21 • • Dexamethasone 20mg PO Days 1, 2, 8, 9, A Dexamethasone 20mg PO Days 1, 2, 8, 9, Newly diagnosed Lenalidomide 15, 16, 22, 23 15, 16, 22, 23 10mg Days 1- multiple myeloma S 21 patients eligible for C autologous Arm B: CCyd Arm B: CCyd transplantation T • • Carfilzomib 20/36 mg/m2 IV Days 1, 2, 8, Carfilzomib 36 mg/m2 IV Days 1, 2, 8, 9, (ASCT) 9, 15, 16 15, 16 To Progression or R • • R Cyclophosphamide 300mg/m2 Days 1, 8, Cyclophosphamide 300mg/m2 Days 1, 8, N= 425 Intolerance 15 15 • • Dexamethasone 20mg PO Days 1, 2, 8, 9, Dexamethasone 20mg PO Days 1, 2, 8, 9, Endpoints: 15, 16, 22, 23 15, 16, 22, 23 Lenalidomide • Primary: VGPR 10mg Days 1- • Secondary: ORR, 21 DoR, TTNT, OS, Carfilzomib 27 MRD mg/m2 IV Arm C: CRd Days 1, 2, 15, • Carfilzomib 36 mg/m2 IV Days 1, 2, 8, 9, 15, 16 Total 12 Cycles 16 • Lenalidomide 25mg/day Days 1 - 21 • Dexamethasone 20mg PO Days 1, 2, 8, 9, 15, 16, 22, 23 MRD (M0) MRD (M4) MRD (M12) MRD (q6Mo)
Daratumumab trial in transplant eligible NDMM Hovon/IFM Stratify by: dara treatment, response, MRD status MaintenanceUntil Induction Consolidation progression 4 cycles 2 cycles VTD + VTD + Dara Dara Dara HDM R R ASCT VTD VTD Observation Endpoints: • sCR Courtesy P Sonneveld • PFS, OS
Elderly patients
VMP (Bortezomib/Melphalan/Prednisone) Current Standard of Care ~52% reduced risk of progression ~36% reduced risk of death 100 100 VMP 90 Percentage of Subjects Without Event 90 VMP MP Percentage of Patients Without Event 80 80 MP 70 70 60 60 50 50 40 40 30 30 Median follow-up 25.9 months 20 20 Median OS not reached Median TTP VMP: 3-year OS rate = 72% 10 VMP: 24.0 months (83 events) 10 MP: 3-year OS rate = 59% MP: 16.6 months (146 events) 0 HR = 0.644, P = .0032 HR=0.483, P < .000001 0 0 3 6 9 12 15 18 21 24 27 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 Time (Months) Time (Months) San Miguel JF, et al. ASH 2008. Abstract 650.
22 FIRST Trial: TTP and Time to 2 nd Anti-myeloma Therapy Time to Progression Time to 2 nd AMT Median Time to Median TTP 2 nd AMT Rd (n=535) 32.5 mos Rd (n=535) 39.1 mos 100 Rd18 (n=541) 21.9 mos 100 Rd18 (n=541) 28.5 mos MPT (n=547) 23.9 mos MPT (n=547) 26.7 mos 80 80 Patients (%) Patients (%) 60 60 40 40 Hazard ratio Hazard ratio 20 20 Rd vs. MPT: 0.66; P <0.00001 Rd vs. MPT: 0.68; P =0.00001 Rd vs. Rd18: 0.62; P ≤0.00001 Rd vs. Rd18: 0.74; P =0.00067 Rd18 vs. MPT: 1.11; P =0.21718 Rd18 vs. MPT: 0.88; P =0.12333 0 0 0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60 TTP (months) Time to 2 nd AMT (months) Rd 535 398 318 263 218 167 105 55 19 2 0 Rd 535 445 371 319 275 224 142 77 28 3 0 Rd18 541 451 375 331 266 181 111 61 16 2 0 Rd18 541 389 317 265 167 108 56 30 7 2 0 MPT 547 379 303 242 169 115 58 28 6 1 0 MPT 547 422 351 293 239 177 101 42 9 1 0 Facon T, et al. Blood. 2013;122:abstract 2.
VRd vs Rd in NDMM Durie et al ASH 2015
Salvage therapy
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