Improving Outcomes in Myeloma

Improving Outcomes in Myeloma
How many and in which order should we use novel agents? Antonio Palumbo, MD Myeloma Unit, Division of Haematology, University of Turin, Italy 45 m

Treatment strategies 2

Sensitive vs Resistant Disease
c Diagnosis 1° Relapse 2° Relapse 3° Relapse 30 months 15 months 7 months 3 months Single agent Single agent Single agent Combination regimen Thalidomide/Dexamethasone vs Dexamethasone: Patient Characteristics Among the patients who were evaluable for response, the 2 arms of the ECOG E1A00 study were well balanced with respect to clinical characteristics The median age of the patients randomized to each group was 65 years Rajkumar SV et al. J Clin Oncol. 2006;24:431 c Sensitive disease Resistant disease Low-risk SAE High-risk SAE

Combination Therapy vs Single Agent
2nd-line treatment 3rd-line treatment Combination therapy Progression 2nd-line treatment 3rd-line treatment 4th-line treatment Progression Single agent Combination could improve PFS only quality of life Combination could improve OS evidence needed

OLD Therapeutic Algorithm
Patients < 65 years Patients > 65 years Diagnosis Autologous transplant (high-dose melphalan) Oral melphalan (low-dose melphalan) 1° Relapse Dexamethasone 2° Relapse Doxorubicin 3° Relapse Cyclophosphamide Thalidomide/Dexamethasone vs Dexamethasone: Patient Characteristics Among the patients who were evaluable for response, the 2 arms of the ECOG E1A00 study were well balanced with respect to clinical characteristics The median age of the patients randomized to each group was 65 years Rajkumar SV et al. J Clin Oncol. 2006;24:431

NEW Therapeutic Algorithm
< 65 years years > 75 years Diagnosis Induction (VD-VCD-VTD) ASCT Mainenance (Len) Full-dose Combination MPV (MPT-Rd) Reduced-dose mpt-rd (mpv) 1° Relapse Bort- Dex Len-Dex Bort-Dex 2° Relapse 3° Relapse Carfilzomib Pomalidomide HADAC inhib Elontuzumab 4° Relapse Thal-Dex Thalidomide/Dexamethasone vs Dexamethasone: Patient Characteristics Among the patients who were evaluable for response, the 2 arms of the ECOG E1A00 study were well balanced with respect to clinical characteristics The median age of the patients randomized to each group was 65 years Rajkumar SV et al. J Clin Oncol. 2006;24:431 Bort-Dex  Bort-Dex-Cyclo (Doxo – Thal –Len) PFS > median expected time  repeat previous regimen Len-Dex  Len-Dex-Cyclo (Doxo – Thal –Len) PFS < median expected time  change previous regimen

Clinical Impact of VTD Consolidation in VGPR Patients After ASCT
Responses after ASCT VGPR 85% CR 15% Responses after VTD VGPR 49% CR 49% 15% 49% 49% 85% VGPR CR Ladetto M, et al. J Clin Oncol. 2010;28:

Complete Response are all the same?
Response Criteria Tumor gene copy number Diagnosis 25, ,000 PR 5,000 – 100,000 VGPR 1,500 – 20,000 Immunofixation-negative CR 1,000 – 10,000 Immunophenotypic CR* 10 – 100 Molecular CR^ 5 – 20 *Paiva et al Blood 2009: 114; ; ^Ladetto et al. J Clin Oncol ;28(12):

Clinical Impact of Minimal Residual Disease
PFS in PCR-negative patients months Ladetto M, et al. ASH Abstract 960. 9 9 9 9

Combinational therapy
Treatment strategy Continuous therapy Prolongs PFS Tumour burden The tumouricidal effect of lenalidomide results from disruption of stromal cell support1,the induction of tumour suppressor genes leading to cell cycle arrest2-5, and the activation of caspases which triggers tumour cell apoptosis2-5. Lenalidomide enhances the activation of immune cells6-8 and increases NK cell recognition and lysis of MM cells9-12. This immunomodulatory effect results in improved IgA levels13, enhanced humoral and cell mediated immune responses following vaccination14 References Hideshima T, Chauhan D, Podar K, et al. Novel therapies targeting the myeloma cell and its bone marrow microenvironment. Semin Oncol. 2001;28(6): Hideshima, T Chauhan D, Shima Y, et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood. 2000;96: Verhelle D, Corral LG, Wong K, et al. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer Res. 2007;67(2):746–55. Schafer PH, Gandhi AK, Zhang LJ, et al. Opposing effects of dexamethasone on lenalidomide activity in multiple myeloma. Clin Lymph & Myeloma. 2009;9(suppl 1): s122[abstractB444]. Mitsiades N, Mitsiades CS, Poulaki V, et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood. 2002;99: Reddy N, Hernandez-Ilizaliturri FJ, Deeb G, et al. Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo. Br J Haematol. 2007;140(1):36-45. Schafer PH, Gandhi AK, Loveland MA, et al. Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. J of Pharm and Exp Ther. 2003;305: Haslett PA, Hanekom WA, Muller G, Kaplan G. Thalidomide and a thalidomide analogue drug costimulate virus-specific CD8+ T cells in vitro. J Infect Dis. 2003;187(6): Chang DH, Liu N, Klimek V, et al. Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood. 2006;108: Davies FE, Raje N, Hideshima T, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001;98: Tai YT, Li XF, Catley L, et al. Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res. 2005;65(24): Wu L, Adams M, Carter T, et al. Lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumour cells. Clin Cancer Res. 2008;14(14): Baz R, et al. Lenalidomide-based therapy leads to improvement of humoral immunity in relapsed or refractory multiple myeloma patients who respond to the therapy. Haematologica. 2009;94 Suppl 2:159 [abstract 0395]. Noonan KA, Ferguson A, Huff CA, et al. The immunomodulatory role of lenalidomide on Prevnar responses in patients with relapsed multiple meyloma: a comprehensive analysis of the immune response. ASH Annual Meeting Abstracts. 2008;Abstract 2772. Combinational therapy Increases CR rate Time 10 10

CR predicts long term outcome Analysis of 1175 elderly patients
25 50 75 100 10 20 30 40 60 70 80 PFS OS 100 CR 75 CR VGPR PR 50 VGPR PR Median PFS all pts 24 months Median VGPR 24 4 year 28% 3y 28% Median PR year 28% 3y 31% CR Median 64, 4year 62% 3 y 65% 25 10 20 30 40 50 60 70 months months Gay F et al. Haematologica 2010; 95[suppl.2]:236, abs 11 11

Outcome and continuous treatment
Lenalidomide maintenance P < 10-7 Revlimid Placebo McCarthy et al. ASCO 2010 Attal et al. ASCO 2010 Palumbo et al. EHA 2010 Bortezomib maintenance HR VGPR vs CR 3.6, PR vs CR 5.5 age 1.5 iss II 1.9 ISS VMP 0.4 vmpt 0.6 mpt 1.3 VMPT VT VMP P = 0.006 0.00 0.25 0.50 0.75 1.00 10 20 30 40 50 60 35 30 25 20 15 10 5 1,0 0,8 0,6 0,4 0,2 0,0 PFS VT: median not reached VP: 23 months HR: 1.7; p=0.05 VT VP Mateos et al. ASH 2009 Palumbo et al. ASH 2009 12

VTD vs TD GIMEMA experience velcade (bortezomib)-thalidomide-dexamethasone thalidomide-dexamethasone
13

Phase 3: VTD vs TD Efficacy
Induction ≥ nCR 31% 11% <0.0001 After first ASCT 52% After double ASCT 55% 41% 0.002 After consolidation 62% 45% 0.0002 Best confirmed overall ≥ nCR and ≥ VGPR 71% 54% ≥ VGPR 89% 74% Cavo et al. ASH 2010 (Abstract 42), oral presentation Cavo et al. Lancet 2010;376:

Phase 3: VTD vs TD Outcome
Median follow-up: 36 months Progression-free survival Estimated 3-year PFS VTD 68% TD 56% Estimated 3-year OS VTD 86% TD 84% VTD TD Percent P=0.0057 Cavo et al. ASH 2010 (Abstract 42), oral presentation Cavo et al. Lancet 2010;376:

Outcome in 590 patients according to chromosomal abnormalities
Overall Survival months no abnorm. del(13q) alone t(4;14)±del(17p) % at 40 mos 89* 81 77* *P=0.003 Progression-Free Survival t(4;14) del(17p) both % at 34 mos 60* 49 24* *P=0.0008 Progression-free survival Overall survival Cavo et al ASH 2010

Phase 2: VRD induction, ASCT, VRD consolidation, lenalidomide maintenance IFM 2008
Patients (n=31), median age 58 years Post induction Post ASCT Post consolidation sCR 13% 26% 38% CR 10% ≥ VGPR 62% 68% 84% ≥PR 94% 91% Neutropenia grade 3/4 39% During induction 26% During consolidation 20% During maintenance 20% Lenalidomide dose reduction 26% Thrombocytop. grade 3 13% During induction 3% During consolidation 10% Anemia grade 3 6% During consolidation 3% Sensory PN all grades Grade 1 Grade 2 68% 45% 23% During induction 55% During consolidation 13% Bortezomib dose reduction 23% Roussel et al. ASH 2010 (Abstract 624), oral presentation

PAD-V vs VAD-T HOVON experience velcade-doxorubicin-dexamethasone bortezomib maintenance vincristine-doxorubicin-dexamethasone thalidomide maintenance 18

Progression-free survival
Outcome Progression-free survival Overall survival HR = 0.79 ( ), P=0.01 HR = 0.73 ( ), P=0.02 19

MPR vs MEL200 20

CRD vs MEL200 23

Treatment schedule Treatment schedule
15/09/2018 Treatment schedule 402 patients (younger than 65 years) randomized from 62 centers Patients: Symptomatic disease, organ damage, measurable disease CRD six 28-day courses C: 300mg/sqm, days 1,8,15 D: 40mg, days 1,8,15,22 R: 25 mg/d, days 1-21 1° R A N D O M I Z T 2° R A N D O M I Z T MAINTENANCE 28-day courses until relapse R: 10 mg/day, days 1-21 Rd* four 28-day courses R: 25 mg/d, days 1-21 d: 40 mg/d, days 1,8,15,22 Median age 71 y; 30% >75 y; Median KPS 80%; 63% IgG; 33% B2M > % albumin < 35 g/L MAINTENANCE 28-day courses until relapse R: 10 mg/day, days 1-21 PDN: 50 mg every other day MEL 200 Two courses M: 200 mg/m2 day -2 Stem cell support day 0 *Thromboprophylaxis randomization: aspirin vs low molecular weight heparin R, lenalidomide; M, melphalan; d, dexamethasone; P, prednisone 24

VMP with MEL-200 VRD consolidation Len maintenance

A randomized phase III study to compare bortezomib, melphalan, prednisone (VMP) with high-dose melphalan followed by bortezomib, lenalidomide, dexamethasone (VRD) consolidation and lenalidomide maintenance in patients with newly diagnosed multiple myeloma INDUCTION 1500 pts 3 VCD + CY 4 VMP (500 pts) 1 HDM (500 pts) 2 HDM (500 pts) NONE VRD NONE VRD NONE VRD Maintenance Maintenance Maintenance HDM at 1° relapse

Standard of Care for Elderly Patients
27

Meta-Analysis: MPT vs MP
MP better MPT better Progression-free survival MPT better MP better Overall survival MPT: melphalan-prednisone-thalidomide; MP: melphalan-prednisone Waage A, et al. EHA Abstract 0567.

LMWH vs Warfarin vs Aspirin for Lenalidomide and Thalidomide
Standard Risk of VTE Lenalidomide Thalidomide LMWH WAR ASA 1 2 3 4 5 6 7 8 Patients (%) High Risk of VTE Previous VTE, infection, immobilization, CVC, doxorubicin LMWH is suggested ASA: Acetylsalicylic acid; LMWH: low molecular weight heparin; VTE: venous thromboembolism; CVC: central venous catheter Palumbo A, et al. EHA Abstract 0214.

VMP (Bortezomib/Melphalan/Prednisone) Current Standard of Care
~52% reduced risk of progression ~36% reduced risk of death Median TTP VMP: 24.0 months (83 events) MP: 16.6 months (146 events) HR=0.483, P < 3 6 9 12 Time (Months) 15 18 21 24 27 10 20 30 40 50 60 70 80 90 100 Percentage of Patients Without Event VMP MP Percentage of Subjects Without Event Time (Months) 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 50 60 70 80 90 100 Median follow-up 25.9 months Median OS not reached VMP: 3-year OS rate = 72% MP: 3-year OS rate = 59% HR = 0.644, P = .0032 VMP MP San Miguel JF, et al. ASH Abstract 650. 30 30

Bortezomib: Once Weekly
VMP (VISTA) twice-weekly once-weekly CR 30% 27% 23% 2-year PFS 48% 56% 58% Sensory PN Any grade 44% 22% Grade 3/4 13% 14% 2% Discontinuation due to PN na 16% 4% Total planned dose 67.6 mg/m2 46.8 mg/m2 Total delivered dose 40.1 mg/m2 39.4 mg/m2 Bringhen S, et al. Blood Aug 31. [Epub ahead of print]

New treatment options 32

Bortezomib-Melphalan-Prednisone-Thalidomide VMPT-VT vs VMP
15/09/2018 Bortezomib-Melphalan-Prednisone-Thalidomide VMPT-VT vs VMP 511 patients (older than 65 years) randomized from 61 Italian centers Patients: Symptomatic multiple myeloma/end-organ damage with measurable disease ≥ 65 yrs or < 65 yrs and not transplant-eligible; creatinine < 2.5 mg/dL VMP Cycles 1-9 Bortezomib 1.3 mg/m2 IV Days 1,8,15,22* Melphalan 9 mg/m2 and prednisone 60 mg/m2 Days 1-4 VMPT Thalidomide 50 mg/day continuously R A N D O M I Z E 9 x 5-week cycles in both arms MAINTENANCE Bortezomib 1.3 mg/m2 IV Days 1,15 Thalidomide 50 mg/day continuously NO MAINTENANCE Until relapse *66 VMP patients and 73 VMPT-VT patients were treated with twice weekly infusions of bortezomib Palumbo A, et al. J Clin Oncol. 2010;Oct 12:[E-pub ahead of print]. 33 33

Bortezomib-Melphalan-Prednisone-Thalidomide
Response Rate 89% 59% 38% VMPT  VT (N=250) .01 .03 .0008 P Value 81% ≥ PR 50% ≥ VGPR 24% CR VMP (N=253) % of patients CR VGPR PR SD PD VMPT  VT VMP Palumbo A, et al. J Clin Oncol. 2010;Oct 12:[E-pub ahead of print]. 34

Bortezomib-Melphalan-Prednisone-Thalidomide Time to first response and time to CR
VMP VMPT  VT 100 80 60 40 20 PR: VMPTVT PR: VMP % of patients CR: VMPTVT CR: VMP Months Palumbo et al. JCO. 2010; [Epub ahead of print]

Bortezomib-Melphalan-Prednisone-Thalidomide
Median follow-up 32 months Progression-Free survival 41% Reduced Risk of Progression Time to next therapy 48% Reduced Risk of Progression 3-years PFS Median PFS VMP VMPT 32% 27.4 months 51% 37.2 months 3-years TNT Median TTNT VMP VMPT 51% 37.6 months 70% Not reached 0.00 0.25 0.50 0.75 1.00 10 20 30 40 50 60 Time (months) Patients (%) HR 0.59 P < 0.00 0.25 0.50 0.75 1.00 10 20 30 40 50 60 Time (months) Patients (%) HR 0.52 P <

Melphalan-Prednisone-Lenalidomide
N = 459, 82 centers in Europe, Australia, and Israel MP M: 0.18 mg/kg Days 1-4 P: 2 mg/kg Days 1-4 PBO: Days 1-21 MPR R: 10 mg/day po Days 1-21 Placebo MPR-R RANDOMIZATION Double-Blind Treatment Phase Disease Progression Continuous lenalidomide treatment Lenalidomide (25 mg/day) ± Dexamethasone Open-Label Extension Phase Stratified by age (≤ 75 vs > 75 years) and stage (ISS I/II vs III) 10 mg/day days 1-21 Cycles (28-day) 1-9 Cycles 10+ M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo; po, orally; ISS, International Staging System. Palumbo A, et al. EHA Abstract 0566.

Melphalan-Prednisone-Lenalidomide Progression-Free Survival
58% Reduced Risk of Progression 65-75 Years of Age 2 2 - - Year PFS Year PFS Median PFS Median PFS 2 2 - - Year PFS Year PFS Median PFS Median PFS 100 5 10 15 20 25 30 35 40 50 75 100 100 100 100 100 MPR MPR - - R R 55% 55% Not reached Not reached MPR MPR - - R R 61% 61% Not reached Not reached MPR MPR 27% 27% 14.7 months 14.7 months 75 75 75 75 75 MP MP 16% 16% 13.0 months 13.0 months MP MP 10% 10% 12.4 months 12.4 months HR 0.315 HR 0.423 50 50 50 50 50 Log rank P < .001 Log rank P < .001 Patients (%) Patients (%) Patients (%) Patients (%) 25 25 25 25 25 HR 0.675 Log rank P = .031 5 5 10 10 15 15 20 20 25 25 30 30 35 35 40 40 5 5 5 10 10 10 15 15 15 20 20 20 25 25 25 30 30 30 35 35 35 40 40 40 Time (Months) Time (Months) MPR-R: melphalan-prednisone-lenalidomide lenalidomide continuous treatment; MPR-R: melphalan-prednisone-lenalidomide; MP: melphalan-prednisone Palumbo A, et al. EHA Abstract 0566.

Melphalan-Prednisone-Lenalidomide Treatment – Initial 9 Cycles
MPRa MP Discontinuation rateb, % 65-75 years of age 17 10 > 75 years of age 34 16 Cumulative dose intensityc, % 88 97 56 a MPR includes MPR-R and MPR for the initial 9 cycles. b Discontinuation due to AEs or withdrawal of consent c Cumulative dose intensity of melphalan and lenalidomide/placebo Palumbo A, et al. EHA Abstract 0566.

Lenalidomide Continuous Therapy
Melphalan-Prednisone-Lenalidomide Landmark Analysis 69% Reduced Risk of Progression MPR Lenalidomide Continuous Therapy 5 10 15 20 25 30 50 75 100 Time (Months) Patients (%) MPR-R MPR HR 0.314 Log rank P < .001 MPR-R: melphalan-prednisone-lenalidomide lenalidomide continuous treatment; MPR-R: melphalan-prednisone-lenalidomide Palumbo A, et al. EHA Abstract 0566.

Lenalidomide-Prednisone Melphalan-Prednisone-Lenalidomide
Cycles (28-day) 1-4 Cycles (28-day) 5-10 RP R: 25 mg/d, days 1-21 P: 50 mg 3 times/week MPR M: 2 mg 3 times/week P: 50 mg 3 times/week R: 10 mg/d, days 1-21 M, melphalan; P, prednisone; R, lenalidomide; Falco P. et al. SIES 2010 (abstract 102

Melphalan-prednisone-lenalidomide (melphalan 0.18  0.13 mg/kg)
RP MPR1 0.13 mg/kg MPR2 0.18 mg/kg MM015 Age 75(65-88) 75 (65-86) 71 (65-87) GR 4 Adverse events % Neutropenia 6 11 36 Thrombocytopenia 13 G-CSF Administration 14 26 66 Response Rates VGPR 18 33 32 M, melphalan; P, prednisone; R, lenalidomide; 1Falco P. et al. SIES 2010 (abstract 102) 2 Palumbo A. et al. EHA 2010 (abstract 0566)

Age-adjusted therapies
43

Are all the same?

Full-dose chemotherapy Autologous transplant Reduced-dose chemotherapy
Age-Adjusted Therapy INCIDENCE: / 31% 33% 36% 65-74 years 25-64 years years Full-dose chemotherapy Autologous transplant Reduced-dose chemotherapy Combination Chemotherapy vs MP: Mortality A retrospective overview of trials assessed combination chemotherapy vs MP Survival curves were obtained for those trials that provided individual patient data Overall, no significant difference in survival was observed (P=0.6, 2-tailed) Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998;16;3832 Regione Piemonte, Assessorato Sanità 2006 45

Full dose chemotherapy Reduced dose chemotherapy
Age - Comorbidities Full dose chemotherapy Reduced dose chemotherapy 65-75 years >75 years Normal: Cardiac Pulmonary Liver Renal function <65 years Abnormal: Recommendations by A. Palumbo Recommendations by A. Palumbo.

Further Dose Redcution
Age-Adjusted Doses 65-75 Years > 75 Years Further Dose Redcution Dexamethasone weekly 40 mg 20 mg 10 mg Melphalan Days 1-4 0.25 mg/kg 0.18 mg/kg 0.13 mg/kg Thalidomide per day 200 mg 100 mg 50 mg Lenalidomide* Days 1-21 25 mg 15 mg Bortezomib 1.3 mg/m2 biweekly 1.0 mg/m2 If a grade 3-4 AE occurs: 1. discontinue therapy; 2. wait for grade 1 AE; 3. restart at a lower dose Recommendations by A. Palumbo. *Lenalidomide plus melphalan starting dose 10 mg/d 47

ISRAEL SPAIN NETHERLANDS GERMANY POLAND CZECH REPUBLIC ITALY TURKEY GREECE NORWAY DENMARK AUSTRALIA AUSTRIA SWEDEN FINLAND UNITED KINGDOM SWITZERLAND PORTUGAL

Improving Outcomes in Myeloma

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