Donna E. Reece, M.D. Princess Margaret Hospital T Toronto, ON t - PowerPoint PPT Presentation

Donna E. Reece, M.D. Princess Margaret Hospital T Toronto, ON t ON 16 October 2008 16 October 2008

Multiple Myeloma in Canada p y � Incidence 4/100,000 � 2,000/yr in Canada � Prevalence � 6500/yr in Canada � 6500/yr in Canada � 1000 deaths per year � Median age 65 yrs g y � Incidence in younger adults appears to be i increasing i Kyle RA, Rajkumar SV. N Engl J Med 2004;351:1860–73 Canadian Cancer Statistics; 2007. Available at www.cancer.ca

Multiple Myeloma Multiple Myeloma � Marrow plasma cells > 10% � Symptomatic myeloma =“CRAB” � Anemia (Hgb < 100) � Bone lesions � Creatinine (> 176 umol/L) Creatinine (> 176 umol/L) � Calcium > 2.8 mmol/L

Interaction between Myeloma Cell and Bone M Marrow Microenvironment Mi i t

Advances in Prognosis � International Staging System (ISS) Stage Stage Criteria Criteria Median Median Serum β 2 -microglobulin <3.5 mg/L I 62 mo. Serum albumin ≥ 3.5 g/dL II Not stage I or III 44 mo. Serum β 2 -microglobulin ≥ 5.5 mg/L 29 mo. III � Cytogenetic abnormalities t(4;14)=15% p53 deletion=10%

Factors Affecting Myeloma Management in Canada � Drug availability D il bilit � Approval from Health Canada � Funding from provinces � Myeloma drugs approved in Canada ye o a d ugs app o ed Ca ada � Melphalan � Cyclophosphamide � Bisphosphonates (pamidronate, zolendronic acid, clodronate) � Bortezomib (2 nd line +) � Bortezomib (2 d line +) � Bortezomib + melphalan + prednisone (1 st line therapy without ASCT) � Lenalidomide for relapsed myeloma Access programs � SAP for thalidomide (but no funding) � EAP for lenalidomide is closing � Trial of bortezomib + melphalan + prednisone (limited number of centers) �

Results of “Traditional” Initial Therapy py Overview Dex-based induction Melphalan + Prednisone + until plateau ASCT � Overall response rate 80% � Overall response rate 80% � Overall response rate 40-50% � Overall response rate 40 50% � CR/nCR 20%-30% � CR/nCR 5% � Median PFS 20-36 mos ed a S 0 36 os � Median PFS 12-15 mos � Median PFS 12 15 mos � Median OS 48-60 mos � Median OS 30-36 mos

Efforts to Improve Initial Therapy Efforts to Improve Initial Therapy Melphalan + Prednisone ASCT � Optimize ASCT (eg. using O ti i ASCT ( i � Tandem ASCT melphalan 100 mg/m 2 ) � Maintenance therapy using � Add novel agents to M+P Add novel agents to M P novel agents novel agents � Use IMiD + dexamethasone � New induction regimens containing novel agents

Novel Agents in Multiple Myeloma Novel Agents in Multiple Myeloma Thalidomide Thalidomide Bortezomib Lenalidomide Bortezomib Lenalidomide Effi Efficacy: - As single agents, with steroids, in combinations - As initial therapy or for relapsed/refractory MM As initial therapy or for relapsed/refractory MM

Novel Agents in Myeloma Agent Agent Class Class Effects Effects Toxicity Toxicity Decreased adhesion, Teratogenicity, PN, Thalidomide IMiD sedation, rash, cytokines production, constipation, DVT angiogenesis angiogenesis Increased anti- myeloma immunity myeloma immunity Decreased adhesion, Fatigue, PN, GI Bortezomib Proteasome toxicity cytokine production, y p , inhibitor inhibitor Decrease in angiogenesis, NFkB, neutrophils, DNA repair platelets and lymphocytes Decreased adhesion Myelosuppression, Lenalidomid IMiD DVT Increased T cell e proliferation, NK cell ( (CC-5013) ) cytotoxicity, IFN- γ and t t i it IFN d IL-2

Activity of Novel Agents in Relapsed/Refractory Myeloma Patients Myeloma Patients Agent CR/nCR PR Overall Thalidomide 1 < 5% 28% 30% Thalidomide +Dex Thalidomide +Dex 2 < 5% < 5% 40-50% 40 50% 50% 50% Bortezomib 3,4 5% / 5% 20-25% 30-40% B Bortezomib + Dex 5,6 t ib + D 5 6 5% / 5-10% 5% / 5 10% 35 55% 35-55% 40 50% 40-50% Lenalidomide 7 Lenalidomide 6% 6% 18% 18% 25 40% 25-40% Lenalidomide + 19% 51% 70% Dex 8,9 1 Glasmacher A, et al,Br J Haematol 132: 584-593,2005; 2 Palumbo A, et al. Hematol J 2004; 5:31 8-320; 3 Richardson PG, et al. N Engl J Med 352:2487-98, 2005; 4 Richardson P, et al. Blood 110:3557-60, 2007; 5 Jagannath S et al. Haematologica 91:929-32, 2006; 6 Kropff MH, et al. Leuk Res 29:587-90, 2005; 7 Richarson PG, et al. Blood 108; 3458-64, 2006; Weber DM, et al. N Engl J Med 357:2133-42, 2007; Dimopoulos M, et al. N Engl J Med 357:2123-32, 2007.

The Changing Landscape of Therapy g g p py Initial Myeloma Therapy in Canada � Elderly patients ineligible for ASCT � Induction therapy before ASCT � Induction therapy before ASCT � Initial therapy in “transplant uncertain” patients � Non-melphalan containing therapy � Non melphalan containing therapy � May be of 2 broad types � Continuous “suppressive” therapy with IMiDs + steroids � Combination therapy with novel agents � High overall and CR/nCR rates

IMF 99-06: Treatment of Newly Diagnosed Myeloma Patients 65–75 Years N=500 3 3 2 2 2 MP-Thal Arm MEL100 x 2 Arm MP Arm VADx2; cyclophosphamide 3 Standard MP MP as Arm 1 + Thal at MTD but ≤ 400 mg/day, g/m 2 ; Melphalan, 100 mg/m 2 at 6-wk intervals x 12 stopped at end of MP Facon T et al. Lancet 2007;360:1209-1218.

IFM 99 06 MP IFM 99-06:MP vs MP-Thal and MP vs Mel MP Th l d MP M l 100 Newly Diagnosed MM Aged 65–75 Years MP MP + thal Mel 100 x 2 Overall response rate (%) 35 76 65 CR rate (%) 2 18 18 Median PFS (mos) Median PFS (mos) 17 8 17.8 27 5 27.5 19 4 19.4 Overall survival (mos) 33.2 51.6 38.3 ≥ Grade 3 toxicity (%) Any non-heme 16 42 58 Neutropenia 26 48 100 VTE 4 12 8 Peripheral neuropathy Peripheral neuropathy 0 0 6 6 0 0 Facon T et al. Lancet 2007;360:1209-1218

Randomized Trials in Elderly Myeloma Patients Myeloma Patients Study Regimen Overall CR/nCR rate PFS/EFS Overall Response Response (%) (%) (mos) (mos) Survival Survival rate (%) (mos) Facon 1 MPT 76 18 27.5* 51.6* MP MP 25 25 2 2 17.8 17 8 33 2 33.2 Palumbo 2 MPT 76 28 21.8* 45 MP MP 48 48 7 7 14 5 14.5 47.6 47.6 Hulin 3 MPT 61 7 24.1* 45.3* MP 31 1 19.1 27.7 San VMP 71 35 24.0* 83%* Miguel 4 MP 30 4 16.6 70% (2 (2 yrs) ) 1 Facon et al. Lancet 2006;370:1209-18; 2 Palumbo et al. Blood May 26 2008 [Epub]; 3 Hulin et al. Blood 2007;110:abstract #75; 4 San Miguel et al. Blood 2007;110:abstract # 76 . *statistically significant

Randomized Trials in Elderly Myeloma Patients: Toxicity Comparisons Toxicity Comparisons Study Rx Duration Thal ≥ Gr 3 non- ≥ Gr 3 VTE ≥ Gr 3 of Rx of Rx dose dose heme toxicity heme toxicity Neutropenia Neutropenia PN PN (%) (%) (%) (%) (%) (%) Facon Facon 1 MPT MPT 72 72 400 mg 400 mg 42 42 48 48 12 12 6 6 MP 72 16 26 4 0 Palumbo 2 MPT 52 100 mg 49 16 12 10 MP 52+ 25 17 2 1 Hulin 3 MPT 72 100 mg 53 15 7 2 MP MP 72 72 15 15 4 4 2 2 San VMP 54 46 40 1 14 ‐‐ Miguel 4 MP 54 36 38 1 0 1 Facon et al. Lancet 2006;370:1209-18; 2 Palumbo et al. Lancet 2006; 367:825-31; 3 Hulin et al. Blood 2007;110:abstract #75; 4 San Miguel et al. Blood 2007;110:abstract # 76 .

VMP: Effect of FISH Cytogenetics FISH: any (t4-14, t14-16, 17p Del) vs. None Best M-protein Total High Risk Std Risk Response n Response, n ( (N=165) 16 ) ( (N=26) 26) ( (N=139) 139) (%) CR (IF-) 32% 35% 32% ≥ PR ≥ PR 82% 82% 81% 81% 82% 82% TTP OS VMP standard risk VMP standard risk VMP high risk VMP high risk VMP standard risk (N=142): not reached (16 events) VMP standard risk (N=142): 23.1 months (34 events) VMP high risk (N=26): not reached (3 events) VMP high risk (N=26): 19.8 months (7 events) HR = 1.009 (95% CI: 0.278, 3.663) HR = 1.297 (95% CI: 0.55, 3.06) San Miguel et al. Blood 2007;110: abstract #76

New Approaches in Elderly Myeloma Patients: Summary � Addition of novel agent to melphalan and prednisone improves outcome � Whether MP followed by novel agent at relapse produces similar or inferior results is uncertain � Toxicity is greater Toxicity is greater � Thalidomide regimens require thromboprophylaxis � Peripheral neuropathy is a concern � Data needed for risk groups � In Canada, options include: � Try to obtain funding for thalidomide T t bt i f di f th lid id � Clinical trial

Management of Elderly Myeloma Patients in Canada: Clinical Trials � NCIC MY11 trial (closed) � Melphalan 5 mg/m 2 days 1-4 � Melphalan 5 mg/m days 1-4 � Lenalidomide 10 mg/days 1-21 � Ortho Biotech trial of V MP O th Bi t h t i l f V � Celgene MM020 international trial � Celgene MM020 international trial � Lenalidomide + weekly dex until progression � Lenalidomide + weekly dex for 18 months � MPT

New Approaches before ASCT New Approaches before ASCT � Background: Patients in CR/nCR/VGPR after ASCT have better PFS and OS � Hypothesis: Achievement of CR/nCR/VGPR before ASCT will translate into improved outcome after ASCT