Structure. Thalidomide (Thalomid ) The Original IMiD. Lenalidomide (Revlimid) A New Treatment Option in Myelodysplastic Syndrome and Multiple Myeloma

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1 Lenalidomide (Revlimid) A New Treatment ption in Myelodysplastic Syndrome and Multiple Myeloma National ncology Pharmacy Symposium Pierre Laneuville, MD FRCPC Division of Hematology McGill University Health Center Royal Victoria Hospital, Montreal Thalidomide (Thalomid ) The riginal IMiD ral immunomodulator Derivative of glutamic acid Immunomodulatory agent with antiangiogenic and apoptotic properties N H N Major Side Effects of Thalidomide Structure Tetatogenic Somnolence Constipation Peripheral Neuropathy Thalidomide Lenalidomide Richardson et al, DeVita PP updates. Feb 1 Lenalidomide (CC-513; Revlimid ) More potent immunomodulator than thalidomide Up to 5, times more potent inhibitor of TNFα - to 1-fold in cytokine modulation Increased stimulation of T-cell proliferation Augmented stimulation F IL- and IFNγ production Fewer side effects: no significant constipation, neuropathy, or sedation Not teratogenic NH N Multiple Myeloma Marriott JB et al.? 3;3(3):181 Schey SA et al. J Clin ncol. 4;:1? Richardson P, Anderson K. J Clin ncol. 4;:1? NH 1

2 Age-Adjusted SEER Incidence (1997-1) Hematological Malignancies ~ 1% all Cancers Estimated Number of New Patients Diagnosed Annually in Canada NHL MM AML CLL HL CML ALL ther Incidence Prevalence ~ Median age Median survival 3-5 y Incidence X in African Americans Incidence M > F Total n = 1,85 NHL MM AML CLL HL CML ALL ther Development of Myeloma Cells Ig gene changes leading to MM VDJ rearrangement Somatic mutation Class switching V X D Y J Z C m V X D Y J Z C m V X D Y J Z C m V X D Y J Z C g Stem cell CD38 Pre-B cell CD34 B-cell CD1 Cell surface markers CD19/ Kuehl & Bergsagel. Nature Rev Cancer ; : Hideshima T, Anderson K. Nat Rev Cancer. ;:97 ncogenic Event V X D Y J Z C g V X D Y J Z C g Plasma cell CD38/138 MM cell CD5 Multiple Myeloma Malignancy of plasma cells Hallmarks: Anemia Renal failure Bone destruction (lytic bone lesions) Hypercalcemia Presence of monoclonal protein Increased risk of infection Criteria for Diagnosis of Myeloma Initial Approach to Treatment of MM MGUS <3 g M spike <1% PC AND No anemia, bone lesions normal calcium and kidney function Kyle RA. N Engl J Med ; 34: 54 Smoldering MM 3 g M spike R 1% PC Active MM 1% PC M spike + AND Anemia, bone lesions, high calcium or abnormal kidney function Clearly not a transplant candidate based on age, performance status and comorbidity Conventional chemotherapy* or clinical trial *Thal/,, or VAD if immediate response is needed Potential transplant candidate Non-alkylator based induction x 4 cycles Stem cell harvest

3 Angiogenesis in Myeloma CD 34 staining MM cell Interaction of MM Cells and Their Bone Marrow Microenvironment Cytokine-mediated signaling Adhesion-mediated signaling TNFα PI3K/AKT MAPK JAK/STAT3 IL- IGF1 SDF-1α MAPK NF-kB NF-kB Adhesion molecules MM cell Normal Marrow Myeloma Marrow ICAM1 VCAM1 LFA1 MUC1 VLA4 CRE c-fs SRE homology BMSC Rajkumar SV 4 Reprinted with permission from Hideshima T, Anderson KC. Nat Rev Cancer. ;:97 Signaling Cascades Mediate Growth, Anti-Apoptosis, and Migration in Myeloma Novel Therapies Targeting the Myeloma Cell In Its Bone Marrow Microenvironment IL- IGF1 TNFα IL-1 SDF-1α IL- IL-1 IL- IGF1 TNFα SDF-1α RAF MEK p4/44 MAPK Proliferation JAK PI3K STAT3 AKT (PKB) BAD NF-κB FKHR BCL-X L MCL1 Caspase-9 PKC Cyclin D KIP1 Anti-apoptosis (drug resistance) Cell cycle Migration MM cells BMSC Targeting MM cell Telomestatin 17AAG, Statin, IGF1R inhibitor Epothilone B, Farnesyltransferase Inhibitor, Genasense, TRAIL, Rituximab, CD4 MoAb Targeting BM microenvironment PS-1145/4 IKK inhibitor, VX-745, P38MAPK inhibitor MM cells Targeting MM cell and BM microenvironment Thalidomide/Lenalidomide PS341, PTK787 SAHA/LAQ84 ME, LPAAT inhibitor Atiprimod Reprinted with permission from Hideshima T, Anderson KC. Nat Rev Cancer. ;:97 Stromal cells Thalidomide/Lenalidomide Target MM Cells in the BM Microenvironment bfgf MM cells A.Thalidomide /IMiD D. Thalidomide /IMiD Hideshima et al. Blood 9: 943, Davies et al. Blood 98: 1, 1 Gupta et al. Leukemia 15: 195, 1 C. Thalidomide/IMiD PBMC IL- TNFα B.Thalidomide /IMiD IL-1β Bone Marrow Vessels ICAM-1 Bone Marrow Stromal Cells IL- IFNγ CD8+ T Cells E. Thalidomide /IMiD NK Cells Mitsiades et al. Blood 99: 455, Lentzsch et al Cancer Res : 3, Apoptotic Signaling Triggered by Conventional and Novel Agents FAS/FASL, TRAIL Conventional chemotherapy Ionizing radiation Thal/IMiDs PS-341 As 3 amethasone Caspase-8 Caspase-3 PARP cleavage Caspase-9 Apoptosis IL- IGF1 Reprinted with permission from Hideshima T, Anderson KC. Nat Rev Cancer. ;:97 3

4 IMiDs Augment Anti-MM Immunity Dendritic Cell Apoptotic MM Cell T Cell IL- NFAT PKCζ PI3K IL- CD8 IMiDs NK Cell IL- MM Cell Clinical Trials Multiple Myeloma Bone Marrow Stromal Cell LeBlanc R et al. Blood. 4;13:1787; Hayashi T et al. In press; Richardson PG et al. Blood. ;1:33; Bartlett JB et al. Nature Reviews/Cancer. 4;4:314; Multiple Myeloma, Richardson, 4, p 57; Hideshima,T, Anderson K. Nature Reviews/Cancer. ;:97 Lenalidomide for Myeloma Resistant MM Phase1 (Richardson et al, Blood 98(11): abst 35, 1 Phase1 (Zangari et al, Blood 98(11): abst 3, 1) Total # Pts. Response(%) Clinical Trials for Relapsed or Refractory Multiple Myeloma Phase (Richardson et al, Blood: abst 85, Two Phase III Randomized, Double- Blind, Placebo-Controlled Trials of Lenalidomide + amethasone versus Placebo + amethasone for Relapsed or Refractory Multiple Myeloma Lenalidomide MM-9/1 Two Phase III Trials of Lenalidomide/ in Relapsed or Refractory MM North American MM-9 (48 Centers USA/Canada): Weber (354 patients) International MM-1 (51 Centers Europe/Australia/Israel): Dimopoulos (351 patients) ts) Inclusion criteria 3 3 prior therapies No resistance Normal liver/renal function Lenalidomide 5 mg d 1 1 Placebo d 8 4 mg, d 1 4, 9 1, 17 4 CURSES Placebo d mg, d 1 4, 9 1, 17 Primary endpoint: TTP (by Bladé criteria) Secondary endpoints: S, RR, safety, 1 st skeletal-related event, PS Additional stratification by β M (.5 mg/dl vs >.5 mg/dl), prior transplant ( vs >1) and prior MM treatment regimens (<1 vs >1) CNTINUE UNTIL PD Same, except d 1 4 Weber D. ral presentation at: ASC Annual Meeting; May 13 17, 5; rlando, FL. Available at: Dimopoulos M et al. Blood. 5;1:a [abstract ] 4

5 n Male, % Median age, yr ECG PS 1, % DS stage III, % Lytic lesions, % 1 prior SCT, % MM-9/1: Patient Characteristics Mean marrow plasmacytosis, % Mean time from Dx to Tx, yr prior MM regimens, % Len MM Len MM-1 Weber D. ral presentation at: ASC Annual Meeting; May 13 17, 5; rlando, FL. Available at: Dimopoulos M et al. Blood. 5;1:a [abstract ] % of Patients Prior Therapies Bortezomib Thalidomide amethasone SCT Response Rate (%) 8 4 MM-9: EBMT Response Data 1.%* 34.7% Len/ *P<.1.8%*.5% 18.7% 9 4.1% PR+CR PR (>5%) CR (IF-) Bladé J et al. Br J Haematol. 1998;1:1115 Weber D. ral presentation at: ASC Annual Meeting; May 13 17, 5; rlando, FL. Available at: Response Rate (%) Data cut-off /5 8 4 MM-1: EBMT Response Data 4% PR Len/ verall Response Rate: Len/ Placebo/ P MM % 3.9% <.1 % ncr 15% CR % PR Bladé J et al. Br J Haematol. 1998;1:1115; Dimopoulos M et al. ral presentation at ASH Annual Meeting; December 1-13, 5; Atlanta, GA.% ncr 3.4% CR MM-9/1: Time to Progression MM-9/1: Grade 3/4 Adverse Events Proportion of Patients Len/ (15. mo) 9 alone (5.1 mo) 1 Len/ (11.3 mo) 1 alone (4.7 mo) P< Time to Tumor Progression (mo) Bladé J et al. Br J Haematol. 1998;1:1115; Weber D. ral presentation at: ASC Annual Meeting; May 13 17, 5; rlando, FL. Available at: Dimopoulos M et al. Blood. 5;1:a [abstract ] PE DVT Thrombocytopenia Febrile Neutropenia Neutropenia Anemia Weber D. ral presentation at: ASC Annual Meeting; May 13 17, 5; rlando, FL. Available at: Dimopoulos M et al. ral presentation at ASH Annual Meeting; December 1-13, 5; Atlanta, GA Len/ 9 9 Len/ 1 1 5

6 Grade 3/4 Hematologic Toxicity Grade 3/4 ther Adverse Events Neutropenia, % Febrile Neutropenia Thrombocytopenia Anemia Len/ N = MM-9 N = Len/ N = MM-1 N = DVT/PE, % Atrial Fibrillation CHF Constipation Diarrhea Fatigue Neuropathy Len/ N = MM-9 N = Len/ N = MM-1 N = Dose Reductions / Discontinuations MM-9/1: Summary AE leading to dose reduction, % AE leading to discontinuation Len/ N = MM-9 N = Len/ N = MM-1 N = Len/ is associated with 3x higher response rate and 3x longer TTP than dex Neuropathy, constipation, fatigue less than thalidomide Myelosuppression greater than thalidomide, manageable with dose reduction Thrombosis may be a problem, prophylactic anticoagulation? Lenalidomide is being assessed in untreated Multiple Myeloma Lenalidomide (CC-513) and amethasone for Newly Diagnosed Multiple Myeloma SCT Planned; ff-treatment Clinical Trials in Newly Diagnosed Multiple Myeloma Patients Newly diagnosed MM (n=34) Lenalidomide 5 mg/day P Days mg Days 1 4, 9 1, 17 Aspirin daily for DVT prophylaxis CR/PR/Stable at 4 months No SCT; Remain on-treatment at MD discretion* Progressive disease; fftreatment * For patients continuing tx >4 months, to 4mg on days 1-4 of each cycle Rajkumar SV et al. Blood. Pre-published online August 3, 5

7 Lenalidomide and amethasone for Newly Diagnosed Multiple Myeloma Response Category verall bjective Response Complete Response Very good partial response Near complete response Partial response Minor response No response *bjective response defined as: 5% reduction in serum M protein and 9% reduction in urine M protein, or reduction to < mg/4 hr. Responses confirmed by two consecutive determinations at least 4 weeks apart. Rajkumar SV et al. Blood. Pre-published online August 3, 5 Number of Patients % Patients Responding 91% % 3% 53% % 3% Lenalidomide and amethasone for Newly Diagnosed Myeloma: Adverse Events Profile Hematologic toxicity, % Anemia Neutropenia Leukopenia Lymphopenia Non-hematologic toxicity, % Fatigue Muscle weakness Pneumonitis Skin rash Anxiety Grade 1/ Rajkumar SV et al. Blood. Pre-published online August 3, Grade 3/4 ne patient developed PE, but recovered with therapy no other DVT or PE ngoing Cooperative Group Trials of Lenalidomide ECG E4A3 S. Vincent Rajkumar, MD A Randomized Phase III Study of CC-513 plus amethasone vs CC-513 plus Low Dose amethasone in Multiple Myeloma with Thalidomide plus amethasone Salvage Therapy for Non-Responders SWG S3 Jeffrey Zonder, MD A Double-Blind, Placebo Controlled, Phase III Trial of amethasone vs the Combination of CC-513 plus amethasone in Patients with Newly Diagnosed Myeloma CALGB 114 Philip McCarthy, MD A Phase III Randomized, Double-blind Study f Maintenance Therapy With CC-513 or Placebo Following Autologous Stem Cell Transplantation for Multiple Myeloma Lenalidomide Plus Standard or Low-Dose amethasone in Newly Diagnosed Myeloma Newly diagnosed, untreated MM (n=41) ECG 4A3: Phase III Randomized Study Courses repeat every 8 days up to 1 yr in the absence of PD or unacceptable toxicity Arm I. Lenalidomide 5 mg/day P, Days 1 1 Standard-Dose amethasone 4 mg/day P, Days 1 4, 9 1, 17 (n=) Arm II. Lenalidomide 5 mg/day P, Days 1 1 Low-Dose amethasone 4 mg/day P, Days 1, 8, 15, (n=) If PD within 4 mo Arm III. Salvage therapy Thalidomide mg/day P, Days 1 8 Standard-Dose amethasone 4 mg/day P, Days 1 4, 9 1, 17 Arm IV. Salvage therapy Thalidomide mg/day P, Days 1 8 Low-Dose amethasone 4 mg/day P, Days 1, 8, 15, Endpoints: Response Rate, Safety in Arms I, II; Response Rate in Arms III, IV SWG S3: Lenalidomide/ in Newly Diagnosed Myeloma Induction Therapy Courses repeat every 35 days up to 3 courses in the absence of PD or unacceptable toxicity Newly diagnosed, untreated MM (n=5) Lenalidomide 5 mg/day P, Days 1 8 amethasone 4 mg/day P, Days 1 4, 9-1, 17- (n=5) PD (Unblinded induction) Placebo 5 mg/day P, Days 1 8 amethasone 4 mg/day P, Days 1 4, 9-1, 17- (n=5) Maintenance Therapy* If PR, CR, SD on induction - courses repeat every 8 days until progression/relapse Lenalidomide 5 mg/day P, Days 1 1 amethasone 4 mg/day P, Days 1 4, PD (Unblinded induction) Endpoints: PFS, Response Rate, verall Survival Placebo P Days 1 1 amethasone 4 mg/day P, Days 1-4, ngoing Study of Lenalidomide As Maintenance Therapy Following Autologous PBSCT for MM CALGB 114: Phase III Randomized, Placebo-Controlled Trial Patients with active MM, stable disease or responsive to 4 4 months induction therapy (n=588) PBSCT RE- STAGING 9 1 days after PBSCT 1 Endpoint: Time to disease progression after autol ogous PBSCT Lenalidomide 1 mg/day po (n=5) Placebo (n=5) Endpoints: CR rate, PFS, overall survival, feasibi lity of long-term lenalidomide R A N D M I Z E 7

8 Incidence of DVT in Multiple Myeloma Thalidomide <-3% 3% VAD 4-1% Thal/ 15% TAD/VAD 5-35% Len 3% Len+ (HD) 8.5% Len+ +ASA 3% Thromboembolic Complications in Multiple Myeloma from Rx thal/len Risk Factors High dose dex > low dose dex Combination therapy (anthracyclics) Erythropoietin Protein C-deficiency Prophylaxis ASA (81-35 md/d) LMWH ASA + LMWH Myelodysplasia Spectrum of Myeloid Diseases CANADA Majority > 5 years old Incidence ~ 15/year Prevalence ~ 45 AA PNH hypoplastic MDS RA RAEB RARS Secondary AML RAEB-t MDS-AML tld-aml CMML acml CML MDS: Pathophysiologic Abnormalities FAB vs WH Classification Cytogenetic abnormalities FAB Classification WH Classification Medullary angiogenesis Stromal dysregulation MDS Epigenetic DNA modification Accelerated apoptosis RA RARS RAEB CMML RA RCMD 5q- RARS RCMD-RS 5q- RAEB I-II CMML Proliferation RAEB-t AML 8

9 International Prognostic Scoring System (IPSS) All 3 prognostic variables required to generate IPSS score Score Value Prognostic variable Bone marrow blasts (%) < Karyotype* Good Intermediate Poor Number of cytopenias** /1 /3 *Good=normal, -Y, del(5q), del(q); Intermediate=other karyotypic abnormalities; Poor=complex ( 3 abnormalities) or chromosome 7 abnormalities **Hgb <1 g/dl; ANC <18/µL; platelet count <1,/µL Numeric Score MDS: IPSS Risk* Categories Patient Distribution Low.5 1. Int Int-.5 High IPSS Risk Category Int- Risk % High 8% Int-1 Risk 39% Low Risk 31% *Estimated survival and risk of AML transformation Greenberg P et al. Blood. 1997;89:79 Greenberg P et al. Blood. 1997;89:79 Percent Survival and AML Evolution by IPSS Classification Survival Low 7 pts Int pts Int- 179 pts High 5 pts Percent AML-Free AML Evolution Low 35 pts Int-1 95 pts Int- 171 pts High 58 pts Lenalidomide in Transfusion-Dependent Patients With Low/Int-1 1 MDS (MDS-/3) Eligibility RBC transfusion U/8 wk 1 wk transfusion Hx ANC >5/µL Platelets >5,/µL de novo MDS Low/Int-1 MDS MDS-3: del 5q31.1 MDS-: other R E G I S T E R Week: Multicenter Phase II studies Lenalidomide Dosing (1) 1 mg po 1/8 d () 1 mg po qd R E S P N S E Yes No Continue ff Study Dose Reduction 5 mg qd 5 mg qod Years from diagnosis in untreated patients Greenberg P et al. Blood. 1997;89:79 Primary endpoint: transfusion independence (Hgb 1 1 g/dl) Secondary endpoints: cytogenetic response, pathologic response, safety List AF et al. J Clin ncol. 5;3:s [abstract 5] List AF et al. Haematologica. 5;9:37 [abstract 77] Clinical Characteristics of MDS-/3 Patients MDS-/3: Initial IPSS Score Patients eligible, n (%) No. evaluable at 4 wk (%) % Male Characteristic No. of patients Median age (range), yr Median RBCs/8 wk (range) U/mo MDS- Non-del(5q) 15 1 (77) 11 (54) 7 (7 94) 138 (4) 4 U ( 1) 185 (8%) MDS-3 del(5q) (78) 113 (7) 71 (37 95) 51 (34) 5 U ( 1) 14 (7%) Unknown 18% Int-/High 4% Int-1 35% MDS- Non-del(5q) Low 43% Int-/High 5% Unknown 14% Int-1 44% MDS-3 del(5q) Low 37% List AF et al. J Clin ncol. 5;3:s [abstract 5] List AF et al. Haematologica. 5;9:37 [abstract 77] Revlimid (lenalidomide) prescribing information. Available at: List AF et al. ral presentation at: 1 th Congress of the European Hematology Association; June 5, 5; 9

10 MDS-/3: Initial FAB Distribution MDS-/3: Cytogenetic Features CMM L 1% AM L 1% RAEB 1% ther 14% MDS- Non-del(5q) RA 19% RARS 44% CMML % AML 1% RAEB % ther 1% RARS 1% MDS-3 del(5q) RA 53% Normal Karyotype Abnormal Favorable Intermediate +8 abnormalities Unfavorable MDS- (n=185) Parameter del ()(q) -7/del (7)(q) Complex Number (%) 14 (77) 43 (3) 15 (8) (3) 4 (13) 9 (5) 4 () 4 () 4 () 1 MDS-3 (n=148) Parameter Favorable (isolated del 5q) 5q- syndrome Intermediate (del 5q + 1) Unfavorable (complex) del (5) segment (q13q33) (q13q34) (q13q31) (q15q33) ther Unknow n Number (%) 18 (73) 39 () 7 (18) 1 (8) (41) 8 (19) 18 (1) 15 (1) (18) 1 Revlimid (lenalidomide) prescribing information. Available at: List AF et al. ral presentation at: 1 th Congress of the European Hematology Association; June 5, 5; List AF et al. ral presentation at: 1 th Congress of the European Hematology Association; June 5, 5; MDS-/3: Intent to Treat Erythroid Response at 4 wk (Preliminary Report) Transfusion-Independence (TI) Rate by Cytogenetic Pattern (3) Erythroid response Median duration of transfusion independence Median Hgb rise Transfusion indep Minor (>5% ) Transfusion indep + minor MDS- Nondel(5q) (n=15) 58 (7%) 3 (17%) 94 (44%) 43 wk 3.3 g/dl (1. 9.8) MDS-3 del(5q) (n=148) 97 (%)* 14 (9%) 111 (75%) >47 wk 5.3 g/dl ( ) 11.4) Variable Complexity Isolated del 5q Del 5q + Add [1] Complex [>3 ] No. Pts. [N=147]* Pts. T.I. (%) 75 (9) 14 (5) 8 (7) P value.3 Median time to response *P<.1; not reached at median follow-up of 58 wk 4.5 wk ( ) 39.1) 4.4 wk (3. 5.3) No significant differences in erythroid response or time to response between dosing regimens List AF et al. ral presentation at: 1 th Congress of the European Hematology Association; June 5, 5; * Excludes 1 patient defined by FISH only. MDS-3: Cytogenetic Response (3) MDS-/3: Treatment-Related Adverse Events Variable Patients evaluable Cytogenetic response Complete (CCR) Minor ( 5% decrease) No. of patients (%) (7) 51 (44) 3 () Grade 3 Adverse Events Thrombocytopenia Neutropenia Pruritus Rash Diarrhea Fatigue MDS- Non-del(5q) 19% 4% 1% 4% 1% % MDS-3 del(5q) 54% 55% % 7% % 3% Deaths on study Possibly drug related Neutropenic infection MDS- 15 MDS-3 List AF et al. ral presentation at: 1 th Congress of the European Hematology Association; June 5, 5; List AF et al. ral presentation at: 1 th Congress of the European Hematology Association; June 5, 5; 1

11 Lenalidomide Dose Adjustment Feature No. patients Dose reduction Final dose 1 mg qd 5 mg qd 5 mg qod Days to adjustment Median [range] Termination for AE* Most common AE s: thrombocytopenia [N=7 (4.7%)], rash [4 (.7%)], neutropenia [3 (%)] Total (%) (8) 4 (7) 54 (3) 54 (3) 1 [-7d] 17 (1) MDS-/3: Conclusions Lenalidomide promotes transfusion independence (TI) in low-risk, transfusion-dependent MDS patients Erythroid response significantly greater in patients with del(5)(q31) (q31) % became TI at 4 wk vs 7% without del(5)(q31) (P<.1) Median Hgb rise was 5.3 g/dl vs 3.3 g/dl without del(5)(q31) Response was rapid median 4.4 wk vs 4.5 wk without del(5)(q31) Response was durable median duration >47 wk vs 43 wk without del(5)(q31) Complete cytogenetic response 44% of 115 evaluable patients with del(5)(q31) 45% of evaluable patients without del(5)(q31) Myelosuppression common Manageable with treatment interruption and dose reduction List AF et al. ral presentation at: 1 th Congress of the European Hematology Association; June 5, 5;. Press release available at: New Applications? Myelofibrosis A. Tefferi, Blood 18:1158 () Amyloidosis V. Sanchorawaia, Abst 754, ASC () Lymphoma P.H. Wiernik, Abst 175, ASC () CLL K. Miller, Abst 517, ASC () 11