Michel Delforge Belgium. New treatment options for multiple myeloma

Transcription

1 Michel Delforge Belgium New treatment options for multiple myeloma

2 Progress in the treatment of MM over the past 40 years 1962 Prednisone + melphalan 1990s Supportive care 1999 First report on thalidomide April 2005 Bortezomib approved for first relapse in Europe 2007 MPV Phase III and bortezomib front-line trials 1995 onward Melphalan Tandem ASCT From 1980s Myeloablation + ASCT April 2004 Bortezomib EU licence 2006 MPT Phase III trials 2007 Len/dex approved for first relapse in Europe

3 Front-line therapy standard of care High-dose melphalan with ASCT is considered the standard of care for patients aged 65 years VAD has been a standard induction regimen prior to ASCT CR rate with VAD typically only ~ 10% CR + VGPR following ASCT is associated with improved EFS and OS The use of novel agents in induction regimens prior to ASCT has demonstrated improved CR rates Improving CR + VGPR rate following induction could result in further improved long-term outcomes Harousseau. Ann Oncol 2002;13(Suppl 4):49 54 Attal et al. N Engl J Med 1996;335:91 7

4 Thalidomide combinations in the up-front setting Regimen Patients, n Response, % Reference (CR + ncr) Thal-Dex vs Dex 103 vs vs 41 Rajkumar, JCO 2006 Thal-Dex vs Dex vs vs 46 Rajkumar ASH 2006 (7.7) vs (2.6) Thal-Dex vs VAD 100 vs vs 52 Cavo, Blood 2005 (10) vs (8) Thal-Dex vs VAD 102 vs vs 47 Macro ASH 2006 (35) vs (13)* TAD vs VAD 200 vs vs 54 Lokhorst, Hematol.2008 (4) vs (2) T+VA 2 D vs VA 2 D 115 vs vs 66 Zervas, ASH TTP : 22 vs 6.5 months 2 Doxil * VGPR

5 Phase 3 HOVON-50/GMMG-HD3 trial: TAD vs VAD Results post induction TAD (n=201) VAD (n=201) P CR 4% 2% VGPR 33% 15% <0.001 CR + PR 72% 54% <0.001 Results post-asct CR 16% 11% 0.19 VGPR 49% 32% <0.001 CR + PR 79% 76% 0.55 Grade 3-4 events: VAD 33%, TAD 41% (p=0.13) Grade 3-4 neurology: VAD 7%, TAD 12% (p=0.09) VTEs: VAD 4%, TAD 8% (p=0.08) Lokhorst et al. Haematologica 2008;93:124 7

6 Phase 3: Lenalidomide + high-dose dex (RD) vs lenalidomide + low-dose dex (Rd) ECOG trial Patients (n=445) (median age: 65 years) Primary endpoint: RR at 4 months, not designed to evaluate long-term outcomes Treatment RD: lenalidomide 25 mg/day days 1 21 every 28 days dex 40 mg days 1 4, 9 12, every 28 days Rd: same lenalidomide dose; dex 40 mg days 1, 8, 15, 22 every 28 days Results RD (n=223) Rd (n=222) CR 4% 2% VGPR 48% 40% PR 82% 71% TTP 21.7m 22.5m OS at 12m 88% 96% p=0.003 OS at 24m 75% 87% p=0.009 % RD (n=223) Rd (n=222) Neutropenia DVT/PE 25 9 Infections 16 6 Any Gr 3 non-hem AE Any Gr 4 AE 20 9 Early death OS for patients 65 years: at 12m 84% vs 95% (p=0.01), at 24m 67% vs 82% (p=0.009) for RD vs Rd, respectively Successful CD34+ collection in 97% of cases Rajkumar et al. ASH 2007 (Abstract 74)

7 Bortezomib-Dex vs VAD as induction treatment prior to ASCT in newly diagnosed MM (IFM 2005/01) Four 21-day cycles; stem cell collection between cycles 3, 4 after G-CSF Patients with newly diagnosed, symptomatic MM 65 years of age VAD VAD Bortezomib/Dex Melphalan + ASCT* DCEP (2 cycles) DCEP (2 cycles) Melphalan + ASCT* Melphalan + ASCT* (N = 480) Bortezomib/Dex Melphalan + ASCT* Stratification by cytogenetics, β2-microglobulin level Primary analysis: post-induction response *Second ASCT or reduced-intensity conditioning allogeneic transplantation if < VGPR. Harousseau et al. ASH 2007( abstract 450 )

8 Bortezomib-Dex vs VAD: response rates (Intention-to-Treat (ITT) Analysis) VAD n=242 Bortezomib-Dex n=240 Response after induction P value CR 2.9 % 9.6% CR + ncr 8.3% 21.3% < > VGPR 18.6% 46.7% < > PR 62.8% 80% < Response after ASCT CR + ncr 23.6% 35% >VGPR 41.7% 61.7% < > PR 72.7% 80.4% Response by Investigator Assessment Harousseau et al. ASH 2007 (abstract 450)

9 Toxicities during induction VAD N = 239 Bortezomib-Dex N = 238 Any AE, n (%) Grade 3, n (%) Grade 4, n (%) SAE, n (%) AE leading to study drug discontinuation, n (%) AE leading to death, n (%) Fatigue (all grades) Rash (all grades) GI symptoms (all grades) Peripheral Neuropathy Grade 1 Grade 2 Grade (85.4%) 97 (40.6%) 34 (14.2%) 74 (31%) 10 (4.2%) 7 (2.9%) 16.7% 5.4% 25.9% 22.6% 14.6% 6.7% 1.3% 209 (87.8%) 91 (38.2%) 25 (10.5%) 60 (25.2%) 16 (6.7%) 2 (0.8%) 21.4% 10.1% 22.3% 35.3% 17.2% 11.8% 6.3% Harousseau et al. ASH 2007( abstract 450 )

10 Bortezomib-Thalidomide-Dex (VTD) vs Bortezomib-Dex (TD) (GIMEMA study) RANDOMIZATION INDUCTION VEL-THAL-DEX INDUCTION THAL-DEX PBSC COLLECTION CTX TRANSPLANTATION MEL 200 MEL 200 CONSOLIDATION VEL-THAL-DEX CONSOLIDATION THAL-DEX MAINTENANCE DEX Cavo et al ASH 2007 (abstract 73)

11 Bortezomib-Thalidomide-Dex (VTD) vs Bortezomib-Dex (TD) VTD (%) TD (%) Responses after induction (n=256) P CR/nCR 36 9 < VGPR < < PR Progres. 0 5, Responses after ASCT (n=153) P CR < CR/nCR < VGPR Cavo et al ASH 2007 (abstract 73)

12 Comparison of phase 3 induction trials CR + ncr Results post-induction Harousseau Vel/dex vs VAD (n= 240 vs 242) Cavo VTD vs TD (n= 129 vs 127) Lokhorst TAD vs VAD (n=201 vs 201) Rajkumar RD vs Rd After 4 cycles (n=223 vs 222) 21% vs 8% 36% vs 9% 4% vs 2%* 2% vs 1% VGPR CR + PR 46.7% vs 18.6% 60% vs 27% 33% vs 15% 44% vs 26% 80% vs 62.8% 93% vs 80% 77% vs 54% 82% vs 70% *CR only Harousseau et al. ASH 2007 (abstract 450) Cavo et al. ASH 2007 (abstract 73) Lokhorst et al. Haematologica 2008;93:124 7 Rajkumar et al. ASH 2007 (abstract 74)

13 Need for new first-line regimens for elderly patients with myeloma Autologous transplant has become the standard of care for young MM patients More than 50% of all patients with MM will not receive a transplant Almost half of MM patients are aged >70 years Some young patients are not transplant candidates due to co-morbidities Melphalan and prednisone (MP) combination Response rate: 40 60%, CR rare, RFS: 18 m, OS: 3 years Urgent need for more active therapies for elderly patients and patients not eligible for transplantation Reece. Hematology (Am Soc Hematol Educ Program) 2005:

14 Thalidomide combinations in the upfront setting Elderly patients Regimen n CR+PR (%) CR + VGPR(%) PFS/EFS OS Reference Thal/MP vs MP & m 13.6m No statistically significant difference Palumbo, et al. Lancet 2006;367: Thal/MP vs MP vs MEL m 17.8m 19.4m Facon, et al. Lancet 2007;370: Thal/MP vs MP (>75y) * 31* m 19m Hulin, et al. ASH 2007 (Abstract 75) Thal/MP* vs MP 362 total Not reported Not reported TTP: small, but significant advantage for MPT over MP PFS: no significant difference No significant difference Waage, et al. ASH 2007 (Abstract 78) Thal/Dex* vs MP Not reported Ludwig, et al. ASH 2007 (Abstract 529) PLD=pegylated liposomal doxorubicin * Thal doses: mg & : CR+nCR

15 Lenalidomide plus melphalan and prednisone (MPR) in newly diagnosed MM Dose-escalating study N=54 Median age 71 (57 77) Results MTD: 0.18 mg/kg melphalan + 10 mg lenalidomide (n=21) Responses data at MTD CR 24% VGPR 24% PR 33% MR 19% 81% 1-year EFS: 92% 1-year OS: 100% del13 and t(4;14) did not affect response rate and survival high β2-microglobulin predicted shorter EFS Grade 3/4 AEs at MTD: neutropenia (52.4%), thrombocytopenia (23.8%), febrile neutropenia (9.5%), thromboembolic events (4.8%) Palumbo et al. JCO 2007;25:

16 VISTA: VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone Randomized, international, Phase III trial of VMP vs MP in previously untreated multiple myeloma patients who were not candidates for HDT-ASCT Patients: symptomatic multiple myeloma/end organ damage with measurable disease 65 years or <65 years and not transplant-eligible; KPS 60% R A N D O M I Z E VMP Cycles 1 4 Bortezomib 1.3 mg/m 2 IV: days 1,4,8,11,22,25,29,32 Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 days 1 4 Cycles 5-9 Bortezomib 1.3 mg/m 2 IV: days 1,8,22,29 Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 days x 6-week cycles (54 weeks) in both arms MP Cycles 1 9 Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 days 1 4 Primary endpoint: TTP Secondary endpoints: CR rate, ORR, TTR, DOR, PFS, TNT, OS, QoL (PRO) Response and progression assessed q3 weeks per EBMT 1 using central laboratory for M-protein quantification; results reported in real time to investigator for evaluation HDT-ASCT, high dose therapy-autologous stem-cell transplantation San Miguel et al. ASH 2007 (abstract 76) 1. Bladé et al. Br J Haematol 1998;102:

17 Results 682 patients randomized December 2004 September 2006 from 151 centers in 22 countries worldwide IDMC recommended study stop in September 2007 Based on protocol-specified interim analysis (data cut-off 15 June 2007) VMP was significantly superior for all efficacy endpoints Efficacy endpoint HR 95% CI p-value TTP PFS OS TNT CR 11.2* < *Odds ratio San Miguel et al. ASH 2007 (abstract 76)

18 Response to treatment High CR with VMP VMP, N=336 MP, N=331 M- protein* EBMT 1 M-protein EBMT 1 p-value ORR (CR+PR) 82% 71% 50% 35% < CR (IF-) 35% 30% 5% 4% < PR 46% 40% 45% 31% VGPR ( 90%( M-protein) 10% N/A 5% N/A *Measured in serum or urine by centralized laboratory San Miguel et al. ASH 2007 (abstract 76) 1. Bladé et al. Br J Haematol 1998;102:

19 Time to progression ~52% reduced risk of progression on VMP Percentage of subjects w/o event (%) VMP MP VMP: 24.0 months (83 events) MP: 16.6 months (146 events) HR = 0.483, P< Time (months) San Miguel et al. ASH 2007 (abstract 76)

20 Overall survival ~ 40% reduced risk of death on VMP Percentage of subjects w/o event (%) VMP MP Median follow-up 16.3 months VMP: not reached (45 deaths) MP: not reached (76 deaths) HR=0.607, P= Time (months) 30 2-years 82.6% in VMP vs 69.5% in MP <75 years 2-years 84% in VMP vs 74% in MP 75 years 2-years 79% in VMP vs 60% in MP Treatment related deaths on each arm: VMP 1%; MP 2% San Miguel et al. ASH 2007 (abstract 76)

21 Relationship between TFI and TNT Time on therapy Treatment-free interval Next therapy Percentage of subjects w/o event (%) VMP MP VMP: not reached (73 events) MP: 20.8 months (127 events) HR=0.522, P= Time to next therapy Time (months) TNT not reached for VMP vs 20.8 m for MP (P= ) Patients on VMP were 48% less likely to start secondline therapy For VMP vs MP patients, 35% vs 57% at 2-years started second-line therapy TFI not reached for VMP vs 9.4 m for MP (P=0.0001) San Miguel et al. ASH 2007 (abstract 76)

22 Grade 3/4 adverse events (%) Serious adverse events were 46% for VMP vs 36% for MP VMP (n=340) MP (n=337) Gr 3 Gr 4 Gr 3 Gr 4 Neutropenia Thrombocytopenia Anemia GI <1 Peripheral Sensory Neuropathy 13 <1 0 0 Fatigue Asthenia 6 <1 3 0 Pneumonia Herpes Zoster Transfusion (26% vs 35%) and EPO support (34% vs 42%) were somewhat lower on the VMP arm Peripheral neuropathy resolved or improved in 75% of cases in a median of 64 days DVT was low and the same on both arms (1%) DVT, deep vein thrombosis San Miguel et al. ASH 2007 (abstract 76)

23 Tolerability and safety VMP was well tolerated; patients remained on therapy for a median of 46 weeks (8 cycles) vs 39 weeks with MP (7 cycles) Patients received the same percentage of planned MP dose intensity in both arms (M=99%, P=100%) 14% of patients discontinued due to AEs in each arm San Miguel et al. ASH 2007 (abstract 76)

24 Current status in the treatment of relapsed/refractory MM with novel agents In the EU Bortezomib Approved as monotherapy after one prior line of therapy Lenalidomide Approved in combination with dexamethasone after one prior line of therapy Thalidomide Not approved

25 Efficacy of single agents in relapsed/refractory MM Regimen Phase n CR + PR CR + ncr Reference Bortezomib (APEX) III % 16% Richardson et al. Blood 2005;106 (Abstract 2547) Thalidomide II % 1.6% % 1.6% Prince et al. Leuk Lymphoma 2007;48:46 55 Glasmacher et al. Br J Haematol 2006;132: Lenalidomide II % Not stated % 4% Richardson et al. Blood 2005;106 (Abstract 1565) Richardson et al. Blood 2006;108:

26 How can responses be maximized? Regimen Phase n CR + PR CR + ncr Reference Bortezomib + DOXIL (Caelyx) % 13% Bortezomib, intermediatedose dex, cyclophosphamide Bortezomib, low-dose melphalan, dex Bortezomib, doxorubicin, dex + thal/dex % 16% (CR only) 1/ % 34% % 68% Orlowski et al. J Clin Oncol 2007;25: Kropff et al. Br J Haematol 2007;138:330-7 Popat et al. Blood 2007;110 (Abstract 2713) Lee et al. Blood 2007;110 (Abstract 2731) Bortezomib, melphalan, prednisone, thalidomide % 43% (CR + VGPR) Palumbo et al. Blood 2007;109: DOXIL, pegylated liposomal doxorubicin

27 Is it feasible to retreat with bortezomib? Data from 3 retrospective studies, and 1 prospective Phase IV study, show: Retreatment with bortezomib is feasible and results in objective responses 1 4 Retreatment does not result in cumulative toxicity Available data suggest that PN does not increase with retreatment Additionally, initial results from Phase IV study show: 4 Time from initial treatment to second relapse: 32 months 2.9 months initial treatment (median duration) 2.8 months retreatment (median duration) Prospective studies are needed to further investigate retreatment with bortezomib PN, peripheral neuropathy 1. Conner et al. Blood 2006;108 (Abstract 3531) 2. Wolf et al. Blood 2006;108 (Abstract 3532) 3. Hrusovsky et al. Blood 2007;110 (Abstract 2720) 4. Sood et al. Annals Oncology 2006;17 (Abstract 679P)

28 Bortezomib for treatment of patients with myeloma-induced (light chains) renal impairment Rationale Short time to response 1 Median time to initial response: 1.2 months First response within 4 cycles: 86% High overall and complete responses Reduces inflammation in myeloma kidney disease 2 Half-life independent of renal clearance 3 Well tolerated with toxicity similar in patients with and without renal impairment 4,5 1 Richardson P et al. Blood 2005;106:(Abstract 2547); 2 Ludwig et al. Haematologica 2007;92: ; 3 Mulkerin et al. ASH 2007:(Abstract 3477); 4 Jagannath S et al. Cancer 2005;103: ; 5 Chanan-Khan et al. Blood 2007;109:

29 Phase II: recovery of renal impairment by bortezomib-doxorubicin-dex (1) Patients 37 patients with MM-induced acute renal failure 17 patients with de novo MM; 20 with progressive disease Treatment 21-day cycle: bortezomib 1.0 mg/m 2, days 1, 4,8,11; doxorubicin 9 mg/m 2, days 1, 4, 8, 11 (until safety analysis) then 9 mg 2, days 1, 4; dex 40 mg, days 1, 4, 8, 11 Results Tumor response Evaluable patients (n=22) Glomerular filtration rate (GFR) (ml/min) Baseline Best response CR/nCR (13 45) 62.5 (20 134) PR 4 25 (15 44) 81 (16 114) MR 3 17 (10 45) 35 (33 45) NC/PD 3 13 (4 15) 18 (11 25) CR + PR 16 GFR >75 ml/min: 9 (56%) Ludwig et al. Blood 2007;110:(Abstract 3603)

30 Phase II: recovery of renal impairment by bortezomib-doxorubicin-dex (1) Results (continued) CR + PR 73%, CR + VGPR 54% Median baseline GFR 17 ml/min (4 45) improved to 46 ml/min (11 134) Significant increase in GFR (>75 ml/min) in 9 patients with PR No improvement in GFR in patients with <PR Safety (n=25) Grade 3/4 AE: anemia 9%, neutropenia 23%, thrombopenia 9%, infections 18%, PN 1% 3 patients died in cycle; 2 from pneumonia (1 sepsis) and 1 myocardial infarction Reduction in doxorubicin to days 1 and 4; addition antibacterial and antiviral prophylaxis Conclusion Acute renal failure could be reverted in 41% of the total number of patients or in 56% of patients with >PR AE, adverse event; CR, complete response; PN, peripheral neuropathy; PR, partial response; VGPR, very good partial response Ludwig et al. Blood 2007;110:(Abstract 3603)

31 Bone disease in multiple myeloma Myeloma cells Osteoblasts DKK1, sfrp-2 RANKL Bone marrow stromal cells Osteoclast precursor RANK IL-6 Activated osteoclasts Effects of bortezomib: Inhibits osteoclast activity Stimulates osteoblast activity Bone resorption Bone matrix Terpos E & Dimopoulos MA. Ann Oncol 2005;16:

32 Effect of novel agents on myeloma-related bone disease Bortezomib Large number of preclinical and clinical studies 1 9 inhibitory effect on bone resorption (osteoclasts) stimulatory effect on bone formation (osteoblasts) Effect on bone is direct and not due to anti-myeloma activity Bone anabolic effect unique to bortezomib Lenalidomide In vitro inhibitory effect on osteoclast differentiation 10 Thalidomide Inhibition of bone resorption 11,12 No effect on osteoblasts 4 1. Boissy et al. Blood 2006;108 (abstract 3508) 2. Pennisi et al. Blood 2006;108 (abstract 509) 3. Giuliani et al. EHA 2007 (abstract 884) 4. Heider et al. Eur J Haematol 2006;77: Zangari et al. EHA 2007 (abstract 695) 6. Terpos et al. Br J Haematol 2006;135: Terpos et al. IMW 2007 (abstract PO-320) 8. Zangari et al. ASH 2007 (abstract 2719) 9. Terpos et al. ASH 2007 (abstract 3596) 10. Breitkreutz et al. Blood 2006;108 (abstract 3485) 11. Terpos et al. Leukemia 2005;19: Tosi et al. Eur J Haematol 2006;76:

33 Conclusions The use of novel agents (Thalidomide, Lenalidomide, Bortezomib combinations) in induction regimens prior to ASCT or as 1st line treatment in elderly patients not appropriate for ASCT has demonstrated improved CR rates, better overall survival and PFS. Bortezomib induction regimens result in high ORR and CR pre- and posttransplant Bortezomib-Dex or VTD are superior to VAD or TD No effect on stem cell collection VMP is significantly superior over MP Rapid and durable responses with unprecedented CR rate Prolonged TTP, time to next therapy/treatment-free interval, and OS Bortezomib is effective in patients with renal impairment/failure Improvement in renal function observed Bortezomib is a highly effective treatment which can be combined with other agents in the front-line and relapsed/ refractory setting