Christine Chen Princess Margaret Cancer Centre September PDF Free Download

Christine Chen Princess Margaret Cancer Centre September 2013

Disclosures Research Support Celgene, Janssen, GSK Employee N/A Consultant N/A Major Stockholder Speakers Bureau/ Scientific Advisory Board N/A Celgene, Janssen, Lundbeck, Roche

Objec.ves Review the data supporting the use of maintenance in myeloma Post-transplant and transplant-ineligible patients Using thalidomide, lenalidomide, bortezomib Issues selection, toxicities, logistics

Maintenance Therapy Description Ideal characteristics Goal Endpoint Prolonged duration Low intensity Often single agent Minimal longterm, cumulative toxicity Convenient (oral) Cheap Stabilization and ongoing control of disease (not necessarily aiming to improve quality of response) PFS/EFS, TTP, TTNT, DOR (OS)

Maintenance Therapy in MM Phase 3 trials Post- transplant o Thalidomide 7 trials (thalidomide +/- steroids) o Lenalidomide IFM 2005-02 (consolida>on and maintenance) CALGB 100104 o Bortezomib Hovon MM 65/GMMG- HD4 (btz alone) Following non- transplant therapy o Thalidomide o 4 RCTs comparing MPT vs MP used thalidomide maintenance o CEMSG thal + IFN o MRC IX thal alone o Lenalidomide MM- 015 (MPR- R) o Bortezomib GIMEMA (VT following VMP- VT) PETHEMA (VT vs VP)

Thalidomide maintenance after ASCT Author (year) N Thalidomide dose (mg) / duration PFS / EFS OS Attal (2006) 597 Thal 200mg (med) vs obs / until PD + + Spencer (2006) 243 Thal 200mg + pred vs pred / 12 months + + Maiolino (2008) 212 Thal 200mg + dex vs dex / 12 months + NS Barlogie (2006) 668 Thal 400mg / until PD + NS, + in hi-risk Morgan (2012) - Thal 50-100mg / until PD +/- NS Lockhorst (2010) 550 Thal 50mg / until PD + - Stewart (2010) 325 Thal 200mg + pred vs obs / 48 months + NS Thalidomide maintenance in non-asct patients Author (year) N Thalidomide dose (mg), duration PFS / EFS OS Palumbo (2008) 331 Thal 100mg/day until relapse + NS Wijermans (2010) 333 Thal 50mg/day until relapse + + Waage (2010) 357 Thal 200mg/day until relapse NS NS Beksac (2011) 122 Thal 100mg/day continuously NS NS Ludwig (2010) 124 Thal 200mg/day + IFN until relapse + NS Morgan (2012) 327 Thal 50-100mg/day until relapse + NS Ludwig et al. IMWG consensus on maintenance in MM 2012;119:3003

The biggest problem with thalidomide maintenance is toxicity Up to 80% of patients discontinue or dose-reduce thalidomide due to toxicity NCIC Stewart et al. Blood 2013 THAL-PRED associated with significant worsening of QOL: Physical: 34% vs. 21% worsened (p=0.03) Role: 29% vs. 17% (p=0.04) Cognitive: 54% vs. 41% (p=0.01) Global: 40% vs. 26% (p=0.01)

Patients with high risk disease, particularly del(17p), have particularly poor outcomes with thalidomide maintenance High risk ifish: t(4;14), t(14;20), t(14;16), gain(1q), del(1p32), del(17p) Morgan et al. Blood 2012;119:7-15

Summary: Thalidomide maintenance Pros: Convenient (oral) PFS improvement Not myelosuppressive Cons: OS benefit unclear Cumula>ve toxici>es (neuropathy 50%) most cannot tolerate >1-2 years Not useful (may even be harmful!) in high risk disease (17pdel) Costly $1650/month at 100mg/ day Can improve quality of response (bezer as consolida>on?)

Maintenance Therapy in MM Phase 3 trials Post- transplant o Thalidomide 7 trials (thalidomide +/- steroids) o Lenalidomide IFM 2005-02 (consolida.on and maintenance) CALGB 100104 o Bortezomib Hovon MM 65/GMMG- HD4 (btz alone) Following non- transplant therapy o Thalidomide o 4 RCTs comparing MPT vs MP used thalidomide maintenance o CEMSG thal + IFN o MRC IX thal alone o Lenalidomide MM- 015 (MPR- R) o Bortezomib GIMEMA (VMPT- VT)

Lenalidomide maintenance

CALGB 100104 IFM 2005-02 N= 460 Patients 70 yo Patients < 65yo N= 614 I80% IMiD (35% Len, 45%Thal) 41% bortezomib Induction 90% VAD or bortezomib-dex 25% received additional DCEP Non-progressive after 1x ASCT Non-progressive after 1-2x ASCT Randomization Randomization Placebo (N=231) maintenance Primary Endpoint PFS/TTP Lenalidomide 10 mg/d until relapse (N=229) Lenalidomide consolidation 25 mg days1-21 q28d x 2 Placebo (N=307) maintenance Lenalidomide 10-15 mg/d until relapse (N=307) McCarthy et al. NEJM 2012;366:1770-81 Attal et al. NEJM 2012;366:1782-91

Lenalidomide Maintenance Post- ASCT Effect on PFS/EFS CALGB 100104 IFM 2005-02 39.6 mo 42 mo 21.9 mo 24 mo 24 mo Progression Free Survival (PFS) Event Free Survival (EFS) McCarthy P et al., N Engl J Med 2012;366:1770-81. Attal M., et al., N Engl J Med 2012;366:1782-91.

Lenalidomide Maintenance Post- ASCT Overall Survival Benefit? CALGB 100104 IFM 2005-02 23 deaths in len arm, 39 deaths in placebo arm Median follow-up 28 mos, P=0.018 Median followup 30 mos, P=NS McCarthy et al. NEJM 2012;366:1770-81. Attal M et al. NEJM 2012;366:1782-91

MM- 015 Phase 3 trial in non- ASCT pa.ents N = 459 Double-Blind Treatment Phase Open-Label Extension Phase Cycles (28-day) 1-9 Cycles 10+ RANDOMISATION MPR-R M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 MPR M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 MP M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 PBO: days 1-21 Continuous Lenalidomide Treatment 10 mg/day days 1-21 Placebo Placebo Disease Progression Lenalidomide (25 mg/day) +/- Dexamethasone Stratified by age ( 75 vs > 75 years) and stage (ISS I/II vs III) M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo; po, orally; ISS, International Staging System.

MP vs MPR vs MPR- R (Len maintenance) in non- ASCT pa.ents PFS OS MPR is no bezer than MP however, the addi>on of R maintenance prolongs PFS (landmark from start of maintenance: median PFS from 7 to 26 mos (HR 0.34) Palumbo et al., NEJM 2012;366:1759-69.

Are the toxicities of maintenance lenalidomide worth it? Grade 3-4 Toxicity IFM 2005-02 CALGB Len Placebo Len Placebo Neutropenia 51% 18% 45% 15% Thrombocytopenia 14% 7% 14% 4% Febrile neutropenia 1% <1% 5% 1% Documented Infection 13% 5% 6% 3% VTE 6% 2% 1% 0% Discontinuation due to toxicity Second primary malignancies 27% 15% 6% 3% 8% 4% 7.8% 2.6% 1/3 of pa.ents on lenalidomide maintenance in MM- 015 trial needed GCSF support Attal et al. NEJM 2012;366:1782-91. McCarthy et al. NEJM 2012;366:1770-81.

Is the risk of SPM cumulative over time? Incidence Rate (per 100 Patient Years) 6.00 4.00 2.00 0.00 SEER Age-specific IR of invasive cancers in ages 60-70 = 2.09 2.08 2.12 2.13 2.35 2.45 All Patients (N=3,846) 12 (N=697) 18 (N=450) 24 (N=313) 36 (N=130) Treatment Duration (Months) Incidence Rate Dimopoulos et al. Blood 2012;119:2764

Early survival benefit balanced with median >me to diagnosis of SPM (MDS/AML 28 mos; solid tumors 15 mos) Should we truncate maintenance to 1-2 years? McCarthy et al. NEJM 2012;366:1770-81

Would high risk disease benefit from lenalidomide maintenance? Risk group No. Endpoint Therapy Present Absent Reference t(4;14) 28/102 Median OS LD in RRMM 18 mos 23 mos MM- 016 26/158 Median OS LD in RRMM 9 mos 15 mos IFM 152/355 Median PFS Lenalidomide maintenance 27 mos 42 mos IFM- 2005 Del(17p) 12/118 Median OS LD in RRMM 4 mos 23 mos MM- 016 6.60% Median PFS Lenalidomide maintenance 29 mos 42 mos IFM 2005 Unfavorable FISH 16/84 3- y OS LD 77% 86% Mayo 21/105 2- y OS LD 76% 91% E4A03 Although lenalidomide improves the outcomes of cytogene>cally high risk MM, outcomes are consistently worse than low/standard risk pa>ents. Bergsagel Blood 2013;121:884

Does maintenance lead to drug resistence? MM-015 Double-Blind Treatment Phase Open-Label Extension Phase Cycles (28-day) 1-9 Cycles 10+ RANDOMISATION MPR-R M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 MPR M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 MP M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 PBO: days 1-21 Continuous Lenalidomide Treatment 10 mg/day days 1-21 Placebo Placebo Disease Progression Lenalidomide (25 mg/day) +/- Dexamethasone Stratified by age ( 75 vs > 75 years) and stage (ISS I/II vs III) M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo; po, orally; ISS, International Staging System.

Does maintenance lead to drug resistence? MM- 015 trial Received 2 nd line therapy MPR-R (N = 81) MPR (N = 117) MP (N = 127) Patients receiving Lenalidomide containing regimens Time from 2 nd to 3 rd line after a Lenalidomide regimen Time from 2 nd to 3 rd line after a Bortezomib regimen Time from 2 nd to 3 rd line after Other regimens 24 (30%) 68 (58%) 92 (72%) 18 mos 23 mos 18 mos 14 mos 16 mos 12 mos 13 mos 8 mos 10 mos Patients relapsing on Len maintenance had similar second-line treatment duration compared with those relapsing while on placebo Maintenance lenalidomide may NOT lead to more aggressive or resistant relapse Palumbo et al. ASH 2012 abstract 944

Could we achieve the same without maintenance and reserving lenalidomide for relapse? Resistent relapse Randomiza>on Post- transplant A B Len maintenance TTP 46 mos Nothing Nothing TTP 27 mos Relapse TTP? Len for relapse TTP 11 mos Which approach leads to longer survival? Route A may use up 2 therapies Nonresponders

Summary: Lenalidomide maintenance Pros: Convenient (oral) Impressive PFS improvement May not predispose to resistance Cons: OS benefit unclear Hematologic toxici>es Risk of Second Primary Malignancies (SPM) Not as effec>ve in high risk disease Costly $11,000/month using 10mg/day dosing (plus cost of GCSF $225 per 300ug vial)

HOVON- 65/GMMG- HD4 Trial: bortezomib induc.on and maintenance N=827 3 x VAD Randomiza.on 3 x PAD Bortezomib 1.3 mg/ m 2 IV Doxorubicin 9 mg/m 2 Dex 40 mg CAD + GCSF CAD + GCSF MEL 200 + PBSCT In GMMG 2 nd MEL 200 + PBSCT Thalidomide maintenance 50 mg/day for 2 years Allogeneic Tx MEL 200 + PBSCT In GMMG 2 nd MEL 200 + PBSCT Bortezomib maintenance 1.3 mg/m 2 / 2 weeks for 2 years Landmark analysis 12 mos aeer randomiza.on showed both PFS and OS benefit to Btz arm Sonneveld P et al. JCO 2012;30:2946-2955

HOVON-65/GMMG-HD4 Trial: PFS and OS in del(17p) N=65 PFS 26.2 mos 3 yr OS 69% PFS 12 mos 3 yr OS 17% Arm A VAD induction, ASCT, thal maintenance Arm B PAD induction, ASCT, bortezomib maintenance Typically, PFS post- ASCT for del(17p) is 8 mos, OS 15 mos Neben et al. Blood. 2012 Jan 26;119(4):940-8

HOVON-65/GMMG-HD4 Trial: Renal Failure OS Arm B - btz Arm A - thal Renal Failure (creatinine >2mg/dL) Months since randomisation Sonneveld et al. JCO (2012) 30:2946-2955

GIMEMA: VMPT-VT versus VMP in non-asct elderly patients Patients > 65yo (median=71) Randomization Phase III N= 511 Arm A Induction VMPT (Thal 50mg/day) Arm B Induction VMP maintenance VT x 2 years bortezomib 1.3mg/m 2 d1,15 thalidomide 50mg/d continuous Nothing Palumbo et al. JCO 2010;28:5101

VMPT-VT versus VMP in the elderly Median follow- up: 47.2 mos VMPT-VT VMP P Median PFS Not reached 27.3 mos < 0.0001 5-year OS 59.3% 45.9% 0.04 1 yr landmark analysis after induction: 4-year OS 64.6% 49.7% 0.02 2 year OS from relapse 40.7% 50.2% NS Median dura>on of VT maintenance 23.8 mos 7% grade 3-4 neuropathy 12% discon>nued due to AEs Palumbo et al. ASH 2012, abstract 200

Summary: Bortezomib maintenance Pros: OS benefit strongest of all novel agents à even in high risk disease No apparent risk of secondary malignancies and minimally myelosuppressive Cons: Limited data Inconvenient Neuropathy risk Costly - $1180 per dose (average BSA)

Conclusions: so what should we do? S>ll debatable, but Thalidomide maintenance appears passé but may s>ll have a role if used appropriately limited to 1 year, low- dose, in low- risk disease, if VGPR incorporated into consolida>on (?) Consider maintenance lenalidomide in non- high risk pa>ents 18 mos PFS benefit is s>ll remarkable, even if you don t believe there is an OS benefit Need to inform the pa>ent about risks, including SPM Dura>on unclear reasonable to aim for 1-2 years

Conclusions: so what should we do? Consider maintenance bortezomib in pa>ents who have the most to lose with progressive disease High risk 17p dele>on Renal failure Consolida.on may be the bezer route shorter dura>on, greater compliance, fewer longterm toxici>es (lower SPM risk?), likely less expensive (?) Most compelling evidence for VTD thus far but limited data More studies needed

Thank- you! PMCC Myeloma Group Dr. Donna Reece Dr. Chris>ne Chen Dr. Suzanne Trudel Dr. Vishal Kukre> Dr. Rodger Tiedemann Clinical trials manager - Giovanni Piza Transplant coordinator - Andrew Winter