To Maintain or Not to Maintain? Lymphoma and Myeloma 2015 Waldorf Astoria Hotel, New York Sundar Jagannath Director, Multiple Myeloma Program Tisch Cancer Institute Mount Sinai Medical Center
Maintenance therapy Goal: The purpose of maintenance therapy is to prolong remission duration and life expectancy without compromising QOL Strategy for maintenance Chemotherapy: low intensity chemotherapy to eliminate or suppress the minimal residual disease Immunotherapy: Antibodies, checkpoint inhibitors Vaccine Controversies When: after maximum tumor cytoreduction has been achieved Post transplant - fixed Non-transplant - variable End Point: Is PFS a surrogate for OS PFS1 or PFS2 Patient subgroup: best for high risk?
Endpoint: PFS not surrogate for OS PFS as Primary Endpoint Minimal change ( 25%) in paraprotein - little impact on OS Frequency of measurement arbitrary Median absolute increase in PFS by 6-9 mo - no impact on OS Post progression therapy influences OS Novel Drug combo Maintenance improves PFS and not OS 1-3 Standard Drugs PFS Crossover and/or Long Term toxicity Other TRT Altering tumor population inducing drug resistance Altering microenvironment evolution of aggressive clone, MDS Maintenance improves PFS and OS 4-6 No access to novel agent upon relapse favors treatment arm PFS Other TRT OS OS 1. Palumbo et al. N Engl J Med 2012 2. Attal et al. N Engl J Med 2012 3. Morgan et al. et al. Blood 2012 4. McCarthy et al. N Engl J Med 5. Gay et al. Blood 2013 6. Palumbo et al. J Clin Oncol 2015 7. Booth et al.,2012, ASCO
PFS Duration Regimen Duration Median F/U (mo) PFS (mo) OS (mo) Reference Thal v. no treatment Progression 71 Len v. placebo 2y 67 Len v. placebo Progression 48 22 v. 15 Δ7 46 v. 24 Δ22 TTP:50 v. 27 Δ23 Both: 60 Morgan et al. 82 v. 81 Attal et al. NR v. 73 McCarthy et al. Len v. no treatment Progression 51.2 PAD/HDM/bort v. VAD/HDM/thal 2 y 74 Bortezomib and thalidomide suboptimal Lenalidomide is better 41.9 v. 21.6 3-yr OS: Δ20.3 88.0% v. 79.2% 36 v. 27 Δ9 NR v. 84 Palumbo et al. Sonneveld et al. 1. Mohty et al., 2015, BMT
Thalidomide Therapy- MRC IX trial n=1970 R Intensive N=1144 Non Intensive N=856 CTD CVAD MP CTDa Maintenance Thal N=408 No Thal N=410 High Risk Did poorly No Survival Difference 1. Morgan et al., 2012, Blood 2. Morgan et al., Clin Can Res, 2013
Overall survival by risk group FISH + ISS VAD PAD 100 100 75 50 25 0 good intermediate poor good intermediate poor At risk: 46 83 30 44 73 22 N 46 83 30 D 6 37 24 43 68 18 41 54 9 39 48 8 31 35 5 good intermediate poor 0 12 24 36 48 60 72months 84 Cumulative percentage 19 13 2 5 3 1 75 50 25 0 good intermediate poor good intermediate poor At risk: 56 73 27 50 67 23 N 56 73 27 D 12 28 15 49 60 19 47 55 16 44 46 16 38 38 10 good intermediate poor 0 12 24 36 48 60 72months 84 27 11 4 10 30 Good Risk: no t(4;14)/del17p/add1q and ISS I Intermediate Risk: either t(4;14)/del17p/add1q and ISS I or no t(4;14)/del17p/add1q and IISS II/III Poor Risk: t(4;14)/del17p/add1q and ISS II/III 1. Neben et al 2012
PFS2 an option? Maintenance improves PFS and not OS Long Term toxicity Altering tumor population inducing drug resistance Altering microenvironment evolution of aggressive clone, MDS The European Medicines Agency (EMA) recommends use of PFS2 1.Dimopoulos et al. Haematologica 2015
PFS2 is not the answer EMA has recently recommended using PFS2 PFS on next line therapy (PFS1 + 2 nd PFS) 1. 2 nd PFS = from 1 st to 2 nd progression First line Second line Third line 4 th line x th line death 2. PFS 2 = 1 st PFS + 2 nd PFS First line Second line Third line 4 th line x th line death MM-015 Post hoc assessment showed benefit for early and continuous use of lenalidomide No overall survival benefit Dimopoulos et al. Haematologica 2015
MM-015: PFS and PFS2 9 1 st Line Tx MPR-R (n=152) MP (n=154) PFS Median: 31 mos Median: 13 mos 2 nd Line Tx No PD n=62 Deaths before 2 nd line n=5 Pts who Started 2 nd Line Tx (n=85) Bort N=42 MP + Late Deaths Len (n=154) Median: before 28.8 2 nd mos line No PD n=5 n=20 Pts who Started 2 nd Line Tx (n=129) Len N=93 PFS2 MPR-R (n=152) Median: 39.7 mos MP (n=154) Median: 28.8 mos 1. Dimopoulos MA Haematologica 2015.
Continuous Therapy Trials in >65 yrs First N=535 Rd cont. Rd x18 (72 weeks) MPT x12 (72 weeks) Benboubker et al. NEJM 2014; 371:906 MM015 N=459 MPR+R MPR x9 MP x9 Palumbo A. N Engl J Med. 2012;366:1759-69 EMN N=660 RD x9 CPR x9 MPR x9 R RP Palumbo et al. Blood 2013;122:21 Abs#536 1. Palumbo et al. JCO 2015
Treatment of MM: Continuous therapy is better Rdc N = 535 FIRST Rd 18 N=541 FIRST MPT N=547 FIRST MPR-R N = 152 MM-015 MPR N=153 MM-015 MP N=154 MM-015 MPV N = 337 San Miguel Age (>75) 35% 36% 34% 24% 24% 25% 31% Efficacy CR + PR 75% 73% 62% 77% 68% 50% 71% CR 15% 14% 9% 10% 3.3% 3.2% 30% PFS (mos) 26 21 21 31 12 15 22 OS at 2 yrs 80% 78% 76% 84% 80% 80% 78.5% 1. Continuous therapy gives better outcome 2. Length of induction >12 mo. No further improvement in CR rate 3. Adding Proteasome Inhibitor increase CR rate 1. Benboubker et al. NEJM 2014; 371:906 2. Palumbo A. et al. N Engl J Med. 2012;366:1759-69 3. San Miguel JF et al. N Engl J Med. 2008; 359:906
PFS2 is better for no maintenance! % of patients Induction- Consolidation 1.00 Maintenance Median CT 32 months PFS1 FDT 40 months PFS2 0.75 0.50 PFS2 0.25 PFS1 0 0 12 24 36 48 60 Months 1. Adapted from Palumbo, 2014 ASCO
Patients (%) Second Primary Malignancies All Patients 100 PD/Death Hematologic SPM Solid Tumor MPR -R 100 MPR 100 MP 75 75 75 50 50 50 25 25 25 0 0 0 0 20 40 60 0 20 40 60 0 20 40 60 Time (Months) Time (Months) Time (Months) SPM, n (IR per 100 per year) MPR -R MPR MP (n = 150) (n = 152) (n = 153) Total Invasive SPMs 12 (3.04) 10 (2.57) 4 (0.98) Hematologic 7 (1.75) 6 (1.54) 1 (0.24) Solid tumors 5 (1.26) 5 (1.28) 3 (0.74) Non -melanoma skin cancer 2 (0.50) 5 (1.29) 6 (1.50) 1. Palumbo ASH 2011; abs#470
Maintenance Therapy - Conclusion Chemotherapy maintenance: Treat until maximum tumor cytoreduction and a minimum of 12 months Good Risk No Maintenance High Risk Continuous Therapy Post-transplant: Consider second transplant or consolidation if less than VGPR Consider maintenance not in VGPR or better New paradigm with Immunotherapy Elotuzumab Check point inhibitors Vaccines