Multiple Myeloma: Transplant Controversies and Organ Damage

Multiple Myeloma: TransplantControversies and Organ DamageAdetola Kassim, M.D.Associate Professor of MedicineHematology / Stem Cell TransplantVanderbilt-Ingram Cancer CenterNashville, TennesseeVanderbilt-IngramCancer Center

Disclosures: Adetola Kassim, M.D.I have the following financial relationships to discloserelevant to the content of this presentation:• Advisory Board: Millennium, Celgene, NovartisVanderbilt has determined that there are no conflicts ofinterest.

Presentation Outline Stem Cell Transplantation- Autologous- Allogeneic- Consolidation + Maintenance Organ Damage- Bone disease- Peripheral neuropathy- Renal Disease

Pre-Transplant Novel Agents and AHCTOutcome – ASH Abstract 1347, Osman et. al Impact of pre-transplant remission status on AHCToutcome: Thalidomide/Lenalidomide/Boretzomib N = 63; median age 53 yrs (44 – 72); 63% male 66% DS stage III; 34% stage I/II; KPS 90; HCT-CI – 0 Pts had single AHCT; Mel200 (140 S.Cr >2mg/dl) 31pts with PR -> 15 CR, 2 VGPR, 14 PR and 1 SD 17pts with CR remained in CR s/p AHCT 6 pts VGPR -> 2 CR, 14 maintained VGPR 9 pts SD -> 5 CR, 3 PR, 1 SD

Pre-Transplant Novel Agents and AHCTOutcome – ASH Abstract 1347, Osman et. alMedian follow-up of 36 monthsComparison groups N = 63 OS P PFS PP vs No-P-group 54 / 9 58 / 60% 0.93 22 / 31% 0.74V vs No-V-group 40 / 23 44 / 62% 0.53 22 / 24% 0.72All patients NRM = 5%

Long-Term Follow-up: Tandem auto-allo vs autoautoin newly diagnosed myeloma, Italianexperience. Bruno et. al, ASH Abstract # 525 162/199 (81%) of patients were HLA-typed. Induction with VAD-based regimens; median f/up of7.3yrs (range 5.4 – 10.7+ years) 58/46 patients received auto-allo vs auto-auto Median OS NR/5.3yrs (HR 0.55, CI 95% 0.32-0.94,p=0.02), whereas EFS was 39/33 months (HR 0.62, CI95% 0.40-0.96, p=0.02) respectively. TRM was 11% and 2% at 2 years respectively. CR rate was: 55% versus 26% (p=0,0026), Having an HLA matched sib, correlated with OS/EFS

Tandem Autologous Stem Cell Transplants (auto-auto) with orwithout Maintenance Therapy versus Single Autologous TransplantFollowed by HLA-Matched Sibling Non- MyeloablativeAllogeneic Stem Cell Transplant (auto-allo) for Patients (pts) withHigh Risk (HR) Multiple Myeloma (MM): Results from the Bloodand Marrow Transplant Clinical Trials Network(BMT-CTN) 0102 TrialEdward A. Stadtmauer, Amrita Krishnan, Marcelo Pasquini, MarianEwell, Joseph Antin, Hugo Castro-Malaspina, Adetola Kassim,Robert Negrin, Muzaffar Qazibash, J. Douglas Rizzo, Scott Rowley,Firoozeh Sahebi, David Vesole, Dan Vogl, Daniel Weisdorf, NancyGeller, Mary M. Horowitz, David Maloney, Sergio GiraltOn behalf of the Blood and Marrow Transplant Clinical Trials Network

BMT-CTN 0102 Trial Phase III multicenter trial that biologically assignedpatients to auto-auto (+ 1 year of ThalDex) vs auto-allo HR = -13q deletion and beta-2 microglobulin >4 mg/dl 85 HR, 48 auto-auto (24 ThalDex; 24 Obs); 37 auto-allo 59 (31 auto-auto, 28 auto-allo): median age 57 vs 51yr; Compliance with ThalDex was poor in auto-auto 3yr PFS 35% vs 46% (p=0.6); TRM 8% vs 20% Equivalent 3yr PFS and OS in both groups Trends in late PFS, TTP and relapse need follow-up

Proportion SurvivingBMT-CTN 0102 Trial(b) Progression Free Survival Post First Transplant. High Risk Group.10.90.80.795% CI at 3 years0.60.50.40.330.270.22p-value=0.740.60.50.4Auto/Allo0.30.2Auto/AutoNumber at risk:48 39 33 23 20 17 14 3 2 Auto/Auto37 30 20 18 15 14 13 4 4 Auto/Allo0 6 12 18 24 30 36 42 48 54 60Month Post 1st Transplant

Reduced Intensity Conditioning (RIC) AllograftStrategies in Myeloma: ASH Abstract # 3512, Sahebi et. Al Retrospective analysis of EBMT database; n = 504 Auto-allo (253/356) vs early RIC-allo (148) as first SCT Early RIC pts were younger (51 vs. 53 yrs; p=0.03); 51%had SCT between 1998-2002 vs. 33% (P CR at HCT (17% vs. 9% P=0.008). Median follow-up of 52 months, auto-allo had best CR62 vs. 47%; PFS 31 vs 17%; OS at 5ys 60 vs 37% (p

Role of Reduced Intensity Conditioning (RIC) Allograftin Relapsed Multiple Myeloma after Autograft:Donor vs No Donor: ASH Abstract #3534, Patriarca et. Al 169 pts; 24 sibling donor (35%), 44 MUD (75%). Median age: donor vs no donor (53/59 years, p

Phase 3 Study Evaluating Lenalidomide Maintenance inPatients > 65 years with Newly Diagnosed MultipleMyeloma (NDMM): ASH Abstract 622, Palumbo et. al. 459 pts; stratified by age and ISS stage Randomized to receive MPR-R, MPR or MP Primary comparison was MPR-R vs MP Update of 70% interim analysis at 21 months MPR-R vs MP reduced the risk of disease progressionby 58% (HR 0.423, P < .001) and MPR-R vs MPR by69% (HR 0.314, P < .001); limited follow-up for OS ORR, CR, VGPR and PFS better with MPR-R Discontinuation due to AEs 20 and 8%

Lenalidomide MaintenanceLong-Term Maintenance with Lenalidomide Improves PFS inMultiple Myeloma patients with High Rsk Cytogenetics:An IFM study. ASH Abstract #1944: Herve Avet-Loiseau. et al.- Median PFS for del(4;14), del(17p) and placebo were 27, 29 and14 months respectively, favoring ―no abnormality‖Lenalidomide Maintenance Following Non MyeloablativeAllogeneic Stem Cell Transplant in Patients with MultipleMyeloma: Results of the HOVON 76 study:ASH Abstract #3502: Minnema et. al.- 35 pts treated with 10mg lenalidomide 21/28 days x 24 mths- 10pts responses: 5 PR -> 3 VGPR, 2 CR; 5 VGPR -> CR- 63% acute (late onset) GvHD; PFS similar to HOVON 54 study

Weekly Maintenance Bortezomib s/p Auto-PBSCT inMultiple Myeloma: Results of a Phase II ProspectiveStudy. ASH Abstract #2399, Sahebi et. al 39/45 received bor/dex, 4-8 weeks s/p PBSCT 25 pts completed planned 6 months of Rx At 6 mths15/25 pts (60%) achieved CR; 9/25(36%) upgraded their response with bor/dex. 8 pts (24%) d/c due to toxicities; at 1 year,14/28 pts (50%) remain in CR. 8 pts developed new PN, all are grade I-II. Median bortezomib dose is 1.3 mg /m 2 / week.

Effect of Thalidomide Maintenance on PFS and OS inMultiple Myeloma: MRC Myeloma IX Results.ASH Abstract #623, Morgan et. al 818/820 evaluable; median age 65 yrs (31−89). Median f/up was 38 months (12−66). Median time on maintenance 7 months (0−50). Improved PFS by 13% (CI 6%−20%) from 24 -66 months (HR 1.36; CI 1.15−1.61; P < 0.001). However, no apparent impact on OS (P = 0.40). No response upgrade or impact of novel agents

Consolidation Therapy in Multiple Myeloma:ASH Abstract #861, Terragna et. al. Molecular sub-study to the phase 3 GIMEMA trial Induction with VTD vs. TD -> Tandem-Auto -> twoconsolidation therapy with VTD or TD starting 3 monthsafter ASCT(s), independently from prior response 67/84 pts were analyzed for MRD by qPCR Upgrade in PCR-ve 37.5% ->52% with TD consolidationand 43% -> 67% with VTD consolidation (p=0.05). Post-consolidation PCR-ve >VTD vs. TD (p=0.05). Median 1 log reduction in tumor burden with TDconsolidation vs. a median 5 log reduction with VTDconsolidation (p=0.05) .

Bone Destruction and Myeloma Growth—aStimulatory LoopOsteolytic lesionBPBone matrixOsteoclastOsteoblastTGF-bFGF-1&2IGF-1&2PDGFMyeloma cellsRANKLTNF-bIL-1bIL-6Stromal cells17

MRC Myeloma IX-AnalysisSchematic for ZOL vs CLON = 1,960Patients with newlydiagnosed MM(stage I, II, III)RANDOMISATIONZoledronic acid (4 mg a IV q 3-4 wk) +intensive or non-intensive chemotherapy(n = 981)Bisphosphonate treatment continued at leastuntil disease progressionClodronate (1,600 mg/d PO) +intensive or non-intensive chemotherapy(n = 979)Endpoints (ZOL vs CLO)Primary: PFS, OS, and ResponseSecondary: SREs (time to first SRE, SRE incidence) and SafetySREs were defined as vertebral fractures, other fractures, spinal cord compression,and the requirement for radiation or surgery to bone lesions, or the appearance ofnew osteolytic bone lesions.Abbreviations: CLO, clodronate; IV, intravenous; MM, multiple myeloma; OS, overall survival, PFS, progression-free survival; PO, oral;18SRE, skeletal-related event; ZOL, zoledronic acid.aDose-adjusted for patients with impaired renal function, per the prescribing information.

MRC Myeloma IX - Study Endpoints Primary endpoints• Overall survival (OS)• Progression-free survival (PFS), defined as time fromrandomisation to disease progression or death• Response Secondary endpoints• Proportion of patients with an SRE; SRE timing• Safety Statistical methods• PFS and OS were assessed by Kaplan-Meier and Coxproportional hazards models• Statistical significance was assigned for P < .05 with no correctionfor multiplicity of comparisons

MRC Myeloma IX- Trial Status N = 1960; 121 centers in the UK Median follow-up: 3.7/3.8 years – ZOL/CLO Median time on study drug (days)- Intensive: 396 ZOL; 409 CLO- Non-intensive 320 ZOL; 306 CLO Off-study:- Progressed or died: 59.5% ZOL; 64% CLO- Stopped before progression:24% ZOL and 19% CLO

MRC Myeloma IX Study – ASCO Update 28% on ZOL and 26.7% on CLO- no bone disease (BD-) PFS amongst BD+: 20.4 vs 18 mo (HR = 0.90; P= .101);BD- pts: no difference for ZOL vs CLO (18 mo each; HR= 0.99; P = .885). ZOL improved PFS (HR = 0.88; P = .0179) vs CLO Overall, risk of SRE was 0.36 for CLO and 0.29 for ZOLwith BD (a 19% reduction), and 0.12 for CLO and 0.07for ZOL in pts without BD (42% reduction).ASCO 2011: Abstract #8010, Boyd et. al.

Cumulative Incidence FunctionMRC Myeloma IX—ZOL Maintained Trendto 1st SREs vs CLO Beyond 3 Years0.200.15P = .1012 log–rank0.100.05CLOZOL3 years00 6 12 18 24 30Time Since 3-Years Post-randomisation, monthsPatients, nZOL 190 133 92 61 32 15CLO 162 105 78 48 25 9Abbreviations: CLO, clodronate; SRE, skeletal-related event; ZOL, zoledronic acid.ASCO 2011: Abstract #8011 Davies et. al.

MRC Myeloma IX Study – ASCO Update:Benefits to long-term bisphosphonate treatment In MMIX, Median OS was 5.5 months longer with ZOL vsCLO (hazard ratio [HR]=0.84; 95% CI, 0.736, 0.963;P=.012). OS benefit from ZOL vs CLO was especially profoundduring the first 4 months ZOL significantly reduced the risk of death by 36%relative to CLO (HR=0.64; P=.004).ASCO 2011: Abstract #8011 Davies et. al.

MRC Myeloma IX- ZOL OS and PFS vs CLO(Overall Population)OS (overall)0.842Riskreduction16%P value.01185.5 months(adjusted for SRE) a0.85015%.0178PFS (overall)0.88312%.01792.0 months0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2Hazard ratio (ZOL versus CLO)In favour of ZOLIn favour of CLOAbbreviations: CLO, clodronate; OS, overall survival; PFS, progression-free survival SRE, skeletal-related event; ZOL, zoledronic acid.Time to first SRE was included as a time-dependent covariate in an exploratory Cox modelexamining OS.Data from Morgan GJ, et al. Lancet. 2010;376(9757):1989-1999.

Comparative Effectiveness ofBiphosphonates in Multiple Myeloma 18 RCTs were included enrolling 4,970 patients. Only 3RCTs employed head to head comparison ofbisphosphonates in patients with MM using MTC. OS: ZOL > CLO and Eti; PFS: ZOL > CLO SRE: ZOL > CLO, IBAN, PAM Incidence of ONJ was higher in zoledronate [OR: 12.03(95% CI: 3.68 to 39.26)] compared to clodronate. Efficacy: ZOL > CLO > PAMASH 2010: Abstract #3028, Mhaskar et. al.

Comparative Effectiveness ofBiphosphonates in Multiple MyelomaComparison Outcome HR 95%CI Numberneeded totreat (range)ZOL vs. CLO OS 0.83 0.73 - 0.94 15 (9 -35)ZOL vs. ETI OS 0.48 0.31 – 0.71 4 (3 - 8)ZOL vs. IBAN OS 0.70 0.42 – 1.11 ---------ZOL vs. PAM OS 0.84 0.61 – 1.13 ---------ZOL vs. CLO PFS 0.88 0.78 -0.99 21 (11 – 270)ZOL vs. PAM PFS 0.93 0.32 - 2.17ZOL vs. CLO SREs 0.75 0.64 – 0.88 13 (8 – 16)ZOL vs. ETI SREs 0.74 0.29 – 1.61ZOL vs. IBAN SREs 0.44 0.26 – 0.72 4 (3 – 10)ZOL vs. PAM SREs 0.65 0.42 – 0.95 12 (6 – 86)ASH 2010: Abstract #3028, Mhaskar et. al.

Evaluation of Peripheral Neuropathy (PN)(PASS) of Lenalidomide vs Other Therapies inPatients with R/R Myeloma. Prospective study, 1011 pts with MM in 177institutions in 15 European countries Baseline PN- 39% in Lenalidomide (22% due toprior bortezomib, 15%-thalidomide); 21% inBortezomib (3%-bortezomib, 13%-thal, 2%-vincristine, non-drug- 4-6%) Patient discontinuation due to AEs: Thal-24.5%;Lenalidomide 14.1% and bortezomib 15.5%ASH 2010: Abstract #1939, Delforge et. Al.

AEs in Lenalidomide, Bortezomib andThalidomide cohortsPatients with at least one drugrelatedAE, n (%)Patients with at least one drugrelatedAE of PN, n (%)Patients with at least one drugrelatedgrade 3* or 4**AE ofPN, n (%)Patients with at least one AE ofPN leading to treatmentdiscontinuation, n (%)Lenalidomide(n = 658)Bortezomib(n = 207)Thalidomide(n = 53)326 (49.5) 93 (44.9) 37 (69.8)30 (4.6) 41 (19.8) 7 (13.2)7 (1.1) 9 (4.3) 05 (0.8) 10 (4.8) 0*Grade 3: symptomatic (sensory) or weakness (motor), interfering with ADL**Grade 4: disabling:ASH 2010: Abstract #1939, Delforge et. Al.

Baseline PN does not impact the efficacyand tolerability of Carfilzomib in R/R MM 89% (n = 266) pts on PX-171-003-AI had h/o PN fromprior therapies (Thal 41%, BTZ 50%, both 6.4%) 77% had G1/2 PN at baseline, MDD 5.9yrs, 5-PLT Median duration of response was 7.4 months (>PR) AEs > primarily hematological 65%; fatigue 7% New or worsening PN uncommon: any grade 15%; G3PN 0.4%, paraesthesias 6.8%; dysesthesias 0% PN has no impact on depth or durability of responsesASH 2010: Abstract #3031, Martin et. Al.

Renal Dysfunction in Newly DiagnosedMyeloma: Survival outcome 1478 pts at Mayo Clinic- Jan 1999 – 2009 Median age 64 years; 50% male; median follow-up 3years; 781 pts alive at analysis Serum Cr (sCr) >15 mg/dl 22.5%; >2.5 mg/dl in 10% Median OS if sCr was >1.5 vs 1.5 mg/dl at 4 months ?negative impact of organ dysfunction on survivalASH 2010: Abstract #2970, Kumar et. Al.

Renal Dysfunction in Newly DiagnosedMyeloma: Overall survival from Diagnosis1: Cr 1.5 mg/dL at diagnosis but improved to 1.5 mg/dL at diagnosis and never recovered to