Myeloma 2013-What we know-What we don’t know and what we don’t know we don’t know. Sergio A. Giralt, MD Chief, Adult Bone Marrow Transplant Service Division of Hematologic Oncology Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York

Disclosures Grant Support Honoraria Most important I am a transplanter Celgene Millenium Onyx Honoraria Novartis Sanofi/Genzyme Most important I am a transplanter

Initial Presentation 45-year-old woman Presents with proteinuria. Normal Physical Laboratory findings Hemoglobin 11 gm/dl normal iron stores Total proteinuria 5.82 g/day Bence Jones protein (BJP) 3.6 g/day Hypogammaglobulinemia Albumin 3.9 g/dL β2-microglobulin 4.7 mg/L Creatinine 1.7 mg/dl No paraprotein peak but kappa light chain 120000 with lambda light chain at 0.01 Kappa/lambda ratio=12000000

Bone marrow biopsy Cellularity 80% with 25% plasma cells Cytogenetics 46, XX, inversion 9 (p11;q13) FISH no abnormalities Skeletal survey: extensive lytic bone disease with healing fractures of left 7th and the 8th ribs MRI of the spine: diffuse hyper-intense homogenous signal on STIR sequence MRI of the pelvis: diffuse marrow infiltrative changes due to myeloma Comorbidities: Diabetic on metformin, no history of coronary artery disease or other comorbidities

Multiple Myeloma: Analysis Hyperdiploidy t(6:14) SC Pre Pro Early Mid SHM ICS PC t(14;16) t(4:14) t(11;14) M0 M1 M2 M3 M4 M5 M6 M7 Myeloma 3 decades Images courtesy of Raphael Fonseca, MD. 5

Multiple Myeloma Treatment Linesa Front-line treatment Maintenance Relapsed Induction Consolidation Maintenance Rescue SCT Observation IMID:Thal-Len Proteosome Inh-Bor Steroids:Dex-Pred IMID:Thal-Len-Pom Proteosome Inh:Bor-Car Steroids: Dex-Pred Alkylators:Mel-Cy-Benda Investigational IMID:Thal-Len Proteosome Inhibitor: Bor-Car Steroids: Dex-Pred Alkylator: Cyclo-Mel Anthracycline: LipoDnr-Adr aTransplant eligible patients. Bor/Dex = bortezomib, dexamethasone; Bor/Dex/Dox = bortezomib, dexamethasone, doxorubicin; Bor/Thal/Dex = bortezomib, thalidomide, dexamethasone; Len/Dex = lenalidomide, dexamethasone; SCT = stem-cell transplant; Thal/pred = thalidomide, prednsione; Bor/Liposomal/Dox = bortezomib, liposomal doxorubicin. NCCN, 2009. 6

Is there an optimal induction regimen? What we know… Is there an optimal induction regimen?

Protocol GIMEMA 26866138-MMY-3006 VTD vs TD incorporated into double ASCT for MM RANDOMIZATION INDUCTION VEL-THAL-DEX TRANSPLANTATION MEL 200 CONSOLIDATION MAINTENANCE DEX THAL-DEX PBSC COLLECTION CTX

RESPONSE TO PRIMARY THERAPY % of patients RESPONSE VTD (n=129) TD (n=127) P value CR+nCR 36 9 <0.001 ³ VGPR 60 27 < PR 7 20 0.003 Progression 5.5 0.008 EBMT criteria (with added nCR and VGPR categories)

RESPONSE (CR+nCR) TO PRIMARY THERAPY ACCORDING TO GENETIC ABNORMALITIES VTD VTD vs TD P=0.06 P=0.1 P<0.001 P=0.002 VTD VTD TD neg pos neg pos 13 pos t(4;14) pos 13 t(4;14)

Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy GIMEMA: Results Primary endpoint: CR + nCR (VTD vs TD as induction therapy) Secondary endpoints PFS OS 96% (VTD) vs 91% (TD); P = .2 1.0 Response, % VTD (n = 226) TD (n = 234) P Value CR + nCR 32 12 < .001 ≥ VGPR 62 29 ≥ PR 94 79 Progression 4.7 .001 Modified EBMT and Uniform Criteria (nCR and VGPR categories) 0.8 0.6 0.4 2-yr rates VTD (n = 226): 90% 0.2 TD (n = 234): 80% P = .009 0.0 5 10 15 20 25 30 Mos Cavo M, et al. ASH 2008. Abstract 158. 11

Meta-analysis

Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy Newly Diagnosed MM Phase II Study of Len, Bortezomib, and Dex (RVD) in Newly Diagnosed MM (Richardson et al) Pts 35 enrolled in phase II; median age 59 (22-86) yrs; ISS Stage II/III 54%/11% Dose Lenalidomide 25 mg/d, d 1-14 in 21 day cycle Bortezomib 1.3 mg/m2 d 1, 4, 8, 11 Dexamethasone 20 mg day of and after bortezomib Aspirin and antiviral prophylaxis Results At 19 mos of follow-up, TTP, PFS, and OS have not been reached Median stem cell collection in 15/35 patients: 4.4 x 106 CD34+ cells/kg Response n = 35 evaluable CR/nCR 52% < VGPR 74% ORR (≥PR) 100% Safety Grade > 3 PN in 1 pt only, VTE in 2 pts, no rx related mortality

Kaplan-Meier analyses of treatment outcomes. Kumar S et al. Blood 2012;119:4375-4382 ©2012 by American Society of Hematology

Stem Cell Collection After 4 cycles of RVD she achieves a VGPR with kappa light chains reduced to 10 and lambda light chains recovered to 0.1. Her marrow reveals 4% kappa restricted plasma cells. MRI demonstrates significant resolution of infiltrative images. She agrees to proceed to stem-cell collection and transplantation.

Optimal mobilization strategy What we know… Optimal mobilization strategy

Effect of Lenalidomide Duration of Therapy on Stem Cell Collection Lenalidomide Therapy Other Induction Therapies P value = 0.0002 P value=0.0025 P value = 0.07 P value = 0.0011 35 9 4.5 50 n=40 8 n=40 n=18 8 45 30 40 7 3.5 25 n=18 n=40 35 6 6 30 20 5 2.5 n=16 Days Percentage 25 CD34+ Count (Cells µl-1) CD34+ Count (in Millions) 15 4 4 20 3 1.5 10 15 2 2 10 5 1 0.5 5 Mean Peripheral Blood CD34+ Count Total CD34+ Cells collected (Mean x 106 cells Kg-1) Mean number of days of collection Percentage of patients who failed first collection Paripati H. Leukemia. 2008;22:12821284.

Overcoming the Negative Effects of Lenalidomide on Stem Cell Mobilization Utilizing Plerixafor Plerixafor + G-CSF N = 60 patients with myeloma frontline mobilization: 20 patients & CUP: 40 pts Median CD34 collected 5.6 x 106 CD34/kg 87% collected ≥ 2 x 106 CD34/kg 63% collected ≥ 5 x 106 CD34/kg Up front pts: 100% (≥ 2) & 95% (≥ 5) CUP pts: 80% (≥ 2) & 48% (≥ 5) Micallef I, et al. Haematologica. 2009;94(suppl 2):0718; Tarantolo S, et al. Biol Blood Marrow Transplant. 2009;15(2 suppl 2):91.

What we don’t know Is VRD superior to VTD or CyBorD? Should the goal be ‘X” number of cycles and proceed to SCT or should patients continue induction until best response? Is “response adapted” therapy appropriate? Is there a role for carfilzomib based induction? Should anybody be chemomobilized in the era of plerixafor?

Stem Cell Transplantation She collects 10 million CD34 cells per kg over 3 days and is ready to be admitted for high dose melphalan and autologous stem cell transplantation. She asks what is it going to be like and does she really need a SCT?

Role of sct in the era of imids and proteosome inhibition What we don’t know… Role of sct in the era of imids and proteosome inhibition

BENEFIT OF AUTOGRAFTING FOR MYELOMA Figure 2 BENEFIT OF AUTOGRAFTING FOR MYELOMA Koreth et all BBMT Copyright © 2007 American Society for Blood and Marrow Transplantation Terms and Conditions Source: Biology of Blood and Marrow Transplantation 2007; 13:183-196 (DOI:10.1016/j.bbmt.2006.09.010 )

Early-vs-Late SCT Study? Optimal induction regimen COLLECT HD THERAPY + SCT A A A Maintenance A A A m m m HARVEST AND HOLD SCT UPON RELAPSE Risk profile

IFM/DFCI 2009 Study Newly Diagnosed MM Pts (SCT candidates) Randomize, stratification ISS & FISH VRD x 3 Induction VRD x 3 CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg CY (3g/m2) MOBILIZATION Goal: 5 x106 cells/kg Collection Melphalan 200mg/m2* + ASCT VRD x 5 Consolidation VRD x 2 Maintenance Lenalidomide 12 mos Lenalidomide 12 mos SCT at relapse MEL 200 mg/m2 if <65 yrs, ≥65 yrs 140mg/m2 http://www.clinicaltrials.gov/ct2/show/NCT01208662?term=nct01208662&rank=1

stem cells mobilized with cyclophosphamide + G-CSF Melphalan/Prednisone/Lenalidomide (MPR) vs MEL200/ASCT Following Lenalidomide/Dexamethasone (Ld) Induction Consolidation n=402 <65 years R A N D O M I Z E R A N D O M I Z E MPR (n=202) Melphalan: 0.18 mg/kg/d, days 1–4 Prednisone: 2 mg/kg/d, days 1–4 Lenalidomide: 10 mg/d, days 1–21 q 28 days ×6 No maintenance Lenalidomide: 25 mg, days 1–21 Low-dose Dex: 40 mg, days 1, 8, 15, 22 q 28 days ×4 Tandem MEL200 ASCT stem cells mobilized with cyclophosphamide + G-CSF Maintenance lenalidomide: 10 mg/d, Days 1–21 q 28 days until relapse Primary end point: PFS Palumbo A et al. Blood. 2009;114:Abstract 350. 25

Progression Free Survival 49.4% Reduced Risk of Progression Median follow-up 26 months 2-years PFS MPR MEL200 54% 73% Median PFS Not reached 25.26 mos 0.00 0.25 0.50 0.75 1.00 5 10 15 20 25 30 35 40 45 Patients (%) Months HR 0.506 P = 0.0002 MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; PFS, progression free survival; HR, hazard ratio; mos, months

Conclusions MPR MEL200 P value CR 20% 25% P=0.55 PFS @ 24 months 54% 73% P=0.0002 OS @ 24 months 87% 90% P=0.19 Less G3-4 hematologic toxicity in MPR arm (P<0.001) Less mucositis and infections in MPR arm (P<0.001) No difference in term of early deaths Significantly longer PFS after ASCT (P<0.001) Longer follow up is needed to assess OS MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; CR, complete response; PFS, progression-free survival; OS, overall survival; ASCT, autologus stem cell transplantation

E4A03: Landmark Analysis at Median Follow-up of 36 mo 431 patients alive at 4 cycles Off therapy n=183 Primary therapy beyond 4 cycles n=248 no transplant N=93 (median age 68) Transplant n=90 (median age 57) Ld n=140 (median age 66) LD n=108 (median age 65) Rajkumar SV et al. The Lancet Oncology, Volume 11, Issue 1, Pages 29 - 37, January 2010 28 28

Outcomes in pts Age <65 Progression Free Survival Overall Survival

What we don’t know Should everybody be collected upfront? How much? Who should undergo upfront SCT? All patients? Only those with suboptimal response? What is suboptimal? PR VGPR Near CR Who is truly transplant ineligible? What about low risk patients in CR? What role does risk stratification play in deciding therapies?

FUNCTIONAL ASSESSMENT

Aging Heterogeneity Community Dwelling, Healthy Age 82 Community Dwelling, Frail Ages 19, 82, 23 Community Dwelling, Typical Institutionalized, Frail Ages 84,81

Transplant-related Mortality after Autologous Hematopoietic Cell Transplantation for Malignant Diseases by HCT-CI, 2007-2009 100 20 40 60 80 90 10 30 50 70 Incidence, % Years 15 5 25 p<0.001 HCT-CI ³ 3 (n=2,388) HCT-CI=1-2 (n=2,813) HCT-CI=0 (n=5,185) Xz12_56.ppt

100-Day Mortality by HCT-CI After Autologous Hematopoietic Cell Transplantation According to Performance Score and Disease Indication P<0.001 P<0.001 100 day mortality ,%

Rate of SCT in US according to Age Costa et al ASH 2012 <50 years 50-64 years ≥ 65 years Figure 1

Randomized Phase II LD/HD CD34

In my humble opinion High dose melphalan is one of the most active agents in myeloma today 30-40% CR 24 months median remission duration without maintenance Name another agent with similar single agent activity It is also cost-effective With stem cell support it can be given safely to older patients with comorbidities. Thus not planning for it’s use upfront is similar to telling a patient I am never going to use bortezomib or lenalidomide during your disease course because “I don’t like it” or I don’t believe in it”. Whether early or late, once twice or more times it remains an active agent that can be extremely effective in all stages of the patients disease journey.

Post sct therapies

Both have a 10/10 sibling donor available. Tales of Two Cases Case 1 55-year-old female presents with asymptomatic anemia of 10 gm/dL and total serum protein 10 gm/L Workup reveals 30% plasma cells Cytogenetic diploid IgA kappa peak of 3.2 β2M of 3.0 Receives 4 cycles of Bz/Thal/Dex Followed by Auto SCT on day 60 documented stringent CR Case 2 55-year-old female presents with asymptomatic anemia of 10 gm/dL and total serum protein 10 gm/L Workup reveals 30% plasma cells Cytogenetic t(4;14) IgA kappa peak of 3.2 β2M of 3.0 Receives 4 cycles of Bz/Thal/Dex Followed by Auto SCT on day 60 documented paraprotein peak of 0.4 g/dL Both have a 10/10 sibling donor available.

PRIMARY ENDPOINT : 3yr Progression Free Survival BMT CTN 0102 Study Schema Multiple Myeloma meeting eligibility criteria HLA typing of all patients with siblings *Biologic assignment occurred when HLA-typing results were available after enrollment. High-dose melphalan (200 mg/m2) + autologous PBSC transplant Biologic assignment* Eligible HLA-matched sibling donor No eligible HLA-matched sibling donor 60 to 120 days Non-myeloablative conditioning TBI 200 cGY allogeneic PBSC transplant High-dose melphalan (200 mg/m2) + autologous PBSC transplant Randomization† † Randomization occurred once patients were assigned to auto-auto Observation Thalidomide Dexamethasone x12 months. PRIMARY ENDPOINT : 3yr Progression Free Survival 40

1st Autologous Transplant N=710 No Sibling Donor Auto-Auto N=484 Sibling Donor Auto-Allo N=226 High Risk N=48 Standard N=189 N=436 N=37 Main groups compared

Number of Myeloma Cells Rate of molecular CR with HDT is 5% Monitoring Disease CR Definition Does Matter With Regards to Depth of Remission 1 × 1012 At diagnosis Number of Myeloma Cells Partial response – 50% reduction in M protein Near complete remission – immunofixation positive only Complete remission – immunofixation negative Nonquantitative ASO-PCR 1 × 108 Quantitative ASO-PCR flow cytometry 1 × 106 MRD 1 × 104 Rate of molecular CR with HDT is 5%

Summary High dose melphalan with autologous stem cell support remains the standard of care for consolidation therapy for patients with chemosensitive disease Current therapy with high dose melphalan followed by maintenance therapy results in more than 70% major responses and median remission durations of around 3.5-4 years. Moving forward minimizing toxicities, developing more effective conditioning regimens and better risk stratification will allow us to provide each patient with the best chance of a long life with myeloma control, good quality of life with the least treatment burden