Survival in patients with newly diagnosed myeloma undergoing ...

Hematology Highlights 2013 Frontline Therapy and Maintenance for Newly Diagnosed Multiple Myeloma P. Leif Bergsagel, M.D. Professor of Medicine Scottsdale, Arizona March 14, 2013 Rochester, Minnesota Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center Jacksonville, Florida Frontline Therapy and Maintenance for Newly Diagnosed Multiple Myeloma Smoldering multiple myeloma Transplant ineligible patients Transplant eligible patients Doublets versus Triplets Integrating Novel Agents into Frontline Regimens Proteasome inhibitors and

immunomodulatory agents Duration of maintenance SMOLDERING MULTIPLE MYELOMA AT HIGH-RISK OF PROGRESSION TO SYMPTOMATIC DISEASE: A RANDOMIZED TRIAL OF LEN-DEX AS INDUCTION FOLLOWED BY MAINTENANCE THERAPY WITH LEN ALONE VS NO TREATMENT High risk smoldering MM Both Bone marrow plasma cells >10% High M-spike IgG >3g/dL, IgA >2g/dL, Bence Jones >1g/day Or one of the above plus both: 95% phenotypically aberrant PCs by flow cytometry Immunoparesis Reductions in 1 or more uninvolved immunoglobulins of >25% Mateos et al, EHA 2012 abstract 283 SMOLDERING MULTIPLE MYELOMA AT HIGH-RISK OF PROGRESSION TO SYMPTOMATIC DISEASE: A RANDOMIZED TRIAL OF LEN-DEX AS INDUCTION FOLLOWED BY MAINTENANCE THERAPY WITH LEN ALONE VS NO TREATMENT Group A (57 patients) Lenalidomide 25mg d1-21 Dexamethasone 20mg d1-4, 12-15 Lenalidomide 10mg d1-21 Addition of Dex 20mg d1-4 for biochemical progression x 9 cycles

x 15 cycles Group B (62 patients) No treatment Mateos et al, EHA 2012 abstract 283 SMOLDERING MULTIPLE MYELOMA AT HIGH-RISK OF PROGRESSION TO SYMPTOMATIC DISEASE: A RANDOMIZED TRIAL OF LEN-DEX AS INDUCTION FOLLOWED BY MAINTENANCE THERAPY WITH LEN ALONE VS NO TREATMENT Induction After maintenance ORR 81% PR 56% VGPR 11% CR 7% sCR 7%

sCR 16% Mateos et al, EHA 2012 abstract 283 SMOLDERING MULTIPLE MYELOMA AT HIGH-RISK OF PROGRESSION TO SYMPTOMATIC DISEASE: A RANDOMIZED TRIAL OF LEN-DEX AS INDUCTION FOLLOWED BY MAINTENANCE THERAPY WITH LEN ALONE VS NO TREATMENT Progression Median TTP 3-year OS Len-dex 9/57 (16%) Not reached 93% Observation 37/61 (59%) 23 months 76% (p<0.04) Median f/u 32m Conclusion: High-risk SMM has a high mortality with

observation that can be abrogated by early treatment Mateos et al, EHA 2012 abstract 283 Proposed future state definition of multiple myeloma Current revised definition of multiple myeloma Clonal bone marrow plasma cells 10% (or biopsy proven plasmacytoma) and Evidence of end-organ damage or bone marrow plasma cell percentage 60% Future state definition of multiple myeloma Clonal bone marrow plasma cells 10% (or biopsy proven plasmacytoma) At least one of the following: Evidence of end-organ damage Bone marrow plasma cell percentage 60% High involved over uninvolved free light chain ratio (100) High levels of circulating plasma cells Absence (<5%) of normal plasma cells by immunophenotyping High bone marrow plasma cell proliferative rate by S-phase assessment on flow cytometry Deletion 17p on cytogenetic studies

3 focal lesions on MRI studies Evolving pattern: significant increases in monoclonal protein or light chain levels over time Unexplained decrease in creatinine clearance by 25% accompanied by a rise in urinary M protein or serum free light chain levels Rajkumar, Merlini, San Miguel, Nat Rev Clin Oncol 2012 (9) 494 Newly diagnosed Elderly non-transplant VMPT trial CarCtxDex Transplant candidates CarLenDex CarThalDex MLN9708-LenDex CyCarThalDex R2V2 Overall Survival Benefit for Bortezomib-Melphalan-PrednisoneThalidomide Followed by Maintenance with Bortezomib-Thalidomide (VMPT-VT) Versus Bortezomib-Melphalan-Prednisone (VMP) in Newly Diagnosed Multiple Myeloma Patients Palumbo Blood 120(21) 2012, abstract 200 VMPT+VT versus VMP for Elderly Palumbo Blood 120(21) 2012, abstract 200 VMPT+VT versus VMP for Elderly PFS VMPT+VT VMP

Palumbo Blood 120(21) 2012, abstract 200 OS VMPT+VT VMP VMPT+VT versus VMP for Elderly OS: Landmark Analysis VMPT+VT VMP VMPT+VT VMPT+VT VMP Insufficient data on bortezomib availability at Relapse VMP VMPT+VT VMPT+VT VMPT+VT VMP VMP Palumbo Blood 120(21) 2012, abstract 200 VMP

What happens in 1st 12 months? MP vs VMP MP vs MPT VTP vs VMP Fayers pooled Len-Dex v. Len-dex MP vs TD VMP vs VMPT Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for Newly Diagnosed Multiple Myeloma (MM) Patients. Palumbo Blood 120(21) 2012, abstract 730 Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for Newly Diagnosed Multiple Myeloma (MM) Patients. Palumbo Blood 120(21) 2012, abstract 730 Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for Newly Diagnosed Multiple Myeloma (MM) Patients. Palumbo Blood 120(21) 2012, abstract 730 Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for Newly Diagnosed Multiple Myeloma (MM) Patients. Palumbo Blood 120(21) 2012, abstract 730

Newly diagnosed Elderly non-transplant VMPT trial CarCtxDex Transplant candidates CarLenDex CarThalDex MLN9708-LenDex CyCarThalDex R2V2 Induction Regimens Response Rates (%) & Survival 1 Trial N nCR/ sCR >=VGPR >=PR PFS OS CarLenDex 20 75

85 95 NA NA CarThalDex1 50 18 60 92 1 yr 88% NA MLN9708Len-Dex 65 23 58 90 1 yr 93% NA CyCarThalDex 27 26 74

96 1 yr 90% NA R2V2 40 73 97 1 yr 97% 1 yr 100% 30 Induction portion of CTD x 4 followed by HDM and consolidation with CTD x 4 Blood 120(21) 2012: Korde, Abstract 732 Sonneveld Abs 333 Kumar Abs 332 Mikhael Abs 445 Kaufman Abs 336: Lenalidomide, Bortezomib, Dexamethasone, and Vorinostat The Overall, VGPR, and nCR/CR Rates for a Selection of Phase 2 and Phase 3 Trials Do we pick the therapy with the biggest green bar and call it a day? Stewart A K et al. Blood 2009;114:5436-5443 2009 by American Society of Hematology In RCT, bortezomib, but not thalidomide, is associated with improved OS in high-risk MM

Bergsagel, Mateos, Gutierrez, Rajkumar, San Miguel. Blood 2013 121:884 FISH Transplant Eligible Other Standard Risk* Intermediate* High Risk t(11;14) t(6;14) Hyperdiploid t(4;14) del17p t(14;16) t(14;20) All others Cytogenetic deletion 13 Or hypodiploidy Or PCLI>3% GEP High Risk Signature 4 cycles of Rd| or CyBorD 4 cycles of CyBorD

4 cycles of VRd Autologous stem cell tx Autologous stem cell tx especially if not in CR Bortezomib based therapy for minimum of 1 year VRd for minimum of 1 year Rd or MPT|# MP + weekly Bortezomib or weekly CyBorD VRd Observation Bortezomib maintenance Autologous stem cell tx Transplant Ineligible Collect Stem Cells # Continue Rd www.mSMART.org

Less is more for patients with high-risk cytogenetics No Cytogenic Abnormality CA13 or Hypodiploidy Other CA TT1 TT2-Thal TT2+Thal TT3a TT3b TT4 TT4-Lite 12 24 36 12 24 36 12 24 36 Overall Survival TT4 MVTD-PACE x 2, HDM200 x 2, VTD-PACE x 2, VRD x 3 years

TT4-Lite MVTD-PACE x 1, MEL50 qd x 4d with VTD, VTD-PACE x 1, VRD x 3 years Van Rhee Blood 120(21) 2012, abstract 193 Transplant Effect of Pre-transplant Salvage Therapy Prior to Autologous Transplant (AHCT) in Patients Not Responding to Initial Induction for Multiple Myeloma (MM) Trends in Utilization and Outcomes of Autologous Hematopoietic Cell Transplantation (AHCT) in the Upfront Management of Patients with Multiple Myeloma: A CIBMTR Analysis Second Primary Malignancies (SPM) following Autologous Hematopoietic Cell Transplantation (AHCT) for Multiple Myeloma (CIBMTR) Secondary Myelodysplasia-Associated Metaphase Cytogenetic Abnormalities in Newly Diagnosed Multiple Myeloma Treated On Total Therapies 2 & 3 Influence of Cumulative Dosing of Maintenance Drugs Effect of Pre-transplant Salvage Therapy Prior to Autologous Transplant (AHCT) in Patients Not Responding to Initial Induction for MM Planned upfront AHCT after initial induction improves both overall and progression free survival (OS and PFS) for patients with MM. However, it is unknown if patients with less than partial

response (PR) after a finite period of initial induction: should receive AHCT immediately or undergo salvage therapy to improve the level of response pre-AHCT Vij Blood 120(21) 2012, abstract 597 MM06-04-12_3.ppt Effect of Pre-transplant Salvage Therapy Prior to Autologous Transplant (AHCT) in Patients Not Responding to Initial Induction for MM Salvage Cohort Salvage Chemotherapy Diagnosis and Initial Induction Autologous Transplant < PR to induction No Salvage Cohort Autologous Transplant Diagnosis 12 months from diagnosis to AHCT Vij Blood 120(21) 2012, abstract 597 AHCT MM06-04-12_6.ppt

Status at Time of HCT Characteristics No Salvage Salvage P Disease status prior to transplant CR 0 (0) 25 (8) <0.001 PR 0 (0) 152 (47) MR/NR/SD 234 (93) 146 (45) PROG 17 (7) 1 (<1) Sensitivity for chemotherapy (overall) Sensitive 0 (0) 177 (55) 0.001 Time from Dx to AHCT, median (range) 7 (2-12) 8 (3-12) <4 months 86 (34) 57 (18) <0.001 4-8 months 101 (40) 85 (26) 8-12 months 64 (26) 182 (56) Vij Blood 120(21) 2012, abstract 597 MM06-04-12_10.ppt Probability of Survival, based on Response to Initial Chemotherapy (Reality Check)

PFS 100 90 OS 100 4yr PFS p = 0.0014 90 80 CR/PR to induction therapy (n=2326) 70 60 CR/PR to induction therapy (n=2326) 40 50

4 6 8 0 10 Years (Source: Txz12_19 & _20) MM06-04-12_13.ppt Outcomes with/without Pre-AHCT Salvage PFS 100 OS 100 90 90 P = NS 80 P = NS 70 80 NO SALVAGE (n=251)

60 50 SALVAGE (n=324) SALVAGE (n=324) 30 40 30 20 20 NO SLAVAGE (n=251) 10 0 0 60 50 40 10 70 2

4 6 Years 8 10 0 4 6 8 Years Median follow-up Salvage No Salvage Months Vij Blood 120(21) 2012, abstract 597 2 0 10 68 (110-180) 61 (9-181) (Source: Txz12_23 & _24) MM06-04-12_15.ppt Effect of Pre-transplant Salvage Therapy Prior to Autologous Transplant (AHCT) in Patients Not Responding to Initial Induction for MM

Multivariate Analysis: Cox proportional hazard models (left truncated to reduce waiting time bias in the SALVAGE group) Age Gender Karnofsky PS Immunoglobulin isotype Stage Serum creatinine at Dx Year of transplant Vij Blood 120(21) 2012, abstract 597 Salvage vs. no Salvage Dz status pre-ASCT Conditioning regimen Time from Dx to ASCT Single or Tandem ASCT Use of thal, bort, or len MM06-04-12_6.ppt Effect of Pre-transplant Salvage Therapy Prior to AHCT in Patients Not Responding to Initial Induction for MM: Multivariate Analysis Reference NRM Relapse/PD Mortality/OS Group* HR P HR P HR P SALVAGE vs NO SALVAGE1.03 0.93 1.01 0.3429 Creatinine at diagnosis >1.5 2.68 0.008 1.09 0.4417

Novel agent use prior to AHCT0.37 0.04 1.11 0.3207 Vij Blood 120(21) 2012, abstract 597 0.87 0.2622 1.51 0.003 0.79 0.1091 MM06-04-12_17.ppt Effect of Pre-transplant Salvage Therapy Prior to Autologous Transplant (AHCT) in Patients Not Responding to Initial Induction for MM: Conclusions In patients achieving a less than partial response (PR) after a finite period of initial induction, additional salvage therapy prior to AHCT improves the depth of response However additional salvage therapy prior to AHCT was not associated with an improvement in PFS or OS Vij Blood 120(21) 2012, abstract 597 MM06-04-12_19.ppt Trends in Utilization and Outcomes of Autologous Hematopoietic Cell Transplantation (AHCT) in the Upfront Management of Patients with Multiple Myeloma: A CIBMTR Analysis: Inclusion Criteria Recipients of first AHCT in US or Canada

First autologous transplant 1995-2010 First autologous transplant <1 year from diagnosis (upfront) Registered at CIBMTR (TED dataset) Reported to CIBMTR (CRF dataset) At least 100 days of follow up Costa Blood 120(21) 2012, abstract 596 Utilization 1995-2010 (US data only) Estimated new cases of MM 238,235* Estimated 32,151 AHCT performed in the period (23,725 registered) 68.3% performed < 1 year from diagnosis Estimated 13.4% of new cases of MM received AHCT 9.2% within one year of diagnosis Costa Blood 120(21) 2012, abstract 596 * SEER database Utilization (US data only) 65 years 60000 50000 40000 <50 years 60000 60000 50000

50000 40000 40000 30000 30000 20000 20000 10000 50-64 years First transplant in 12 months First transplant at any time Number of newly diagnosed patients 30000 20000 10000 10000 2005... 2000...

0 1995... 2005-2009 2000-2004 2005-2009 2000-2004 Costa Blood 120(21) 2012, abstract 596 1995-1999 0 1995-1999 0 Characteristics of AHCT Recipients <1 year from diagnosis (US and Canada) Two datasets: Transplant essential data (TED N= 29,489) Case report forms (CRF N= 4,373) 1995-1999 2000-2004 2005-2010 P

Median age* 54 57 58 <0.001 65* 8% 19% 24% <0.001 Stage 3 (DSS or ISS) 64% 64% 44% <0.001 1 line of therapy 70% 63%

63% <0.001 Thalidomide use <1% 22% 52% <0.001 Lenalidomide use 0% <1% 21% <0.001 Bortezomib use 0% 2% 35% <0.001 CR/PR prior to AHCT 79%

87% Costa Blood 120(21) 2012, abstract 596 *TED dataset 88% #CRF dataset <0.001 Progression-free Survival (PFS) after Auto-HCT Stratified by Period of Transplant (CRF) 100 100 90 80 Probability, % 90 Does this convergence suggest that improved induction not buying more in overall PFS? 70 80 70 60 60 50

1995-1999 (n=686) 40 50 2000-2004 (n=1,464) 40 30 30 20 20 2005-2010 (n=2,218) 10 10 0 Years 0 0 1 1995-99 2000-04 2005-10

Costa Blood 120(21) 2012, abstract 596 2 3 4 50% 55%* 57%* 5 26% 27% 23% * vs. 1995-1999, P<0.05 Txz12_17a.ppt Overall Survival (OS) after REL/PROG Stratified by Period of Transplant (CRF) 100 100 90 90 Probability, % 80 80

2005-2010(n=1,190) 70 70 60 60 50 50 40 1995-1999 (n=499) 30 40 2000-2004(n=1,021) 30 20 20 10 10 0 Years

0 0 1 1995-99 2000-04 2005-10 Costa Blood 120(21) 2012, abstract 596 2 3 4 5 58% 65%* 72%*# 22% 24% 24% * vs. 1995-1999, P<0.05 # vs. 2000-2004, P<0.05 Probability of Overall Survival (OS) after Auto-HCT Stratified by Period of Transplant (CRF)

Probability, % 100 100 90 90 80 80 2005-2010 (n=2,223) 70 60 60 2000-2004 (n=1,464) 50 50 1995-1999 (n=686) 40 40 FDA allowances 30 30

1998 Thalidomide Rx permitted, but no MM indication 5/03 Bortezomib approved 6/06 Lenalidomide approved 6/06 Thalidomide MM indication 20 10 Years 70 20 10 0 0 0 1 1995-99 2000-04 2005-10 Costa Blood 120(21) 2012, abstract 596 2 3 4 72%

81%* 86%* # * vs. 1995-1999, P<0.05 5 47% 55%* 57%* # vs. 2000-2004, P<0.05 Bortezomib maintenance UAMS: TT3 vs TT2: Bortezomib induction and maintenance improved t(4;14) OS IFM: BzD vs VAD induction: Improved t(4;14) OS HOVON: Bz induction and maintenance vs Thal induction and maintenance: Improved del17p OS PETHEMA: TV vs T vs IFNa maintenance bortezomib did not overcome impact of adverse genetics Rosiol, Blood 120(21) 2012, abstract 334 Secondary Primary Malignancies Post Transplant, with an focus on lenalidomide maintenance Study (Median follow-up)

Treatment Schedule % SPM % t-MDS/t-AL IFM 2005-02, Attal et al NEJM 2012 (45 months) Len Placebo 8% 4% 2.6% 1.3% CALGB 100104, McCarthy et al NEJM 2012 (34 months) Len Placebo 7.8% 2.6% 3% 0% MM-015, Palumbo et al NEJM 2012 (30 months) MPL-L/MPL Placebo

7% 3% 3.6% 0.6% Usmani Blood 2012, abstr 324 TT3A (VTD) TT3B (VRD) NA 3% 10% Raval CIBMTR, Blood 2012, abstr 946 Mostly no maintenance 3% 0.6% SPM-second primary malignancies, t-MDS: therapy related MDS, t-AL: therapy related acute leukemia Usmani, Blood 120(21) 2012, abstract 324 and Raval abstract 946 Secondary Myelodysplasia-Associated Metaphase Cytogenetic Abnormalities in Patients On Total Therapies 2 & 3 Influence of Cumulative Dosing of Maintenance Drugs Total Therapy Trials Schema TT3b4 TT21 TT3a2,3

n=177 n=668 n=303 INDUCTION D-PACE + T X 4 Cycles VTD-PACE x 2 Cycles VTD-PACE x 2 Cycles TRANSPLANT MEL200 x 2 MEL200 x 2 MEL200 x 2 CONSOLIDATION D-PACE + T X 4 Cycles VTD-PACE x 2 Cycles VTD-PACE x 2 Cycles MAINTENANCE T vs. Control

VTD x 1 year TD x 2 years VRD x 3 years 118 months 78 months 48 months MEDIAN FOLLOW-UP (1) Barlogie et al, NEJM 2003 (2) Barlogie et al, Br J Haematol 2007 Usmani, Blood 120(21) 2012, abstract 324 (3) van Rhee F et al, Blood 2010 (4) Nair et al, Blood 2010 Pronounced Higher Cumulative Incidence of Persistent MDS-CA in TT3B from Onset of Maintenance Incidence of any persistent MDS-CA by protocol at start of maintenance therapy 25% TT2+Thal TT2-Thal TT3a TT3b 20%

Events / N 7 / 174 6 / 157 7 / 214 7 / 120 2-Year Estimate 0.6% (0.6, 0.6) 0.7% (0.7, 0.7) 1.0% (1.0, 1.0) 0.9% (0.9, 0.9) 15% 10% 5% 0% 0 3 6 Years from onset of maintenance therapy 9 12 TT3b vs. TT3a: p= 0.004 TT3b vs. TT2-Thal: p= 0.01 TT3b vs. TT2+Thal: p= 0.0009 TT3a vs. TT2-Thal: p= NS TT3a vs. TT2+Thal: p= NS TT2-Thal vs. TT2+Thal:p= NS

Usmani, Blood 120(21) 2012, abstract 324 Thanks for inviting me Myeloma group at Mayo Rochester Arizona Vincent Rajkumar, MD Francis Buadi, MD Jane Case David Dingli, MD

Angela Dispenzieri, MD Morie Gertz, MD Suzanne Hayman, MD Lisa Hwa Shaji Kumar, MD Robert Kyle, MD Martha Lacy, MD Nelson Leung, MD John Lust, MD Arleigh McCurdy, MD Steve Russell, MD Teresa Russell Steve Zeldenrust, MD Leif Bergsagel, MD Rafael Fonseca, MD Joseph Mikhael, MD Craig Reeder, MD Keith Stewart, MD Jacksonville Asher Chanan-Khan, MD Vivek Roy, MD Tamur Sher, MD

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