Approach to the Treatment of Newly Diagnosed Multiple Myeloma. S. Vincent Rajkumar Professor of Medicine Mayo Clinic

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1 Approach to the Treatment of Newly Diagnosed Multiple Myeloma S. Vincent Rajkumar Professor of Medicine Mayo Clinic Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center

2 No conflicts to disclose

3 NCCN Guidelines 7 regimens 2A for transplant Eligible NCCN. 2013

4 Myeloma Treatment Strategies Aggressive therapy Sequential Therapy Triplet or quadruplet induction Early transplant Lenalidomide maintenance Doublet or mild triplet induction Early or late transplant Optional Maintenance Cure Approach Control Approach Emphasis is on CR Emphasis is on QOL

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6 Principles of Risk Adapted Therapy Avoid unproven therapies in good-risk patients Toxicity QOL Cost Patient wishes and tolerance to risk

7 PROGNOSIS IN MYELOMA Rajkumar SV et al. Blood 2011;118: ; Russell SJ et al. Lancet Oncology 2011

8 TUMOR BURDEN (STAGE) Rajkumar SV. Cecil Textbook of Medicine, 24th Edition, 2011 Rajkumar SV, Dispenzieri A. Abeloff s Clinical Oncology, 4thEdition, 2009

9 HOST FACTORS Age, performance status, comorbidities Renal Failure

10 Myeloma Risk-Stratification msmart.org High-Risk Intermediate-Risk Standard-Risk Del 17p (p53) t(14;16) (C-MAF) t(14;20) (MAF-B) High-risk GEP (gene expression profile) t(4;14) (FGFR3/ MMSET) All others including: Hyperdiploid (trisomies) t(11;14) (CCND1) t(6;14) (CCND3) Median survival <3 years Median survival 3-5 years Median survival 6-7 years *Presence of trisomies converts high risk into standard risk

11 Myeloma Risk-Stratification msmart.org High-Risk* Intermediate-Risk* Standard-Risk Del 17p t(14;16) t(14;20) GEP defined highrisk t(4;14) Hyperdiploid t(11;14) t(6;14) Outcome similar to standard risk if treated with bortezomib CR appears critical Bortezomib Critical Excellent Outcome regardless of how you treat *Presence of trisomies ameliorates high risk

12 CR is critical in patients with high-risk myeloma Low-Risk MM (87%) High-Risk MM (13%) Haessler, J. et al. Clin Cancer Res 2007;13: Copyright 2007 American Association for Cancer Research

13 Rajkumar, S. V. et al. J Clin Oncol 2008; 26: Zonder J A et al. Blood 2010;116: Harousseau J et al. JCO 2010;28: Doublet-Regimens Thal-Dex (TD) Len-Dex (RD) Bortez-Dex (VD) PFS better than Dex/VAD

14 TRANSPLANT ELIGIBLE

15 Can 3 or more drug regimens provide additional benefit? Doublets TD RD VD Triplets* VTD VRD PAD VCD *Other triplets: Anthracycline containing regimens; Carfilzomib-Rd, MLN9708-Rd

16 VTD versus VD Progression-free survival. Moreau P et al. Blood 2011;118: by American Society of Hematology

17 Cavo et al. Lancet 2010 VTD vs TD Progression free survival

18 VTD vs TD: Funzioni OVERALL di sopravvivenza SURVIVAL 1, ,8 80 RAN T-De VT-D T-De VT-D tronc sopravvivenza cumulata Overall Survival 0,6 60 0,4 40 0,2 HR, 0.76 [CI: ] p= ,0 Probability at 3 yrs (%) p= VTD 87 TD FUP Months Cavo ASH

19 PAD vs VAD: PFS and Overall Survival Sonneveld P et al. JCO 2012;30: by American Society of Clinical Oncology

20 PAD vs VAD: OS according to del(17p) Sonneveld P et al. JCO 2012;30: by American Society of Clinical Oncology

21 VRD 66 evaluable pts CR 29% ncr 11% VGPR 27% 67%* PR (33%) Overall response rate: 100% Richardson PG. Blood 2010;116:

22 VCD (CyBorD) Mayo Clinic Response, % VCD (n = 63) CR/nCR 41% VGPR 60% ORR ( PR) 90% Reeder C. Blood 2010

23 Can 4 or more drug regimens provide additional benefit? Doublets TD RD VD Triplets VTD VRD VCD PAD Quadruplets VDCR CTVD CDDV

24 EVOLUTION RANDOMIZED TRIAL VRD vs VCD vs VDCR Response, n (%) VDCR (n = 48) VRD (n = 42) VCD (n = 50) CR 25% 24% 30% VGPR 58% 51% 44% ORR ( PR) 88% 85% 82% Kumar S, et al. Blood 2012;119(19):

25 How do we choose? Doublets TD RD VD Triplets VTD VRD VCD PAD Quadruplets VDCR CTVD CDDV

26 Dose of Dexamethasone Doublets Triplets 1 Quadruplets Rd TD Rd VD VTD VRd VCd VDCR CTVD CDDV RD PAD Once weekly bortezomib) Rajkumar SV, et al. Lancet Oncology 2009

27 msmart.org Transplant Eligible-Off Study High Risk Intermediate Risk Standard Risk 4 cycles of VRd 4 cycles of VCd 4 cycles of Rd or VCd ASCT ASCT ASCT VCd or VTd Dispenzieri et al. Mayo Clin Proc 2007;82: ; Kumar et al. Mayo Clin Proc : ; Mikhael et al. Mayo Clin Proc 2013 April 1. v9 Revised and updated: Apr 2013

28 TRANSPLANT INELIGIBLE

29 MP-plus Regimens MPT VMP Facon T. Lancet 2007;370:1209 San Miguel J et al. N Engl J Med 2008;359:

30 VMPT vs VMP Overall Survival VMPT- VT Patients (%) 0.50 VMP 5-years OS Median OS 0.25 VMPT 61% Not reached VMP 51% 60.6 months HR 0.70 (95% CI, , P < Palumbo A. ASH 2012 Time (months)

31 Options in Transplant Ineligible Patients Non-melphalan based Rd VCd VRd Melphalan based MPT VMP Study Regimen TTP PFS/EFS Overall Survival (months) 3 year OS (%) Facon (Lancet 2007) San Miguel (JCO 2010) Rajkumar (Lancet Oncol 2010) MPT ~65% FIRST TRIAL MPT vs Rd VMP 24 NR* 69% Rd 25 NR* 75% (Rd age 65)

32 msmart.org High Risk Transplant Ineligible Intermediate Risk Standard Risk* VRd VCd VCd or Rd Bortezomib-based maintenance ~24 months months Rd- Can Continue till PD Dispenzieri et al. Mayo Clin Proc 2007;82: ; Kumar et al. Mayo Clin Proc : v9 Revised and updated: Jun 2011

33 MP-plus Regimens: MPR Overall Survival Patients (%) MPR - R MPR MP Time (months) Palumbo A. ASH 2010; N Engl J Med

34 TD versus MP 2009 by American Society of Hematology Ludwig H et al. Blood 2009;113:

35 RISK-ADAPTED THERAPY BIOLOGY STAGE HOST High Risk Intermediate Risk Standard Risk PCL, EMD ARF VRd VCd Rd or VCd VDT-PACE VCD or VTD Once weekly Dex (except VDT-PACE) Once weekly bortezomib (except ARF; VDT-PACE) Rajkumar SV. Am J Hematol 2013; Nature Rev Oncol 2011

36 Rajkumar SV, Merlini G, San Miguel JF. Nat Rev Clin Oncol 2012

37 Myeloma Treatment Aggressive therapy Triplet or quadruplet induction Early transplant Lenalidomide maintenance PATIENT Host Stage Biology CHOICE Sequential Therapy Doublet or mild triplet induction Early or late transplant Optional Maintenance Cure Approach Control Approach