Upfront Therapy for Myeloma Tailoring Therapy across the Disease Spectrum

Transcription

1 Upfront Therapy for Myeloma Tailoring Therapy across the Disease Spectrum 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 PROGNOSIS IN MYELOMA Rajkumar SV et al. Blood 2011;118: ; Russell SJ et al. Lancet Oncology 2011

3 HOST FACTORS Age, performance status, comorbidities Renal Failure

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

5 msmart.org TUMOR BIOLOGY: DISEASE AGGRESSIVENESS Myeloma Risk-Stratification High-Risk Intermediate-Risk Standard-Risk Del 17p t(14;16) (C-MAF) t(14;20) (MAF-B) GEP t(4;14) (FGFR3/ MMSET) All others including: Hyperdiploid t(11;14) (CCND1) t(6;14) (CCND3) *Presence of trisomies ameliorates high risk

6 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) CR appears critical Bortezomib Critical Excellent Outcome *Presence of trisomies ameliorates high risk

7 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

8 Principles Randomized trials Evidence of clinical benefit Survival or QOL Estimated prognosis (Risk-Adapted Therapy) Toxicity and Convenience Cost

9 Principles Risk-adapted Weak therapy for good risk patients Avoid unproven therapies in good-risk patients Toxicity QOL Cost Patient wishes and tolerance to risk

10 Approach Transplant Eligible Transplant Ineligible Melphalan-Containing Regimens Non Melphalan Containing Regimens Melphalan-Containing Regimens Non Melphalan Containing Regimens

11 Approach Transplant Eligible Transplant Ineligible Melphalan-Containing Regimens Non Melphalan Containing Regimens Melphalan-Containing Regimens Non Melphalan Containing Regimens

12 Transplant Candidates Attal M. N Engl J Med 1996; 335:97; Child J. N Engl J Med 2003; 348:1875

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 Can 3 or more drug regimens provide additional benefit? Doublets TD RD VD Triplets VTD VRD VCD

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

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

17 VTD vs TD: OVERALL SURVIVAL F u n z i o n i d i s o p r a v v i v e n z a sopravvivenza cumulata Overall Survival 1100,0 0,8 80 0,6 60 0,4 40 HR, 0.76 [CI: ] p= R A T V T V t 0,2 20 Probability at 3 yrs (%) p= VTD 87 TD 84 0, Months Cavo ASH 2010 F U P 36 48

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

19 eastern cooperative oncology group Rd versus VRd SWOG/ECOG S0777: Phase III New MM R A N D O M I Z A T I O N Rd VRd CR/PR/ Stable Prog. anytime Continue therapy till prog. or toxicity Off Rx

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

21 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):

22 Can 3 or more drug regimens provide additional benefit? Doublets TD RD VD Triplets VCD VTD VRD

23 Can 3 or more drug regimens provide additional benefit? Doublets TD RD VD Triplets VCD VTD VRD

24 Can 3 or more drug regimens provide additional benefit? Doublets TD RD VD Triplets VCD VTD VRD

25 Can 3 or more drug regimens provide additional benefit? Doublets TD RD VD Triplets VCD VTD VRD

26 ECOG E4A03 Trial: Implications for Dex Dosing 1 Survival probability Treatment O/N 1 year OS rate RD 35/223 87% Rd 10/222 96% Months Number at risk RD Rd Rajkumar SV, et al. Lancet Oncology 2009

27 Dex Dosing in Newly Diagnose Myeloma Doublets Td Rd Vd Triplets VCd VTd VRd

28 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) CR appears critical Bortezomib Critical Excellent Outcome *Presence of trisomies ameliorates high risk

29 msmart.org High Risk Transplant Eligible Intermediate Risk Standard Risk 4 cycles of VRd 4 cycles of VCd 4 cycles of Rd or VCd ASCT ASCT ASCT Dispenzieri et al. Mayo Clin Proc 2007;82: ; Kumar et al. Mayo Clin Proc : v9 Revised and updated: Jun 2011

30 TRANSPLANT INELIGIBLE

31 MTCG. J Clin Oncol 1998; 16:3832 Initial Therapy: Non-Transplant Candidates

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

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

34 Options in Transplant Ineligible Patients Non-melphalan based Rd VCd VRd Melphalan based MPT VMP

35 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) MPT ~65% San Miguel (JCO 2010) VMP 24 NR* 69% Rajkumar (Lancet Oncol 2010) Rd 25 NR* 75% (Rd age 65)

36 Options in Transplant Ineligible Patients Non-melphalan based Rd VCd VRd Melphalan based MPT VMP FIRST TRIAL MPT vs Rd

37 Options in Transplant Ineligible Patients Non-melphalan based Rd VCd VRd Melphalan based MPT VMP FIRST TRIAL MPT vs Rd

38 Options in Transplant Ineligible Patients Non-melphalan based Rd VCd VRd Melphalan based MPT VMP FIRST TRIAL MPT vs Rd

39 Options in Transplant Ineligible Patients Non-melphalan based Rd VCd VRd

40 msmart.org High Risk Transplant Ineligible Intermediate Risk Standard Risk* VRd VCd Rd or VCd 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

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

42 VMP vs VTP Trial: Implications for Bortezomib Dosing Lower risk of grade 3 or higher neuropathy with once-weekly dosing of VMP 13% (twice-weekly-vista) vs 7% (once-weekly) Mateos M. Lancet Oncol 2010; 11:

43 VMP vs VMPT Trial: Implications for Bortezomib Dosing PFS Lower risk of grade 3 or higher neuropathy with once-weekly dosing of VMP or VMPT OS 16% (twice-weekly; n=134) vs 3% (once-weekly; n=369) Palumbo A et al. JCO 2010;28: by American Society of Clinical Oncology

44 Newly Diagnosed Myeloma with special circumstances Plasma cell leukemia (PCL) Extensive extramedullary disease (EMD) Acute renal failure due to cast nephropathy

45 Plasma Cell Leukemia Plasma cell leukemia or multiple extramedullary plasmacytomas VDT-PACE x 2 cycles ASCT, if eligible Bortezomib maintenance Usmani S. Leukemia 2012

46 Acute renal failure: Cast Nephropathy Biopsy proven, or Presumptive (ARF with FLC 150 mg/dl VCD or VTD Plasma exchange and If needed hemodialysis Burnette, N Engl J Med 2011

47 Newly Diagnosed Myeloma 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 2012; Nature Rev Oncol 2011