upfront therapy for myeloma - tailoring therapy across the...

Mayo Clinic College of MedicineMayo Clinic Comprehensive Cancer Center

Upfront Therapy for MyelomaTailoring Therapy across the Disease Spectrum

S. Vincent RajkumarProfessor of Medicine

Mayo Clinic

Scottsdale, ArizonaScottsdale, Arizona Rochester, MinnesotaRochester, Minnesota Jacksonville, FloridaJacksonville, Florida

Rajkumar SV et al. Blood 2011;118:3205-3211; Russel l SJ et al. Lancet Oncology 2011

PROGNOSIS IN MYELOMA

HOST FACTORS

• Age, performance status, comorbidities

• Renal Failure

Rajkumar SV, Dispenzieri A. Abeloff’s Clinical Oncol ogy, 4thEdition, 2009

Rajkumar SV. Cecil Textbook of Medicine, 24th Editi on, 2011

TUMOR BURDEN (STAGE)

TUMOR BIOLOGY: DISEASE AGGRESSIVENESSMyeloma Risk-Stratification

� Del 17p� t(14;16) (C-MAF)� t(14;20) (MAF-B)� GEP

All others including:

� Hyperdiploid

� t(11;14) (CCND1)

� t(6;14) (CCND3)

� t(4;14) (FGFR3/ MMSET)

High-Risk Intermediate-Risk Standard-Risk

msmart.org

*Presence of trisomies ameliorates high risk

Myeloma Risk-Stratification

� Del 17p� t(14;16)� t(14;20) � GEP defined high-

risk

� Hyperdiploid

� t(11;14)

� t(6;14)

� t(4;14)

High-Risk* Intermediate-Risk* Standard-Risk

msmart.org


CR appears critical Bortezomib Critical Excellent Outcome

Copyright ©2007 American Association for Cancer Research

Haessler, J. et al. Clin Cancer Res 2007;13:7073-7079

CR is critical in patients with high -risk myeloma

Low-Risk MM (87%) High-Risk MM (13%)

Principles

• Randomized trials

• Evidence of clinical benefit• Survival or • QOL

• Estimated prognosis (Risk-Adapted Therapy)

• Toxicity and Convenience

• Cost

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

Approach

• Melphalan-Containing Regimens

• Non Melphalan Containing Regimens

• Melphalan-Containing Regimens

• Non Melphalan Containing Regimens

Transplant Eligible Transplant Ineligible

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

54

42

Transplant Candidates

Rajkumar, S. V. et al. J Clin Oncol 2008; 26:2171-21 77 Zonder J A et al. Blood 2010;116:5838-5841Harousseau J et al. JCO 2010;28:4621-4629

Thal-Dex (TD) Len-Dex (RD) Bortez-Dex (VD)

Doublet-Regimens

PFS better than Dex/VAD

Can 3 or more drug regimens provide additional benefit?

Doublets• TD

• RD

• VD

Triplets• VTD

• VRD

• VCD

VTD versus VD Progression-free survival.

Moreau P et al. Blood 2011;118:5752-5758

©2011 by American Society of Hematology

VTD vs TDProgression free survival

Cavo et al. Lancet 2010

0 1 2 2 4 3 6 4 8

F U P

0 ,0

0 ,2

0 ,4

0 ,6

0 ,8

1 ,0

sop

ravv

iven

za c

um

ula

taR A N D O M

T -D e xV T -D e xT -D e x- tro n c a taV T -D e x-tro n c a ta

F u n z i o n i d i s o p r a v v i v e n z a

360 12 24

Months

Ove

rall

Sur

viva

l

100

80

60

40

20

0

48

VTD vs TD: OVERALL SURVIVAL

HR, 0.76 [CI: 0.46-1.27]p=0.3071

Probability at 3 yrs (%)p=0.3042

VTD87

TD84

Cavo ASH 2010

VRDEfficacy: Overall

• 66 evaluable ptsCR 29%nCR 11%VGPR 27%

PR (33%)

• Overall response rate: 100%

67%*

Richardson PG. Blood 2010;116:679-686

eastern cooperative oncology groupeastern cooperative oncology group

Rd versus Rd versus VRdVRd

VRdVRd

RdRd CR/PR/StableCR/PR/Stable

Prog.anytimeProg.anytime

Continue therapytill prog. or toxicity Continue therapytill prog. or toxicity

Off RxOff Rx

RANDOMIZATION

SWOG/ECOG S0777: Phase III – New MMSWOG/ECOG S0777: Phase III SWOG/ECOG S0777: Phase III –– New MMNew MM

VCD (CyBorD )

Mayo Clinic

Response, %VCD

(n = 63)

CR/nCR 41%

≥≥≥≥ VGPR 60%

ORR (≥≥≥≥ PR) 90%

Reeder C. Blood 2010

EVOLUTION RANDOMIZED TRIALVRD 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):4375-82.

Can 3 or more drug regimens provide additional benefit?

Doublets• TD

• RD

• VD

Triplets• VCD

• VTD

• VRD

Number at riskRD 223 179 103 37 0Rd 221 192 103 37 0

Sur

viva

l pro

babi

lity

Months

ECOG E4A03 Trial: Implications for Dex Dosing

0

0.2

0.4

0.6

0.8

1

0 6 12 18 24

Treatment O/N 1 year OS rateRD 35/223 87%Rd 10/222 96%

Rajkumar SV, et al. Lancet Oncology 2009

Dex Dosing in Newly Diagnose Myeloma

Doublets• Td

• Rd

• Vd

Triplets• VCd

• VTd

• VRd

Myeloma Risk-Stratification

� Del 17p� t(14;16)� t(14;20) � GEP defined high-

risk

� Hyperdiploid

� t(11;14)

� t(6;14)

� t(4;14)

High-Risk* Intermediate-Risk* Standard-Risk

msmart.org


CR appears critical Bortezomib Critical Excellent Outcome

Transplant Eligible

Standard Risk

4 cycles of Rd or VCd

High Risk

4 cycles of VRd

Intermediate Risk

4 cycles of VCd

ASCT

Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Ku mar et al. Mayo Clin Proc 2009 84:1095-1110v9 Revised and updated: Jun 2011

ASCT ASCT

msmart.org

TRANSPLANT INELIGIBLE

MTCG. J Clin Oncol 1998; 16:3832

Initial Therapy: Non-Transplant Candidates

Facon T. Lancet 2007;370:1209San Miguel J et al. N Engl J Med 2008;359:906-917

MPT VMP

MP-plus Regimens

MP-plus Regimens: MPR

Palumbo A. ASH 2010; N Engl J Med 2012

1

0 5 10 15 20 25 30 35 400

25

50

75

100

Time (months)

Pat

ient

s (%

)

0 5 10 15 20 25 30 35 400

25

50

75

100

0 5 10 15 20 25 30 35 400

25

50

75

100

Time (months)

Pat

ient

s (%

)

•

MPR-R

MPR

MP

MPR-R

MPR

MP

Overall Survival

Options in Transplant Ineligible Patients

Non-melphalan based

• Rd

• VCd

• VRd

Melphalan based

• MPT

• VMP

NR*

NR*

52

Overall Survival (months)

69%24VMP San Miguel(JCO 2010)

75% (Rd age ≥65)

25RdRajkumar(Lancet

Oncol 2010)

Study Regimen TTPPFS/EFS

3 year OS(%)

Facon(Lancet 2007)

MPT 28 ~65%

Non-melphalan based

• Rd

• VCd

• VRd


Melphalan based

• MPT

• VMP


Non-melphalan based

• Rd

• VCd

• VRd

Melphalan based

• MPT

• VMP

FIRST TRIAL

MPT vs Rd


Non-melphalan based

• Rd

• VCd

• VRd

Transplant Ineligible

12-18 monthsRd- Can Continue till PD

Intermediate Risk Standard Risk*

VCd

~24 months

High Risk

VRd Rd or VCd

Bortezomib-based maintenance

Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Ku mar et al. Mayo Clin Proc 2009 84:1095-1110v9 Revised and updated: Jun 2011

msmart.org

VMP vs VTP Trial: Implications for Bortezomib Dosing

Mateos M. Lancet Oncol 2010; 11: 934–941

Lower risk of grade 3 or higher neuropathy

with once-weekly dosing of VMP

13% (twice-weekly-VISTA) vs 7% (once-weekly)

VMP vs VMPT Trial: Implications for Bortezomib Dosi ng

Palumbo A et al. JCO 2010;28:5101-5109

©2010 by American Society of Clinical Oncology

Lower risk of grade 3 or higher neuropathy

with once-weekly dosing of VMP or VMPT

16% (twice-weekly; n=134) vs 3% (once-weekly; n=369 )

PFS

OS

• Plasma cell leukemia (PCL)

• Extensive extramedullary disease (EMD)

• Acute renal failure due to cast nephropathy

Newly Diagnosed Myeloma with special circumstances

Plasma cell leukemia or

multiple extramedullary plasmacytomas

VDT-PACE x 2 cycles

ASCT, if eligible

Bortezomib maintenance

Plasma Cell Leukemia

Usmani S. Leukemia 2012

Acute renal failure: Cast Nephropathy

Biopsy proven, orPresumptive (ARF with FLC ≥≥≥≥ 150 mg/dL

•VCD or VTD•Plasma exchange and •If needed hemodialysis

Burnette, N Engl J Med 2011

Newly Diagnosed Myeloma

Standard Risk

Rd or VCD

High Risk

VRD

Intermediate Risk

VCD

Rajkumar SV. Am J Hematol 2012; Nature Rev Oncol 2011

PCL, EMD ARF

VDT-PACE VCD or VTD

•Once weekly Dex (except VDT-PACE)

•Once weekly bortezomib (except ARF; VDT-PACE)

upfront therapy for myeloma - tailoring therapy across the...

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