Induction Therapy For Multiple Myeloma:

Two vs Three Drug Regimen and Role of Risk Stratification

Ravi Vij MD

Associate Professor

Section of BMT and Leukemia

Washington University School of Medicine

Trends in Overall Survival of MM

Overall survival 1971–2006

Diagnosis period Median OS

1996–2006 45 months1971–1996 30 months

(P<0.001)

Kumar SK, et al. Blood. 2008;111:2516-2520.

Time from diagnosis (Months)

Su

rviv

al

0

0.2

0.4

0.6

0.8

1.0

0 20 40 60 80 100 120 140

2001–2006

1995–2000

2001–2006

1989–1994

1983–1988

1977–1982

1971–1976

OS, overall survival.

2

M

CR and MM• Is CR an adequate surrogate for OS?

• Are all CRs as durable?

• Should we strive for CR pre-transplant?

• What is the role of HDCT for patients in CR pre-transplant?

CR associated with OS prolongation in post-induction and post-transplant settings1-3

1. Lahuerta et al. J Clin Oncol. 2008;26(3):5775-5782. 2. Alexanian et al. Bone Marrow Transplant. 2001;27:1037-1043. 3. Wang, et al. Bone Marrow Transplant. 2010;45(3):498-504.

Survival by response for 291 patients with MM (age <70 y) who received chemotherapy alone (left) and 375 who proceeded to ASCT (right) (CR vs PR or NR P<0.01)

Chemotherapy Alone Chemotherapy and ASCT

4

> 65 yrs

> 75 yrs

Importance of CR in Elderly MM

Gay F et al. Blood. 2011;117(11):3025-3031)

Approach to Treatment of MM

Clearly not a transplant candidate based on age, performance status

and comorbidity

Conventional Therapy

Potential transplant candidate

Non-alkylator based induction x 4 cycles

Stem cell harvest

Bortezomib-Based Induction Prior to SCT

Trial Regimen NCR+VGPR Post-Induction (%)

CR+VGPR Post-ASCT (%) PFS P Value

Cavo et al, 2010VTD

vsTD

236

238

62*

28

82*

64

68% at 3 yr

56% at 3 yr .0057

Moreau et al, 2011IFM 2007/02

VDvs

vTD

99

100

36

49‡

58

74§

Median 30 months

Median 26 mo .22

*P <.001; †P =.001; ‡P =.05; §P =.02GMMG= German Multiple Myeloma Group; SCT = stem cell transplant; CR = complete response; VGPR = very good partial response; PAD = bortezomib (V)/AD; T = thalidomide; VAD = vincristine, doxorubicin (A), dexamethasone (D); vTD = reduced-dose bortezomib.

Cavo M, et al. Lancet. 2010;376:2075-2085. Harousseau JL, et al. J Clin Oncol. 2010;28:4621-4629. Sonneveld P, et al. ASH Annual Meeting Abstracts. 2010;116(21):40. http://web.educationalconcepts.net/Newsletter/MMY015AE1/MMY015AE1.pdf. Accessed July 17, 2012. Moreau P, et al. Blood. 2011;118: 5752-5758.

Fayers PM et alBlood.2011;118(5):1239-1247

MPT vs MP in Elderly MM

Median survival:

MP 32.7 months (95% CI, 30.5-36.6 months)MPT 39.3 months (95% CI, 35.6-44.6 months).

HR 0.83 (95% CI: 0.73-0.94)P=0.004

Overall Survival

Palumbo et al. N Engl J Med 2012;366:1759-69.

MPR vs MP in Elderly MM

Study Regimen N ORR CR/nCR Outcomes

VISTASan Miguel et al.

Mateos et al.Phase III

VMPMP

344338

71%35%

33%4%

5 yr OS: 46%5 yr OS: 34.4%

UPFRONTNiesvizky et al.

Phase III

VMP/VelVTD/VelVD/Vel

30073%79%71%

31%36%34%

ORR: overall response rate; CR: complete response; nCR: near complete response; OS: overall survival; TTP: time to progression; PFS: progression free survival; VMP: Bortezomib-melphalan-dexamethasone; MP: Melphalan-Prednisone; VTP: Bortezomib-thalidomide-dexamethasone; VTD: bortezomib-thalidomide-dexamethasone; VD: bortezomib-dexamethasone; VMPT-VT: bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance

Bortezomib in Transplant Ineligible MM

UPFRONT Study

MM-020: Len + Low-dose Dex vs MPT in Previously Untreated MM

Protocol CC-5013-MM-020/IFM 07-01. 2007; data on file, Celgene Corporation

Inclusion criteria

•Previously untreated MM

•Age 65 years or not a candidate for transplantation

•No neuropathy of grade > 2

•CICr > 30 ml/min

• Lenalidomide 25 mg/day, days 1–21, every 28 days

• Dexamethasone* 40 mg/day, days 1, 8, 15, 22, every 28 days

Until PD

• Lenalidomide 25 mg/day, days 1–21, every 28 days

• Dexamethasone* 40 mg/day, days 1, 8, 15, 22, every 28 days

18 four-week cycles or until PD

N = 1,590Centres in EU, Switzerland, USA and Canada

*In patients older than 75 years• Dexamethasone 20 mg/day• Thalidomide 100 mg/day• Melphalan 20 mg/kg/day

• Melphalan 0.25 mg/kg/day, days 1–4, every 42 days

• Prednisone 2.0 mg/kg/day, days 1–4, every 42 days

• Thalidomide* 200 mg/day, days 1–42, every 42 days

12 six-week cycles or until PD

Conclusions

• Three drug induction regimen are associated with higher CR rates compared to two drug regimen.

• In the transplant eligible population prospective trials have shown a higher CR rate and PFS for two drug regimen. Follow-up is too short for analyses of OS.

• In the transplant ineligible population three drug regimes of thalidomide and bortezomib have a OS advantage compared with MP. Whether non-melphalan containing two drug regime may be equivalent is the subject of ongoing trials.

• We have entered an era of risk stratification for deciding therapy. However no consensus has emerged on treatment paradigms.