Maintenance Therapy in Myeloma

Myeloma Canada National Conference

Donna E. Reece, M.D.Princess Margaret Hospital24 September 2011

Maintenance Therapy in Myeloma Older term derived from childhood acute leukemia therapy

In the past, most cancers not treated with maintenance

“Maintenance” therapy defined as …any treatment administered after the completion of induction therapy in patients whose disease is either responsive or non-progressive at that time, with the goal of prolonging survival…

May be hard to distinguish from “consolidation” therapy Defined as relatively intensive, short-term post-ASCT therapy

Maintenance can be used after ASCT or non-transplant therapy

Maintenance Therapy in Myeloma Maintenance therapy has been tried in myeloma in previous years BUT we only had melphalan, steroids and VAD as anti-myeloma tools Melphalan maintenance not effective and too hard on normal marrow

Older maintenance trials showed limited benefit from Interferon Steroids

What has changed? Availability of more effective myeloma drugs Availability of oral drugs Better understanding of side-effects and their management Weekly and/or subcutaneous bortezomib

Maintenance after ASCT

ASCT No maintenance

?Longest Time in Remission? ?Best Overall Survival?

Relapse Use drug “A”

ASCT Maintenancewith drug “A”

Relapse

Use other drugs

Phase III Maintenance Therapy Trials in Myeloma

Thalidomide 7 randomized studies Different doses and duration of thalidomide; some used

steroids Different control arms

Lenalidomide 2 randomized trials of low-dose lenalidomide 10 mg/day One gave 2 months of “consolidation” with full-dose

lenalidomide first

Bortezomib 2 randomized trials

One used bortezomib before ASCT as well Second is in progress

Thalidomide Maintenance TrialsAuthor/Year N Thalidomide dose

(mg)/duration

Progression-free

Survival

Overall Survival

Attal/2006 597 Thal 200 (median dose) vs obs /progression

+ +

Spencer/2006 243 Thal 200 + pred vs pred/12 months

+ +

Maiolino/2008 212 Thal 200 + dex vs dex/ 12 months

+ NS

Barlogie/2006* 668 Thal 400/progression

+ NS(+ in high-

risk)

Morgan/2008* -- Thal 100/progression

+/- NS(if optimal

relapse Rx)

Lokhorst/2010* 550 Thal 50/ progression + -

Stewart/2010 325 Thal 200 + pred vs obs/48 months

+ NS

Thalidomide Maintenance Trials: Summary

Thalidomide maintenance prolongs PFS BUT peripheral neuropathy and other side-effects limit the dose and duration of maintenance Quality of life negatively impacted

Benefit on survival variable Most patients cannot tolerate it much beyond a year

Likely in part related to availability of “good” therapy when the disease progresses

Summary of Phase III Trials of Lenalidomide Maintenance after ASCT

Author/Year N Pre-ASCT induction # ASCT PFS/TTPMedian 3-year (months) (%)

Overall Survival3-year

(%)

Attal/2010(IFM 2005-02)

614 VAD orVelcade + dex

1 or 2 42 Lenalidomide 60%*24 Observation 33%

Lenalidomide 81% Observation 81%

McCarthy/2010(CALBG 100104)

568 Lenalidomide 32%

Bortezomib 42%Thalidomide 16%

1 42.3 Lenalidomide ~50%*21.8 Observation ~25%

Lenalidomide ~80% Observation ~80%

Attal M, et al. ASCO 2010; abstract #8018; McCathy PL, et al. ASCO 2010; abstract #8017.

Lenalidomide MaintenanceEffect on PFS

39.6 mo39.6 mo

21.9 mos21.9 mos

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36 42

Placebo Revlimid

CALGB100104 IFM 2005-0142 mo

24 mo

Progression Free Survival (PFS) Event Free Survival (EFS)Attal M, et al. ASCO 2010; abstract #8018.McCathy PL, et al. Haematologica 2011; 96 (Suppl 1): S23.

Lenalidomide Maintenance Overall Survival Benefit?

CALGB 100104 IMF 2005-02

Median follow-up of 28 mos. P=0.018 No significant difference

0.00

0.25

0.50

0.75

1.00

0 6 12 18 24 30 36 42

Placebo Revlimid

Attal M, et al. ASCO 2010; abstract #8018.McCathy PL, et al. Haematologica 2011; 96 (Suppl 1): S23.

Significant Toxicity with Lenalidomide Maintenance Phase III Trials

Toxicity IMF 2005-02 CALGB

Len Placebo Len Placebo

Low neutrophils (WBC)

43% 14% 43% 9%

Low platelets 12% 6% 13% 4%

Fever + low WBC 2% 0.1% 6% 2%

DocumentedInfection

10% 4% 16% 5%

Discontinuation of lenalidomide

6% 4% 13% 2%

2º malignancy N=23(6.8%)

N=6(1.6%)

N=18(6.5%)

N=4(2.6%)

Attal M, et al. ASCO 2010; abstract #8018; McCarthy PL, et al. ASCO 2010; abstract #8017; Attal M, personal communications; IMWG Feb 2011.

Secondary Cancers with Lenalidomide Maintenance: Considerations Small increase in incidence, but.....

IFM study counted skin cancers CALGB study had several cases even before starting drug

No increase when lenalidomide used for relapsed myeloma

Other drugs/agents may predispose to second cancers Prolonged oral alkylating agents XRT Other chemotherapy drugs

Plasma cell disorders themselves have a slightly higher risk of leukemia

AWARENESS and monitoring Myeloma is the main wolf barking at the door!

VRD x 3

SC collectionCY + G-CSF Melphalan 200

mg/m2

+ ASCT

VRD consolidation

Len maintenance

Melphalan 200 mg/m2

+ ASCT

Melphalan 200 mg/m2

+ ASCT

Melphalan 200 mg/m2

+ ASCT

Future Directions and Answers: CTN Trial

Randomized TrialVAD +Thalidomide Maintenance vs Bortezomib in Induction and Maintenance

Phase III Trial of VAD or PAD Induction with Thalidomide vs Bortezomib Maintenance: HOVON MM 65/GMMG-HD4

PFS Overall Survival

Sonneveld P, et al. ASH 2010: abstract 40.

3-year PFS 48% vs 42% 3-year OS 78% vs 71%

Maintenance Therapy in MyelomaSummary and Conclusions

Median PFS after ASCT has improved without maintenance using better induction

Maintenance with novel agents further improves PFS Toxicity issues are critical PFS is 3 ½ years with lenalidomide maintenance

Overall survival results are improved in some studies of thalidomide, lenalidomide and bortezomib maintenance

Bortezomib maintenance under further investigation Decisions regarding maintenance will be influenced by

Incidence of toxicity such as 2º cancers Outcome after myeloma progression Identification of subgroups most likely to benefit Funding