Maintenance Maintenance Therapy In Therapy In Multiple Multiple MyelomaMyelomaTzu-Fei Wang, M.D.Tzu-Fei Wang, M.D.

Hematology/Oncology FellowHematology/Oncology Fellow

September 24, 2010September 24, 2010

DisclosureDisclosure

Financial Relationships: I have Financial Relationships: I have nothing to disclose nothing to disclose

OutlineOutline

Overview of multiple myeloma Overview of multiple myeloma treatmentstreatments

Rationale of maintenance therapyRationale of maintenance therapy Regimens of maintenance therapyRegimens of maintenance therapy ConclusionConclusion

Treatments for multiple Treatments for multiple myelomamyeloma

Induction chemotherapyInduction chemotherapy Transplant candidateTransplant candidate Non-transplant candidateNon-transplant candidate

Autologous stem cell transplant Autologous stem cell transplant (ASCT) in selected patients(ASCT) in selected patients

Consolidation therapy-controversialConsolidation therapy-controversial Maintenance therapy-controversialMaintenance therapy-controversial

Maintenance therapy- rationale

Although autologous stem cell transplant (ASCT) and new agents improve response rates, progression-free survival (PFS) and overall survival (OS), compared with conventional chemotherapy, cure is rare and relapse is inevitable and salvage therapies are limited.

There are many interests in the development of effective strategies that can prolong duration of remission.

Maintenance therapy Maintenance therapy optionsoptions

Interferon-Interferon-αα GlucocorticoidsGlucocorticoids ThalidomideThalidomide LenalidomideLenalidomide BortezomibBortezomib

Interferon-Interferon-αα as as maintenance therapymaintenance therapy

Mechanism of action-Mechanism of action- Inhibition of self-renewal capacity of myeloma Inhibition of self-renewal capacity of myeloma

stem cellsstem cells Two independently conducted meta-Two independently conducted meta-

analysis showed similar results- Interferon analysis showed similar results- Interferon (INF) maintenance therapy(INF) maintenance therapy improves median time to progression by 4-6 improves median time to progression by 4-6

monthsmonths improves median survival by 6-7 monthsimproves median survival by 6-7 months both are statistically significantboth are statistically significant only one trial (out of 13 trials) is after ASCTonly one trial (out of 13 trials) is after ASCT

The Myeloma Trialists et al. BJH 2001; 113:1020-1034Fritz and Ludwig. Annals of Oncology 2000;11:1427-1436.Browman et al. J Clin Oncol 1995; 13(9):2354-2360.

Interferon-Interferon-αα as as maintenance therapymaintenance therapy

•Most investigators feel that the benefit was small •When the potential toxicity and cost are taken into consideration, the enthusiasm for INF has subsided.

OS

The Myeloma Trialists et al. BJH 2001; 113:1020-1034Fritz and Ludwig. Annals of Oncology 2000;11:1427-1436.

Maintenance therapy Maintenance therapy optionsoptions

Interferon-Interferon-αα GlucocorticoidsGlucocorticoids ThalidomideThalidomide LenalidomideLenalidomide BortezomibBortezomib

Glucocorticoids as Glucocorticoids as maintenance therapymaintenance therapy

Mechanism of actionMechanism of action suppress the production of IL6 and IL1suppress the production of IL6 and IL1ββ, which , which

are important in myeloma growth and bone are important in myeloma growth and bone diseasesdiseases

induce apoptosis of myeloma cellsinduce apoptosis of myeloma cells reduce NFreduce NFκκB activity; this action enhances B activity; this action enhances

apoptosisapoptosis Studies have shown that glucocorticoids canStudies have shown that glucocorticoids can

prolong the progression free survivalprolong the progression free survival however, the effect on OS is controversialhowever, the effect on OS is controversial most are used after conventional chemotherapymost are used after conventional chemotherapy

Shustik ,et al. BJH 2007;136:203-211Berenson, J. R. et al. Blood 2002;99:3163-3168

Copyright ©2002 American Society of Hematology. Copyright restrictions may apply.

Shustik ,et al. BJH 2007;136:203-211

PFS* PFSP=0.003*

OS OSP=0.05*

Berenson, J. R. et al. Blood 2002;99:3163-3168

Maintenance therapy Maintenance therapy optionsoptions

Interferon-Interferon-αα GlucocorticoidsGlucocorticoids ThalidomideThalidomide LenalidomideLenalidomide BortezomibBortezomib

Thalidomide as Thalidomide as maintenance therapymaintenance therapy

Mechanism of action-Mechanism of action- antiangiogenic effects (inhibiting antiangiogenic effects (inhibiting

fibroblast growth factor and vascular fibroblast growth factor and vascular endothelial growth factor)endothelial growth factor)

immunomodulationimmunomodulation enhances cytotoxic T cell and NK cell enhances cytotoxic T cell and NK cell

medicated immunological responsesmedicated immunological responses disrupts adhesion between multiple disrupts adhesion between multiple

myeloma cells and stromal cellsmyeloma cells and stromal cells

Binker et al. Cancer. 2006; 106(10): 2171-2180.

Thalidomide as Thalidomide as maintenance therapy- after maintenance therapy- after

conventional chemoconventional chemo Conflicting results in two trialsConflicting results in two trials

Offidani et al. British Journal of Haematology. 2009;144:653 659.Ludwig, H. et al. Haematologica 2010;95:1548-1554

Trial Offidani, et al. Ludwig, et al.

N 103 289

Enrollment criteria At least minor response after induction

Stable disease after induction

Induction regimen 6 cycles ofThal+Dex+Peg liposomal doxo

9 cycles of A-thal+dexB-melphalan+prednisone

Maintenance regimen

Thal+dex (TD) vsINF+dex (ID)

Thal+INF vs INF

PFS 2 yr63% vs 32% (p=0.024)

27.7m vs 13.2m (p=0.0068)

OS 2 yr84% vs 68% (p=0.03)

52.6m vs 51.4m(p=0.81)

Offidani et al. British Journal of Haematology. 2009;144:653-659

Figure 2. (A) Time on maintenance therapy

Ludwig, H. et al. Haematologica 2010;95:1548-1554

Thalidomide as Thalidomide as maintenance therapy- maintenance therapy-

after ASCTafter ASCTTrial N Mediandose (mg)

Study design End points

Barlogi, et al. NEJM. 2006;354:1021-30.(Total Therapy II)

668 100(initial 400)

•T vs no T throughout, INF+dex+T vs no T •double transplant•1998-2004

•Primary-PFS•Secondary- OS, CR

Attal, et al. Blood. 2006:108:3289-94.

(IFM-99 02)

597 200(initial 400)

•2 mo after transplant•double transplant•A-no therapy vs B-pamidronate vs C- P+T•2000-2003

•PFS, OS, CR

Spencer, et al. J Clin Oncol.

2009;27;1788-93.

269 100(target 200)

•d42-50 after transplant•single transplant•AP vs AP+T for 12 mo•2002-2005

•Primary-PFS, OS•Secondary- tolerability

Lokhorst, et al. Blood. 2010;115(6):1113-

1119(HOVON)

556 50(maintenance)

•VAD vs TAD for induction•INF vs T for maintenance (2-3 mo after transplant)•single or double transplant•2001-2005

•Primary- EFS•Secondary- CR, VGPR, PFS, OS

Thalidomide as Thalidomide as maintenance therapy- after maintenance therapy- after

ASCTASCTTrial CR+VGPR (%)

PFS/EFS OS AE

Barlogi, et al. NEJM.

2006;354:1021-30.(Total Therapy II)

62 vs 43*(p<0.01)

5 yr PFS56% vs 44%

P=0.01

5yr65% vs 65%

NeuropathyBowel obstructionThromboembolismSyncope

Attal, et al. Blood. 2006;08:3289-94.

(IFM-99 02)

67 vs 55(p=0.03)

3 yr EFS52 % vs 36%

(p<0.009)

4 yr87% vs 75%

(p<0.04)

NeuropathyConstipationNeutropeniaCardiac events

Spencer, et al. J Clin Oncol. 2009;

27:1788-1793.

63 vs 40(p<0.001)

3 yr PFS42 % vs 23%

(p<0.001)

3 yr 86% vs 75%(P<0.0045)

NeuropathyConstipation

Lokhorst, et al. Blood.

2010;115(6):1113-1119

(HOVON)

66 vs 54(p=0.005)

Median EFS34m vs 22m(p<0.001)

median 73m vs 60m

(p=0.77)

NeuropathyGastrointestinal

*CR onlyHarousseau, J-L. Hematology Reviews 2009;1:e12

Thalidomide as Thalidomide as maintenance therapymaintenance therapy

Thalidomide showed activity after autologous Thalidomide showed activity after autologous transplantationtransplantation 4/4 trials with improvement of CR4/4 trials with improvement of CR 4/4 trails with improvement of PFS4/4 trails with improvement of PFS 2/4 trials with improvement of OS 2/4 trials with improvement of OS Longer follow-up showed trend for increasing OS Longer follow-up showed trend for increasing OS

benefitbenefit Neurologic toxicity is a major concern, can lead to Neurologic toxicity is a major concern, can lead to

discontinuation of the drug in up to 60% of patientsdiscontinuation of the drug in up to 60% of patients more of consolidation effect rather than maintenance more of consolidation effect rather than maintenance

effect? more benefit in patients less than VGPR? effect? more benefit in patients less than VGPR? optimal dosage and duration, targeted population optimal dosage and duration, targeted population

remain to be determinedremain to be determined

Maintenance therapy Maintenance therapy optionsoptions

Interferon-Interferon-αα GlucocorticoidsGlucocorticoids ThalidomideThalidomide LenalidomideLenalidomide BortezomibBortezomib

Lenalidomide as Lenalidomide as maintenance therapymaintenance therapy

Lenalidomide is an analog of Lenalidomide is an analog of thalidomide and has demonstrated thalidomide and has demonstrated activity in the induction and relapse activity in the induction and relapse therapy for multiple myelomatherapy for multiple myeloma

Lenalidomide lacks neurologic Lenalidomide lacks neurologic toxicity as in thalidomidetoxicity as in thalidomide

Attal, et al. IFM 2005-02 trial, 2010.

Attal, et al. IFM 2005-02 trial, 2010.

Attal, et al. IFM 2005-02 trial, 2010.

CALGB 100104: Study CALGB 100104: Study designdesign

Phase III, randomized, placebo-controlled trialPhase III, randomized, placebo-controlled trial

N=462, 97 centers, 12/2004-12/2009N=462, 97 centers, 12/2004-12/2009Patients ≤ 70 yr, stable disease or responsive

after ≥2 months of induction therapy

ASCT

Restaging and randomization

Arm IIPlacebo(N=231)

Arm ILenalidomide 10 - 15mg/d po

(N=231)

Primary end-point: TTP (time to progression)Secondary end-points: CR rate, PFS, OS, feasibility of long term treatment

Trial NCT00114101. ClinicalTrials.gov

CALGB 100104: Preliminary CALGB 100104: Preliminary resultsresults

Arm IArm I Arm IIArm II PP

Time to Time to progressiprogressionon

Not yet Not yet reachedreached

25.5 25.5 monthsmonths

Event Event ratesrates

29/21029/210 58/20858/208 <0.0001<0.0001

McCarthy, et al. Blood 2009 114: Abstract 529

Maintenance therapy Maintenance therapy optionsoptions

Interferon-Interferon-αα GlucocorticoidsGlucocorticoids ThalidomideThalidomide LenalidomideLenalidomide BortezomibBortezomib

Bortezomib As Maintenance Bortezomib As Maintenance TherapyTherapy

Mechanism of actionMechanism of action

Orlowski R Z , Kuhn D J Clin Cancer Res 2008;14:1649-1657http://www.ebi.ac.uk/interpro/potm/2006_8/Page2.htm

Bortezomib as maintenance Bortezomib as maintenance therapytherapy

A phase II study done here at Wash U using A phase II study done here at Wash U using bortezomib pre- and post-transplantbortezomib pre- and post-transplant N = 40N = 40 Total response rate 83% (CR+VGPR rate 43%)Total response rate 83% (CR+VGPR rate 43%) EFS at 3 yr 38.2%EFS at 3 yr 38.2% OS at 3 yr 63.1%OS at 3 yr 63.1%

Phase III trial HOVON-65 is ongoingPhase III trial HOVON-65 is ongoing NCCN guideline deemed insufficient data NCCN guideline deemed insufficient data

to recommend Bortezomib as maintenance to recommend Bortezomib as maintenance therapy at the current time.therapy at the current time.

Uy, et al. Bone Marrow Transplantation, 2009;43:793-800

Bortezomib as Bortezomib as maintenance therapymaintenance therapy

Uy, et al. Bone Marrow Transplantation, 2009;43:793-800

ConclusionConclusion Multiple myeloma remains to be mostly incurable, Multiple myeloma remains to be mostly incurable,

and treatments that can prolong remission duration and treatments that can prolong remission duration is neededis needed

INF maintenance can prolong PFS and OS although INF maintenance can prolong PFS and OS although only modest effectonly modest effect

Glucocorticoids maintenance prolongs PFS, but Glucocorticoids maintenance prolongs PFS, but effect on OS is inconsistenteffect on OS is inconsistent

Thalidomide maintenance prolongs PFS, but effect Thalidomide maintenance prolongs PFS, but effect on OS is inconsistent.; likely related to the on OS is inconsistent.; likely related to the induction regimen? induction regimen?

More studies are underway for newer agents such More studies are underway for newer agents such as lenalidomide and bortezomib.as lenalidomide and bortezomib.

ReferencesReferences Attal, M et al. IFM 2005-02 trial, 2010Attal, M et al. IFM 2005-02 trial, 2010 Attal, M et al. “Maintenance therapy with thalidomide improves survival in

patients with multiple myeloma.” Blood. 2006;108:3289-3294. Badros AZ. “The role of maintenance therapy in the treatment of multiple

myeloma.” Journal of the National Comprehensive Cancer Network. 2010;8(1):S21-27.

Barlogi, B et al. “Thalidomide and hematopoietic-cell transplantation for multiple myeloma.” New England Journal of Medicine. 2006;354:1021-1030.

Berenson, J. R. et al. “Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients.” Blood 2002;99:3163-3168.

Binker, B, et al. “Maintenance therapy with thalidomide improves overall survival after autologous hematopoietic progenitor cell transplantation for multiple myeloma.” Cancer. 2006; 106(10): 2171-2180.

Browman et al. “Randomized trial of interferon maintenance in multiple myeloma: a study of the national cancer institute of Canada clinical trials group.” Journal of Clinical Oncology 1995; 13(9):2354-2360.

Cavo M, et al. “Thalidomide maintenance in multiple myeloma: certainties and controversies.” Journal of Clinical Oncology. 2009;27(32):e186-e187.

Fritz E and Ludwig H. “Interferon-α treatment in myltiple myeloma: meta-analysis of 30 randomised trials among 3948 patients.” Annals of Oncology 2000;11:1427-1436.

ReferencesReferences Harousseau, J-L. “Maintenance treatment in multiple myeloma.” Annals of Oncology 19

(supplement 4): iv54-iv55, 2008. Harousseau, J-L. “Maintenance treatment in multiple myeloma.” Hematology Revoews

2009; 1:e12. pp 65-69. Kyle, RA and Rajkumar SV. “Multiple myeloma.” Blood 2008;111:2962-2972.

Laubach, JP, et al. “Thalidomide maintenance in multiple myeloma.” Nature Reviews Clinical Oncology. 2009;6:565-566.

Lokhorst, H. et al. (HOVON)“A randomized phase 3 study on th effect of thalidomide combined with adiamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with mu;tiple myeloma.” Blood. 2010;115(6):1113-1119.

Ludwig, H. et al. “Thalidomide maintenance treatment increases progrssion-free but not overall survival in elderly patients with myeloma.” Haematologica 2010;95:1548-1554.

McCarthy, et al. ASH meeting. Blood 2009 114: Abstract 529McCarthy, et al. ASH meeting. Blood 2009 114: Abstract 529

Morgan, GJ, et al. “Position statement on the use of bortezomib in multiple myeloma.” Int. Morgan, GJ, et al. “Position statement on the use of bortezomib in multiple myeloma.” Int. Journal Lab. Hem. 2008;30:1-10. Journal Lab. Hem. 2008;30:1-10.

Morgan, GJ, et al. “Maintenance thalidomide may improve progression free but not overall Morgan, GJ, et al. “Maintenance thalidomide may improve progression free but not overall survival; results from the myeloma IX maintenance randomisation.” ASH meeting, abstract survival; results from the myeloma IX maintenance randomisation.” ASH meeting, abstract 656. 2008.656. 2008.

ReferencesReferences The Myeloma Trialists’ Collaborative group secretariat based at imperial cancer research

fund/medical research council clinical trial service unit. “Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients.” British Journal of Haematology. 2001; 113:1020-1034.

Shustik ,et al. “A randomised comparison of melphalan with prednisone or dexamethasone Shustik ,et al. “A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7” British Journal of Haematology 2007;136:203-211.myeloma: NCIC CTG MY.7” British Journal of Haematology 2007;136:203-211.

Offidani ,M, et al. “Thalidomide-dexamethasone versus interferon-alpha-dexamethasone as Offidani ,M, et al. “Thalidomide-dexamethasone versus interferon-alpha-dexamethasone as maintenance treatment after ThaDD induction for multiple myeloma: a perspective maintenance treatment after ThaDD induction for multiple myeloma: a perspective multicentre, randomised study.” British Journal of Haematology. 2009;144:653-659.multicentre, randomised study.” British Journal of Haematology. 2009;144:653-659.

Spencer, A, et al. “Consolidation therapy with low-dose thalidomide and prednisolone Spencer, A, et al. “Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure.” Journal of Clinical Oncology. 2009;27;1788-1793.transplantation procedure.” Journal of Clinical Oncology. 2009;27;1788-1793.

Trial NCT00114101. ClinicalTrials.govTrial NCT00114101. ClinicalTrials.gov

Orlowski RZ, Kuhn DJ. “Proteasome inhibitors in cancer therapy: Lessons learned from the Orlowski RZ, Kuhn DJ. “Proteasome inhibitors in cancer therapy: Lessons learned from the frist decade.” Clinical Cancer Research. 2008;14:1649-1657.frist decade.” Clinical Cancer Research. 2008;14:1649-1657.

http://www.ebi.ac.uk/interpro/potm/2006_8/Page2.htm http://www.ebi.ac.uk/interpro/potm/2006_8/Page2.htm

Uy, GL et al. “Bortezomib admission pre-auto-SCT and as maintenance therapy post Uy, GL et al. “Bortezomib admission pre-auto-SCT and as maintenance therapy post transplant for multiple myeloma: a single institution phase II study.”Bone Marrow transplant for multiple myeloma: a single institution phase II study.”Bone Marrow Transplantation, 2009;43:793-800.Transplantation, 2009;43:793-800.