Drug Development in Relapsed or Drug Development in Relapsed or Refractory MyelomaRefractory Myeloma

Asher Asher ChananChanan --KhanKhan

Mayo ClinicMayo Clinic

State of Affairs in MyelomaState of Affairs in Myeloma

•• Myeloma remains incurableMyeloma remains incurable

•• All patients eventually relapse requiring All patients eventually relapse requiring subsequent therapysubsequent therapy

•• Current therapeutic options are Current therapeutic options are generally palliativegenerally palliative

Targets of Relevance and Clinical Drug Targets of Relevance and Clinical Drug Development in MyelomaDevelopment in Myeloma

•• ProteasomeProteasome is the most critical therapeutic target is the most critical therapeutic target in myeloma independent of disease statusin myeloma independent of disease status

•• Resistance to Resistance to proteasomeproteasome inhibition is a major inhibition is a major clinical problem, and strategies to overcome an clinical problem, and strategies to overcome an important clinical task important clinical task

•• Despite significant insight in Myeloma biology, Despite significant insight in Myeloma biology, clinical drug development in myeloma seems clinical drug development in myeloma seems empiric!empiric!

Relapse vs. ResistantRelapse vs. Resistant

•• Is the biology of myeloma cells distinct inIs the biology of myeloma cells distinct in•• relapsed vs. relapsed and refractory?relapsed vs. relapsed and refractory?•• chemotherapy resistant vs. chemotherapy resistant vs. novel novel

therapeutics therapeutics vs. combinationsvs. combinations

•• Does myeloma survival pathways converge Does myeloma survival pathways converge at some point during resistant phase?at some point during resistant phase?

•• Should these factors be considered in drug Should these factors be considered in drug development? development?

Bortezomib/DEX CombinationBortezomib/DEX Combination

Patients Type

Regimen Phase No. of Pts

ResponseORR (CR)

Rel1 VD II 15 74% (7%)

Rel/Ref2 VD II 88 66.9%

Rel/Ref3 VD II 70 59% (7%)

Rel4 V-CD II 50 82% (16%)

Rel5 VMelD I/II 53 68% (23%)

Rel/Ref6 VD-PDL II 25 80%

Rel / Ref7 V-CD II 67 88%

1.1. KrppffKrppff et al 2005,(29);5 et al 2005,(29);5 LeuLeu ResearchResearch2.2. Kobayashi et al 2010 (92);4 Kobayashi et al 2010 (92);4 IntInt Jour of Jour of HematoHemato3.3. CorsoCorso et al 2009 (83);5 et al 2009 (83);5 EurEur Jour of Jour of HemaHema4.4. KropffKropff et al 2007 (138);3 BJHet al 2007 (138);3 BJH

5.5. PopatPopat et al 2009 (144);6 BJHet al 2009 (144);6 BJH6.6. GozzettiGozzetti et al 2010 (10); 1 et al 2010 (10); 1 ClinClin LymLym , , MyelMyel ,& ,& LeuLeu7.7. AhnAhn JS Annals of Hematology 2012JS Annals of Hematology 2012

V; V; velcadevelcade , D; dexamethasone, , D; dexamethasone, C;cyclophosphamideC;cyclophosphamide , Mel; melphalan, PDL; pegylated liposomal , Mel; melphalan, PDL; pegylated liposomal doxorubicin.doxorubicin.

Bendamustine, bortezomib and dexamethasone (BVD) in elderly patients with relapsed/refractorymultiple myeloma: The Intergroupe Francophone

du Myélome (IFM) 2009-01 protocol

Philippe Philippe RodonRodon (1), Cyrille Hulin (2), Brigitte (1), Cyrille Hulin (2), Brigitte PegouriePegourie (3), Mourad (3), Mourad TiabTiab (4), (4), Bruno Bruno AnglaretAnglaret (5), Lotfi (5), Lotfi BenboubkerBenboubker (6), Henri (6), Henri JardelJardel (7), Olivier Decaux (8), (7), Olivier Decaux (8), Brigitte Brigitte KolbKolb (9), Muriel Roussel (10), Laurent (9), Muriel Roussel (10), Laurent GarderetGarderet (11), Xavier (11), Xavier LeleuLeleu(12), Olivier Fitoussi (13), Carine (12), Olivier Fitoussi (13), Carine ChaleteixChaleteix (14), Philippe (14), Philippe CasassusCasassus (15), (15), Pascal Pascal LenainLenain (16), Philippe Moreau (17), Marie(16), Philippe Moreau (17), Marie --Odile POdile P éétillon (12), Claire tillon (12), Claire MathiotMathiot (18), Herv(18), Herv éé AvetAvet --LoiseauLoiseau (17)(17)

1: Hematology CH Blois. 2: CHU Nancy. 1: Hematology CH Blois. 2: CHU Nancy. 3: CHU Grenoble. 4: CH La Roche sur 3: CHU Grenoble. 4: CH La Roche sur YonYon . 5: CH Valence. 6: . 5: CH Valence. 6: CHU Tours. 7: CH Vannes. 8: CHU Rennes. 9: CHU Reims . 10: CHU ToCHU Tours. 7: CH Vannes. 8: CHU Rennes. 9: CHU Reims . 10: CHU To ulouse. 11: Hôpital St Antoine, ulouse. 11: Hôpital St Antoine, Paris. 12: CHU Lille. 13: Polyclinique NordParis. 12: CHU Lille. 13: Polyclinique Nord --Aquitaine, Bordeaux. 14: CHU ClermontAquitaine, Bordeaux. 14: CHU Clermont --Ferrand. 15: Hôpital Ferrand. 15: Hôpital Avicenne, Bobigny. 16: CAC Rouen. 17: CHU Nantes. Avicenne, Bobigny. 16: CAC Rouen. 17: CHU Nantes. 18: 18: InstitutInstitut Curie, Paris.Curie, Paris.

ReviewReview

•• ORR 57.5%ORR 57.5%

•• IMiDIMiD failures had low response rate (52% vs. failures had low response rate (52% vs. 83%)83%)

•• High risk patients also had lower ORR High risk patients also had lower ORR (Del17p(Del17p ++ = 20%, High B2M = 49%)= 20%, High B2M = 49%)

•• 27% Stopped treatment27% Stopped treatment

•• 15% death rate for 215% death rate for 2 ndnd line treatmentline treatment

My AssessmentMy Assessment

•• Significant toxicity in the elderly patientsSignificant toxicity in the elderly patients

•• Responses no better than VD itselfResponses no better than VD itself

•• No significant improvement in depth of No significant improvement in depth of responsesresponses

•• Triple drug combos with PDL or Triple drug combos with PDL or cyclophosphamide may perform better.cyclophosphamide may perform better.

•• In my practice I will be deterred from using In my practice I will be deterred from using this combo in 1this combo in 1 stst relapsed elderly.relapsed elderly.

Melissa Melissa AlsinaAlsina , Robert , Robert SchlossmanSchlossman , Donna M. Weber, , Donna M. Weber, Steven E. Steven E. CoutreCoutre , , SagarSagar LonialLonial , Cristina , Cristina GasparettoGasparetto , ,

GhulamGhulam WarsiWarsi , Michael , Michael OndovikOndovik , , SutapaSutapa MukhopadhyayMukhopadhyay , , Carole Paley, and Paul G. RichardsonCarole Paley, and Paul G. Richardson

PANORAMA 2: A phase II study of PANORAMA 2: A phase II study of panobinostat in combination with panobinostat in combination with bortezomib and dexamethasone in bortezomib and dexamethasone in

patients with relapsed and bortezomibpatients with relapsed and bortezomib --refractory multiple myelomarefractory multiple myeloma

Bortezomib RefractoryBortezomib RefractoryPatients Type

Regimen Phase No. of Pts (refractory)

Response (%)ORR (CR)

Rel/Ref1* (CREST)

VD II 27 33%

Rel/Ref1* (SUMMIT)

VD II 74 18%

Rel/Ref2 VD IIIB 141 11% (1%)

Rel / Ref3 Perifosine +VD I/II 84 32%

Rel/Ref4 Vorinostat + V I/II 9 (total 23)

33%

1.1. JaggannathJaggannath et al 2006 (91); 7 et al 2006 (91); 7 HematologicaHematologica2.2. MikhaelMikhael et al 2009 (114);2 BJHet al 2009 (114);2 BJH3.3. Richardson et al JCO 2012Richardson et al JCO 20124.4. BadrosBadros et al 2009 (15) CCRet al 2009 (15) CCR

ReviewReview

•• Design Design –– Single arm, nonSingle arm, non --randomizedrandomized

•• Study Size Study Size -- 55 patients55 patients

•• Patients received multiple prior Patients received multiple prior BortBortregimens regimens –– median 2 (1median 2 (1 --6)6)

•• ORR = 31% (n=17)ORR = 31% (n=17)

•• Average duration of Average duration of exposure exposure = 4.9 = 4.9 months months

Panobinostat (LBH589) in Myeloma Panobinostat (LBH589) in Myeloma (Overview)(Overview)

Patients Type

Regimen

Phase N Prior Therapies

ResponseORR/CR

Toxicity / Conclusions

Rel / Ref1 Pan II 38 Median 5 2.6%(n=1)

34% G3/4 Hematologic

Rel / Ref2 MPT+Pan

II 31 2/3 had <2 prior therapies

38.5 %No CR

71% NeutropeniaRx Not well tolerated

Rel / Ref3 VD+ Pan

III 672(data on 267 only)

51% had 1 prior therapy

NA Blinded data ?

1.1. Wolf, JL Wolf, JL LeuLeu & & LymLym March 2012March 20122.2. OffidaniOffidani et al et al LeuLeu & & LymLym March 2012March 20123.3. SanSan--Miguel et al ASH 2011Miguel et al ASH 2011

ConsiderationsConsiderations

•• Addition of Addition of DexDex can induce responses in can induce responses in BortBortrefract patients. refract patients.

•• How many patients had their last treatment as How many patients had their last treatment as Bort/DexBort/Dex or or BortBort ??

•• What was the median no. of treatments in the What was the median no. of treatments in the patient who demonstrate response?patient who demonstrate response?

•• Median time from time of diagnosis?Median time from time of diagnosis?

•• Average duration of response is not clear?Average duration of response is not clear?

My AssessmentMy Assessment

•• Single agent does not work !Single agent does not work !

•• Interesting combination DataInteresting combination Data

•• Difficult patient population Difficult patient population

•• Patient heterogeneity precludes Patient heterogeneity precludes practice practice changing conclusionschanging conclusions

•• Exact role of Panobinostat in MM and the Exact role of Panobinostat in MM and the extent of its potential benefit remain to be extent of its potential benefit remain to be addressed through larger randomized addressed through larger randomized studies studies

Alexander K. StewartAlexander K. Stewart 11, Suzanne Trudel, Suzanne Trudel 22, Jeffrey A. Zonder, Jeffrey A. Zonder 33, ,

Suzanne HaymanSuzanne Hayman 11, Charles Erlichman, Charles Erlichman 11, , BriantBriant FruthFruth 11,,

Betsy LaPlantBetsy LaPlant 11, Daniel Sullivan, Daniel Sullivan 44

Phase I Trial of Obatoclax Mesylate in Combination

with Bortezomib for Treatment ofRelapsed Multiple Myeloma

BclBcl --2 and Myeloma 2 and Myeloma

•• Another important target in MMAnother important target in MM

•• Extensive preclinical data support targeting BclExtensive preclinical data support targeting Bcl --2 in MM2 in MM

•• ObatoclaxObatoclax also demonstrated promising in vitro activityalso demonstrated promising in vitro activity

•• Clinically too toxic in the combination studiedClinically too toxic in the combination studied

•• Is the target still clinically important?Is the target still clinically important?

SummarySummary

•• Do we really know which pathway is critical at Do we really know which pathway is critical at which stage of relapse / resistance ?which stage of relapse / resistance ?

•• It is imperative to select a more homogenous It is imperative to select a more homogenous patient population for accurate understanding of patient population for accurate understanding of the compact of the new drugthe compact of the new drug

•• If the drug fails to deliver responses If the drug fails to deliver responses –– is the target is the target still invalid? still invalid?

•• If active If active –– than how much and at what cost to the than how much and at what cost to the patient (toxicity) and to our society (economic)?patient (toxicity) and to our society (economic)?