Presentation on theme: "Relapsed and Refractory Myeloma"— Presentation transcript:
1 Relapsed and Refractory Myeloma Ruben Niesvizky Myeloma Center Myelomacenter.org
2 Multiple Myeloma: Natural History of Disease AsymptomaticSymptomaticRelapsingRefractoryM-Protein LevelRemission duration decreases with each line of therapyActive MyelomaRelapseRemissionMGUS or Indolent Myeloma////Second- or Third-Line TherapyFrontline TherapyDurie B; International Myeloma Foundation.Concise review of the disease and treatment options: multiple myeloma. 2011/2012 edition;Kumar SK, et al. Mayo Clin Proc. 2004;79:
3 Outline Approach to the patient with RRMM: Proteasome inhibitors Evidence basedFactors to be considered in selecting therapyProteasome inhibitorsInmunomodulatory AgentsHDAC inhibitorsAlkylating agents
4 Clinical Considerations for Relapsed/Refractory Disease Disease characteristics/prior therapyLine of therapyPlateau phase=quiescent periodAggressiveness of relapseRelapsed or relapsed and refractory disease“High risk disease”Prior therapies (eg SCT, prior IMiD, bortezomib-based therapy)
5 Clinical Considerations for Relapsed/Refractory Disease Disease characteristics/prior therapyLine of therapyPlateau phase=quiescent periodAggressiveness of relapseRelapsed or relapsed and refractory disease“High risk disease”Prior therapies (eg SCT, prior IMiD, bortezomib-based therapy)
6 Response Duration Decreases With Successive Therapies 578 patients; median age 65 years (follow up 55 months)Overall survivalOne year 72%Two years 55%Three years 22%84% died within five yearsKumar SK, et al. Mayo Clin Proc. 2004;79:
7 APEX: Bortezomib Early or Late Relapse 1 prior therapyn = 132> 1 prior therapyn = 200Median TTP (months)7.04.9CR (%)10%*7%†CR + PR (%)51%*37%†Median Duration of Response (months)8.17.81-year Survival89%73%* Evaluable patients, response to bortezomib after 1 prior therapy: n = 128† Evaluable patients, response to bortezomib after >1 prior therapy: n = 187Sonneveld P, et al. Haematologica. 2005;90: Abstract P ; Data on file; Millennium Pharmaceuticals, Inc.
8 Improved Outcomes with the Early Use of LenDex : TTP and OS Time to Progression Overall Survival2nd Line (LenDex)Median 17.1 months≥ 3th line(LenDex)Median 10.6 months2nd Line (LenDex)Median 42 months≥ 3th line(LenDex)Median 35.8 monthStadmauer EA et al. Eur J Haematol 2009; 82:426-32
9 Clinical Considerations for Relapsed/Refractory Disease Disease characteristics/prior therapyLine of therapyPlateau phase=quiescent periodAggressiveness of relapseRelapsed or relapsed and refractory disease“High risk disease”Prior therapies (eg SCT, prior IMiD, bortezomib-based therapy)
10 Time to Progression After SCT Correlates With OS After Initial Relapse Kumar SK, et al. Bone Marrow Transplant. 2008;42:
11 Clinical Considerations for Relapsed/Refractory Disease Disease characteristics/prior therapyLine of therapyPlateau phase=quiescent periodAggressiveness of relapseRelapsed or relapsed and refractory disease“High risk disease”Prior therapies (eg SCT, prior IMiD, bortezomib-based therapy)
12 Frontline vs Relapsed Refractory Treatment NaiveResponse to Therapy Survival OutcomesHigh risk features Genomic instabilityRelapsed and RefractoryResponse to TherapySurvival OutcomesToxicities and Co-morbiditiesToxicities and Co-morbidities
13 Outcomes in Relapsed and Refractory Multiple Myeloma FrontlineTreatmentRelapsedRelapsed /RefractoryExpectedsurvival (months)20-50Sensitivity totherapySensitiveTreatment limitations/comorbiditiesPeripheral neuropathy (~15% at diagnosis)14-16Less Sensitive/Resistant>80% incidence of peripheral neuropathy Compromised marrow reserveCytopenia6-10ResistantIntolerant to orineligible for available therapyElderly population ( risk for heart, lung, renal, liver dysfunction, diabetes)Adapted from: Durie BGM. Multiple Myeloma. International Myeloma Foundation. 2011/2012 edition.Jagannath S. Clin Lymphoma Myeloma. 2008;8 Suppl 4:S149-S156.For Training and Educational Purposes Only. Not for Distribution.
14 Nature of Relapse How did the patient present? 80% share clinical features with presentationHas been a shift on presentation?Intact immunoglobulin to light chain onlyNon-secretory relapseExtra medullar disease
19 Nature of Relapse How did the patient present? 80% share clinical features with presentation35% relapse both light chain and intact Ig49.6% intact Ig10% free light chain onlyHas been a shift on presentation?Intact immunoglobulin to light chain onlyNon-secretory relapseExtra medullar disease
24 Clinical Considerations for Relapsed/Refractory Disease Toxicity considerationsPeripheral neuropathyThrombotic riskMyelosuppressionImpact of prior therapies (eg, SCT, other cumulative toxicity)
25 Overall survival in 6-year intervals from time of diagnosis ANY PROGRESS?Overall survival in 6-year intervals from time of diagnosisTime (months)Proportion of patients0.20.40.60.81.0204060801001201402001–20061995–20001989–19941983–19881977–19821971–1976Kumar et al. Blood. 2008Brenner et al. Blood. 20082525
32 Bortezomib Retreatment – A Retrospective Multicenter Survey Retrospectively collected data- multicenter non-interventional survey of pts who received bortezomib for a second time (retreatment)Patients: 65 pts,19 centers; median age 65 yrsTreatment receivedMedian 4 prior therapiesRetreatmentInitialbortezomibDiagnosis52 mosMean of 5 cyclesMean of 4 cycles6 pts received additional therapyMedianBortezomib mg/m2InitialRe-treatment1.394%86%1.02%12%other8%4%+ Dex39%61%Results: 49 evaluable (modified ITT)RetreatmentBest ResponseTreatment OutcomesSafety: AE occurring in > 2 patients% PatientsmonthsPatients (n)Hrusovsky I, et al. ASH 2007, abstract #2720
36 Study 003-A1: Open-Label Phase 2b Study of Single-Agent Carfilzomib in Relapsed and Refractory Multiple Myeloma (R/R MM)Study Population (N=266)Relapsed from ≥2 prior lines of therapyMust include bortezomibMust include thalidomide or lenalidomideRefractory to last regimenCarfilzomib IV on days 1, 2, 8, 9, 15 and 16 every 28 days20 mg/m2 in Cycle 1and 27 mg/m2 from Cycle 2 and beyond(maximum 12 cycles)Primary endpoint: ORRIMWG response criteria (IRC assessed)Secondary endpointsCBR (ORR+ MR), DOR, OS, PFS, TTP, safetyCBR = clinical benefit rate; DOR = duration of response; IMWG = International Myeloma Working Group; IRC = Independent Review Committee; MR = minimal response; ORR = overall response rate; OS = overall survival; PFS = progression-free survivalSiegel D, et al. Blood. 2012;120:
37 Single-Agent Carfilzomib: Response Rates TTR: 1.9 mo (≥PR) and 1.0 mo (≥MR)DOR: 7.8 mo (≥PR) and 8.3 mo (≥MR)N = 257 response-evaluable populationDCR = 69%Percentage of PatientsCBR = 37%ORR = 24%Subset analyses of higher risk populations showed similar response rates (e.g., unfavorable cytogenetics, baseline peripheral neuropathy)CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease; TTR = time to response; VGPR = very good partial responseSiegel D, et al. Blood. 2012;120:*IRC-determined; 11 patients had unconfirmed response
38 Single-Agent Carfilzomib: PFS, OS 1.00.80.60.40.20.039121861531221271.00.80.60.40.20.015691824Median OS = 15.6 mo(95% CI 13.0–19.2)Median PFS = 3.7 mo (95% CI 2.8–4.6)Proportion alive and without progressionProportion survivingMonthsN = 257 response-evaluable populationMonthsSiegel D, et al. Blood. 2012;120:38
40 Phase II Trial of Carfilzomib Plus Len/Dex in R/R MM (1-3 prior lines of therapy) Carfilzomib 20/27 mg/m2 IV**20 mg/m2 cycle 1 days 1 and 2 only, 27 mg/m2 thereafterD1/D2D8/D9D15/D16Week 1Week 2Week 3Week 4: restLenalidomide d1-d21 25 mg/d POD1D8D15D22Dexamethasone 40 mg/d POResponse (N = 52 pts receiving maximal planned dose)n (%)ORRStringent CRCRVGPRPRSD40 (77)2 (4)1 (2)19 (37)18 (35)3 (6)Median duration of response, mos (range)22.1 ( )Wang M, et al. Blood. 2013;122:4040
41 For ASH Dec 09Phase III ASPIRE Trial: Carfilzomib + Len/Dex vs Len/Dex in R/R MM (ongoing)Press release-PFS 26.3 vs 17.6 HR 0.69:CRdCarfilzomib27 mg/m2 IV day 1, 2, 8, 9, 15, and 16 (20 mg/m2 on days 1, 2 of cycle 1 only)Lenalidomide25 mg Days 1-21Dexamethasone40 mg once weeklyStudy Population (N=780)Measurable disease1-3 prior regimensRelapse or PDResponse to ≥1 prior regimenExclusion factors:Bortezomib-refractoryLen/dex-refractoryPrior carfilzomibRdLenalidomide25 mg Days 1-21Dexamethasone40 mg once weeklyStratify: Prior bortezomib, prior lenalidomide, β2 microglobulin levelPrimary endpoint: PFS28-day cyclesAvailable at: Accessed April 29, 2014.DRAFT41
42 Phase 1b Study of High-Dose Carfilzomib + Dexamethasone in R/R MM EndpointCFZ20/4520/56TotalORR, %575055CR, %VGPR, %1425PR, %4330DORNRPFS, months5.46.0Study population: N=22(expanded 007 cohort)Median prior regimens: 4Regimen: (28-day cycles)Carfilzomib 20/45 or 20/56 mg/m2 30-min IV D1,2,8,9,15,16Dexamethasone 20 mgD1,2,8,9,15,16 then 40 mg D22EfficacyTreatment-emergent Grade ≥3 AE, %CFZ20/4520/56TotalHematologicThrombocytopeniaAnemiaLymphopenia29145025362718NonhematologicHypertensionHypophosphatemiaPneumonia7139SafetyCFZ = carfilzomibBadros A, et al. ASH Abstract 4036.
43 Phase III ENDEAVOR: Carfilzomib + Dex vs Bortezomib/Dex in R/R MM1 Note use of higher carfilzomib dose—based on results from 004 trial, which suggested dose-response relationship of carfilzomib2CdCarfilzomib20/56 mg/m2 IV D1,2, 8, 9, 15, 16Dexamethasone20 mg PO or IV D1, 2, 8, 9, 15, 16, 22, 2328-day cycleStudy Population (N=888)Measurable diseaseResponsive to at least 1 prior therapyRelapsed following 1-3 prior treatment regimensECOG PS 0-2VdBortezomib1.3 mg/m2 IV or SC D1, 4, 8, & 11Dexamethasone20 mg PO or IV D1, 2, 4, 5, 8, 9, 11, 1221-day cycleStratify: Prior PI, prior lines of therapy, ISS, bortezomib IV vs. SCPrimary endpoint: PFSTreat until PD or unacceptable toxicityClinicalTrials.gov. Available at: Accessed March 26, 2014.Vij R, et al. Blood. 2012;119:
44 Novel PIs Under Investigation in R/R MM AgentStatusIxazomibTwo phase I studies showed activity of single-agent ixazomib[2,3]OprozomibPhase 1 dose-escalation study showed some activity in patients with heavily pretreated hematologic malignancies, including MMRichardson PG, et al. ASH Abstract 302.Lonial S, et al. ASCO Abstract 8017.Kumar S, et al. ASCO Abstract 8514.Savona MR, et al. ASH Abstract 203.
55 Pomalidomide in Relapsed/Refractory Multiple Myeloma POM + LoDEX achieved responses in pts with prior LEN and/or BORT treatment, including those who are refractory1-4StudyPhaseNTreatmentPopulationMedian Prior Tx (Range)≥ PRLacy4260POM: 2 mg(28/28-day cycle)Dex: 40 mg/week1-3 prior Tx, relapsed/refractory2 (1-3)65%34LEN-refractory4 (1-14)32%35DEX: 40 mg/weekLEN- and BORT- refractory6 (3-9)26%POM: 4 mg1-3 prior Tx, LEN-refractory37%6 (2-11)29%1. Lacy MQ et al. J Clin Oncol. 2009;27: Lacy MQ et al. Leukemia. 2010;24:1934.3. Lacy MQ et al. Blood. 2011;118: Lacy MQ et al. Blood. 2011;118: Abstract 3963.55
56 Median No. Prior Regimens Refractory to Recent Therapy (%) PomalidomidePts, nMedian No. Prior RegimensRefractory to Recent Therapy (%)ORR (%)Pomalidomide ± dex119151002534Pomalidomide, dex2706NR2629Pomalidomide, dex384853435Pomalidomide, cyclophosphamide, prednisone432(1 to 3)44*59Pomalidomide, dex, clarithromycin546NR (at least 3)60*Len specifically1. Vij R et al. J Clin Oncol. 2012;30. Abstract 8016.2. Lacy MQ et al. Blood. 2011;118: Leleu X et al. Blood. 2011;118. Abstract 812.4. Palumbo A et al. Blood. 2011;118. Abstract 632.Mark TM et al. Blood. 2011;118. Abstract 635.
57 ClaPd: Study Design Day A single-center, phase 2 study of Clarithromycin combined with Pomalidomide + Low Dose Dexamethasone in RRMMDayDex40mg POPomalidomide 4 mg POClarithromycin 500mg PO BIDp.o., orally; b.i.d., twice a day; RRMM, relapsed, refractory MM.
59 Results Best Response (IMWG Criteria) n (%) Overall (N = 98) ORR (≥ PR)56 (57)CBR (≥ MR)65 (66)sCR6 (6)VGPR17 (17)PR33 (34)MR9 (9)SD23 (23)PD10 (10)98 patients completed at least 1 cycle of ClaPD.median number of cycles received was 6 (range 1–25)median study follow-up was months (range 1.0–25.6)In responding patients, median time to PR was 1 cycle (range 1–7).Median time to best response was 2 cycles (range 1-14).IMWG, International Myeloma Working Group; CBR, clinical benefit rate; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.
60 Treatment History With Len/Bort Did Not Influence Response to ClaPD Best Response (IMWG Criteria)n (%)Overall(N = 98)Lenalidomiderefractory(N = 83)BortezomibRefractory(N = 82)Lenalidomide andbortezomib refractory(N = 72)ORR (≥ PR)56 (57)47 (63)46 (56)39 (54)CBR (≥ MR)65 (66)56 (67)54 (65)(65)sCR6 (6)6 (7)5 (6)5 (7)VGPR17 (17)13 (16)9 (13)PR33 (34)28 (34)25 (35)MR9 (9)8 (10)8 (11)SD23 (23)18 (22)19 (23)16 (22)PD10 (10)8 (12)9 (11)IMWG, International Myeloma Working Group; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.
61 OS by double-refractory state ResultsOS by cytogenetic riskOS by double-refractory state1.001.000.750.75Survival (%)0.50Survival (%)0.50Standard riskHigh riskNot double-refractoryDouble-refractory0.250.25Time (days)Time (days)Number of patients at risk RelapsedRefractoryNumber of patients at risk RelapsedRefractoryAdverse cytogenetics did not appear to influence risk of death as of last study follow-up.HR 1.05, 95%CI (0.49,2.26), P = 0.888A history of being double-refractory, however, approached a significant effect on survival time.HR 2.67, 95%CI (0.93,7.69), P = 0.068
62 IFM 2010-02: Study design End-points Primary: TTP RRMMExposed to Lendel 17p and/or t(4;14)Measurable diseaseECOG 0–2PNn > 1 x109/LPlat ≥ 75 x109/LHb ≥ 8 g/dLCrCl ≥30 mL/minPomalidomide 4 mg/day, po, days 1–21 (of 28 d cycle)Dexamethasone 40 mg, po, days 1, 8, 15, 22Aspirin/LMWH once daily, continuouslyUntil progressionSafety analysis by DMC after 15 patients recruitedEnd-pointsPrimary: TTPSecondary: Safety, Response rate (CBR), DoR, OS, PFS, EFS, cytogenetic groupsMedian follow-up: 8.2 monthsAt data cut-off, 36 patients (72%) had discontinued trialn (%)Progression25 (69)Death other cause1 (3)Toxicity9 (25)Sponsor decision
63 IFM 2010-02: Time To Progression (ITT) del17pt(4;14)ITTO/NMedian95% CIITT population33 / 502.9[2.7;5.0]8-month TTP, %22del17p12 / 22*7.3[2.7;14.7]41t(4;14)24 / 32*2.8[1.9;4.0]12.4
65 40 mg weekly (20 mg after cycle 4) Phase I/II: Carfilzomib/Pomalidomide/LoDEX (Car-Pom-d) in R/R MM28-day cycles(cycles 1-6)Maintenance(cycles 7+)Study Population (N=79)Relapsed and/or refractory measurable MMLenalidomide-refractoryCarfilzomib*20/27 mg/m2 (D1-2, 8-9, 15-16)Pomalidomide*4 mg (D1-21)Dexamethasone*40 mg weekly (20 mg after cycle 4)CarfilzomibD1-2, 15-16PomalidomideunchangedDexamethasoneTreatment continued until PD or unacceptable toxicityAll patients received antiviral treatment and aspirin 81 mg or low molecular weight heparin*Dosing based on MTD established in phase 1Primary endpoint: ORRSecondary endpoints:DOR, TTP, PFS, time to next therapy, OSShah JJ, et al. Blood. 2013;122:690.
66 Car-POM-d in R/R MM: Efficacy Cytogenetic Risk (by mSMART)Response, %High (n = 18)Intermediate (n = 19)Standard (n = 38)All Pts (N = 79)ORR78537470VGPR22263227PR564243Median PFS: 9.7 mos; median DOR: 17.7 months; median OS not reachedNo significant difference in PFS or OS based on cytogenetics80% of pts with del(17p) were alive at 12 mos; 58% were progression-freeShah JJ, et al. Blood. 2013;122:690.
71 Vorinostat Bortezomib vs Placebo Bortezomib Vorinostat: Median PFS: 7·63 months (95% CI 6·87-8·40)Placebo: Median 6·83 months (5·67-7·73)(hazard ratio [HR] 0·77, 95% CI 0·64-0·94;p=0·0100).Dimopoulos et al,Lancet Oncol Oct;14(11):
72 PANORAMA 1: Phase III Trial of Panobinostat + Bortezomib + Dex DexamethasoneStudy Population (N=768)Relapse or relapsed/refractory MMBortezomib-refractory excluded1-3 prior lines of therapyStratification based on prior lines of therapy, prior bortezomibPlaceboBortezomibDexamethasonePrimary endpoint: PFSRichardson PG, et al. ASCO Abstract 8510.
75 Autotransplant for Refractory MM SWOG Trial 8993PFSOSN = 66Median = 11 moN = 66Median = 19 moVesole DH, et al. J Clin Oncol. 1999;17:
76 PBSCT in Relapsed MM TTP median HD Mel 19 months [95% CI 16—25] PADWeekly CTX 400 mg/m2 x 21HD MelInductionConsolidationTTP medianHD Mel 19 months [95% CI 16—25]Cyclophosphamide 11 months [9—12];hazard ratio 0·36 [95% CI 0·25—0·53];p<0·0001).Cook G et al,The Lancet Oncology, Volume 15, Issue 8, Pages , July 2014
77 A Phase 1 Study of Bendamustine and Melphalan Conditioning for Autologous Stem Cell Transplant with Multiple Myeloma.
78 Dose Levels for Bendamustine On Day 1 Melphalan (100mg/m2)On Day 2 Melphalan (100mg/m2)130 mg/m2260 mg/m2390 mg/m2456125 mg/m2100 mg/m2