Presentation on theme: "Maintenance Therapy in Multiple Myeloma"— Presentation transcript:
1Maintenance Therapy in Multiple Myeloma The Role of Other Agents (Besides Lenalidomide)James Berenson, MDInstitute for Myeloma and Bone Cancer ResearchLos Angeles, CA
2Maintenance Therapy in Myeloma GoalsReduce the risk of relapseExtend PFS and OSMaintain response achieved following a new treatment with administration of drugs for a prolonged time periodTherapy must beConvenientSafe and well tolerated LONGTERMNOT prevent use or reduce efficacy of other future treatments
3Maintenance Therapy in Myeloma In what setting- frontline or > 2nd lineMost of the data is in the frontline settingHow long to “maintain” maintenance therapyUntil relapse or for a fixed length of timeTrials have employed both approaches BUT no randomized trials comparing the two w/i a trialWhich agentsHow many to use?Doses?Schedule(s)?Very little data from randomized trials comparing different maintenance regimens as the only randomization
4Maintenance Therapy in Myeloma: Steroids and a-Interferon a. 929 patients in 8 trials had prolongation ofremission duration and survival by 6 and 5 monthsLudwig H. Ann Oncol 1995;467b. Twist analysis: IFN gained 9.8 months withoutrelapse and 5.8 months survival, but with 4.1months of toxicityTherefore, benefits must be balanced against toxicityLudwig H ;16722. Prednisone 50 mg qod prolongs overall and event-free survival after VAD induction therapyBerenson J. Blood 2002;99:3163
5Thalidomide: Maintenance Therapy after Autologous Stem Cell Transplant Initialdose, mg/dMaintenance versus no maintenanceCR, %EFS or PFS, %OS, %Attal et al.1597400 w/ PAM67 vs 55*3-year EFS52 vs 364-year OS87 vs 77Barlogie et al.266840062 vs 435-year EFS56 vs 448-year OS57 vs 44Spencer et al.3243200 w/ steroidvs steroid alone63 vs 40*3-year PFS42 vs 233-year OS86 vs 75Lokhorst et al.45355024 vs 66*Median22 m vs 34 m60 m vs 73 mvs PAM or noneAttal M, et al. Blood Barlogie B, et al. Blood 2008Spencer A, et al. J clin Oncol Lokhorst et al . Blood* CR + VGPR rates.55
6Bisphosphonates: Anti-Tumor Effects in MM DirectInduces apoptosisPrevents prenylation of GTPasesIndirectReduces anti-apoptotic and growth factorsAnti-angiogenicDecreases angiogenic factorsPrevents endothelial cell developmentInhibits angioattractionM2 to M1 reversion of TAMsPrevents adhesion of MM cells to stromaSynergizes w/ other anti-MM drugsImmune stimulatory effects-Increases Vg9d2 T cellsSlide 10: Bisphosphonates – Mechanisms of action (myeloma-related)6
7Pamidronate With or Without Thalidomide as Post-transplantation Maintenance Therapy Intergroupe Francophone du Myeloma (IFM) 99 02Large, randomized, prospective studyNo maintenance therapy(n = 200)Pts with untreatedStage I - III MM< 65 yrs old(N = 780)VAD regimen3-4 cyclesMelphalan 140 mg/m2 and autologous stem-cell transplantMelphalan200 mg/m2and second autologous stem-cell transplantPts who did not progressafter 2 mos(n = 597)Pamidronate(90 mg/mo)(n = 196)Pamidronate(90 mg/mo) + Thalidomide(100 mg/day)(n = 201)VAD; vincristine, doxorubicin, and dexamethasoneSurvival benefit in the combination PAM + Thal arm and not in the single agent PAM armAttal M et al Blood 2006; 108: 3289.
8MRC Myeloma IX: Trial Design for Monthly IV Zoledronic Acid vs Daily Oral Clodronate for Newly Diagnosed MMRANDOMIZATIONZoledronic acid (4 mga IV q 3-4 wk) + intensive or non-intensive chemotherapy (n = 981)N = 1,960Patients with newly diagnosed MM (stage I, II, III)Treatment continued at least until disease progressionClodronate (1600 mg/d PO) + intensive or non-intensive chemotherapy (n = 979)Endpoints (ZOL vs CLO)Primary: PFS, OS, and ORRSecondary: Time to first SRE, SRE incidence, and safetyAbbreviations: CLO, clodronate; IV, intravenous; MM, multiple myeloma; ORR, overall response rate; OS, overall survival, PFS, progression-free survival; PO, oral; SRE, skeletal-related event; ZOL, zoledronic acid.a Dose-adjusted for patients with impaired renal function, per the prescribing information.Morgan G, et al. Lancet. 2010;376:8
9MRC Myeloma IX: ZOL Improved OS and PFS vs CLOa ZOL significantly reduced the relative risk of death by 16% vs CLO (HR = 0.842; 95% CI = 0.736, 0.963; P = .0118)Risk reductionP value0.842OS16%.01180.883PFS12%.017184.108.40.206.8220.127.116.11.82Hazard ratio (ZOL versus CLO)In favor of ZOLIn favor of CLOa Cox model adjusted for chemotherapy, and minimization factors.Morgan G, et al. Lancet. 2010;376:9
10Bortezomib as Maintenance Therapy VMPT-VT vs VMP: Study Design VMPT (n=254)Induction: 9 coursesWeekly BORT (4 doses; 1.3 mg/m2)Melphalan 9 mg/m2Prednisone 60 mg/m2 once daily on days 1-4 of each courseThalidomide 50 mg/day continuouslyVT (n=254)Maintenance: 2 yearsBORT 1.3 mg/m2 or maximum dose tolerated q2wThalidomide 50 mg/day continuouslyR A N D O M I Z ENDMM(N=511)SCT-ineligibleMeasurable diseaseKarnofsky PS ≥60%VMP (n=257)9 coursesWeekly BORT (4 doses; 1.3 mg/m2)Melphalan 9 mg/m2Prednisone 60 mg/m2 once daily on days 1-4 of each courseNo Maintenance Therapy(N=257)Endpoints:Primary: PFSSecondary: RR, OS, and grade ≥3 AEsPalumbo A, et al. Presented at: ASH (abstr 200).
11VMPT-VT vs VMP: PFS and Time to Next Therapy (TTNT) Median PFS, MonthsMedian TTNT, MonthsVMPT-VT35.346.6VMP24.827.8Reduced risk, %42 (of progression)48 (of next therapy)Median follow-up 54 monthsPFSHR: 0.58 (95% CI, ); P<0.0001TTNTHR: 0.52 (95% CI, ); P<0.00011.000.750.500.250.001.000.750.500.250.00Patients, %Patients, %VMPT-VTVMPT-VTVMPVMP10203040506070801020304050607080Time, MonthsTime, MonthsTTNT=time to next therapy.Palumbo A, et al. Presented at: ASH (abstr 200).
12VMPT-VT vs VMP: Overall Survival InductionMaintenance1.000.750.500.250.001020304050607080Proportion of PatientsTime, MonthsHR: 0.74 (95% CI, ); P=0.04Efficacy, %VcMPT-VcTVcMPP Value5-yr PFS2913<0.00015-yr TTNT41195-yr OS61510.013-yr OS from relapse47460.63Palumbo A, et al. Presented at: ASH (abstr 200).
13Impact of Maintenance Therapy: VMPT-VT vs VMP Landmark analysis after finishing 9 cycles of induction VMPT or VMP52% reduced risk of progression with VMPT-VT (HR 0.48, P<0.0001)Irrespective of response (CR or PR)In pts <75 yrs old, but not ≥75 yrsPrognostic factors: response, age, ISS, cytogenetic abnormalitiesGrade 3/4 AE’s during maintenanceVMPT-VTHematologic2%DVT1%Sensory neuropathy6%InfectionCardiologicDiscont. due to AE11%Palumbo et al. ASH 2010 (Abstract 620)
14HOVON-65/GMMG-HD4: Study Design PAD × 3 cyclesBORT 1.3 mg/m2 days 1, 4, 8, 11doxorubicin 9 mg/m2days 1-4dexamethasone 40 mg days 1-4, 9-12, 17-20(n=371)VAD × 3 cyclesVincristine 0.4 mg days 1-4 Doxorubicin 9 mg/m2 days 1-4Dexamethasone 40 mg days 1-4, 9-12, 17-20(n=373)BORT1.3 mg/m2every 2 weeksStem cellcollectionandtransplantation*Thalidomide50 mg/day2 yearsPatients years of age with newly diagnosed stage II/III MM(N=744)Multicenter, International, Phase III TrialPrimary endpoint: PFSSecondary endpoints: response, OS, toxicity*ASCT + melphalan 200 mg/m2; allogeneic SCT with no maintenance offered when possible; German patients enrolled through GMMG underwent 2 ASCTs.German centers performed double SCT; Dutch centers performed single SCT.Sonneveld P, et al. J Clin Oncol. 2012;30:
15HOVON-65/GMMG-HD4: Response, PFS & OS 1008060402010080604020PFS, %OS, %PADVADPADVADP=0.002P=0.0712243648601224364860Time, MonthsTime, MonthsImproved PFS and OS in pts w/ del 17p13 and those w/ creatinine > 2 mg/dLResponseVAD Arm: Thalidomide, %(n=414)PAD Arm: BORT, %(n=413)Pand t ValueCR≥ nCR≥ VGPR≥ PR2434568336497690<0.0010.002Sonneveld P, et al. J Clin Oncol. 2012;30:
16Maintenance thalidomide (n=87) Maintenance interferon (n=90) Phase III PETHEMA/GEM Trial: Bortezomib as Maintenance Therapy in Previously Untreated MM1,2Endpoints: Primary: PFS; Secondary: response rate, OS, safetyPatients: 266 pts <65 yrs of age with previously untreated MM randomized to maintenance therapy; median age 56–58 yrs across arms; 53–59% ISS stage II/III across armsDose and schedule:Induction: thalidomide/Dex (6 cycles) vs VTD (6 cycles) vs VBMCP/VBAD (4 cycles) + bortezomib (2 cycles); followed by ASCT with MEL-200; then second randomization to:Maintenance: 3 armsbortezomib 1.3 mg/m2 days 1, 4, 8, 11 every 3 mos + thalidomide 100 mg/day (VT)thalidomide 100 mg/dayinterferon-α2b 3 MU 3 times/week; for 3 yrsResponse:MaintenanceVT (n=89)Maintenance thalidomide (n=87)Maintenance interferon (n=90)Response before maintenance, %CRVGPRPR53123349113713Response improvement with maintenance, %CR post-maintenanceIncrease in CR7421631569Rosiñol L, et al. ASH 2012, abstract #334; Induction phase publication: Rosiñol L, et al. Blood 2012;120: ; Maintenance therapy previous publication: Rosiñol L, et al. ASH 2011, abstract #3962
17Phase III PETHEMA/GEM Trial: Bortezomib as Maintenance Therapy for Previously Untreated MM1,2 Outcomes: Median follow-up of 34.9 mos; from onset of maintenance therapy:PFS: addition of bortezomib to thalidomide (VT) maintenance resulted in significantly longer PFS vs thalidomide or interferon (p=0.0009)OS: No difference between arms (p=0.47)Bortezomib-containing (VT) maintenance conferred a significant PFS advantage in pts with low-risk (p=0.002) but not high-risk (p=0.5) cytogeneticsSafety:Gr 3/4 thrombocytopenia for VT vs. thalidomide: 10% vs. 2%; p=0.01Gr 3/4 neutropenia: Approximately 13% for VT, 16% for thalidomide, and 17% for interferon*p=0.02 vs thalidomide; #p=0.06 vs thalidomide; †discontinued thalidomide but remained on bortezomibRosiñol L, et al. ASH 2012, abstract #33417
18Induction Randomization step 1 Maintenance Randomization Phase III: VMP vs VTP in Newly Diagnosed Elderly Pts with MM (PETHEMA/GEM Study)Pts (n=260), >65 yrs old (median age 73 yrs)Multicenter, two-stage randomized trialInduction Randomization step 1Induction (max. 6 cycles)One 6-wk cycle, bortezomib 2x wklyFive 5-wk cycles, bortezomib 1x wklyVMPvsVTPMaintenance Randomizationstep 2Maintenance (up to 3 yrs)Bortezomib: 1.3 mg/m2(d 1, 4, 8, 11), every 3 mos+ Thal: 50 mg daily (VT)or Pred: 50 mg every 48 hrs (VP)VTvsVPVTvsVPMateos et al. Lancet Oncol 2010; 11(10):
19PFS and OSNo significant difference in PFS and OS between VMP and VTP groups and not significantly different for VT or VP maintenancePFSOSVMP 3-yr OS 74%VMP 34 mosVTP 3-yr OS 65%VTP 25 mosp=0.1p=0.3Mateos et al. Lancet Oncol 2010; 11(10):
20SummaryThe role of maintenance therapy with novel agents has not been clearly defined (limitations in trial designs)Long term use appears to be safe w/ bortezomib and steroidsBetter trial designs are required to clarify the role of maintenance therapy in myelomaSpecific drugsSingle agent vs combinationDoses and schedulesLength of therapy- fixed vs to progressionEndpoints- PFS vs OS
21In Our Clinical Practice Maintenance therapy is used for all patients responding in both the frontline and salvage settingsDrugs are continued until progressive disease; however, doses may have to be reduced or discontinued due to toxicityDrugs are continued that were part of the treatment regimen EXCEPT chemotherapyNew agents are NOT introduced during maintenance (i.e. the devil you know is better (and shown to be effective) than the one you don’t)- if so, this is NEW treatmentSteroids at equivalent dose intensity (160 mg Dex)/month as oral methylprednisolone qod alone or w/ IV Dex qowBortezomib 1.3 mg/m2 sc qowIMiD drugs- Lenalidomide 10 mg for 14 or 21 days depending on regimen; THAL mg daily and tapered w/ neuropathyZoledronic acid is continued monthly