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Ludwig © 2013 Heinz Ludwig Department of Medicine I Center for Oncology, Hematology and Palliative Care Wilhelminenhospital, Vienna, Austria What we know.

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Presentation on theme: "Ludwig © 2013 Heinz Ludwig Department of Medicine I Center for Oncology, Hematology and Palliative Care Wilhelminenhospital, Vienna, Austria What we know."— Presentation transcript:

1 Ludwig © 2013 Heinz Ludwig Department of Medicine I Center for Oncology, Hematology and Palliative Care Wilhelminenhospital, Vienna, Austria What we know about myeloma in elderly patients from trials and observational studies?

2 Ludwig © 2013  Rapid symptom control  Optimal quality of life  Few and acceptable side effects  Best possible quality of response  Long PFS  Long OS  Cure ? Goals of therapy in elderly patients

3 Ludwig © drug*2 - drugs3- drugs4 - drugs DexBendamustine +P MPTVMPT ThalVDVMP MP*CTD Thal-DexVTD L-ldDex Most commonly used combinations contain 2-3 drugs *only exceptional cases Drug combinations for elderly patients Possible options

4 H. Ludwig 2013 Characteristics of the Elderly Patient Chronological age does not necessarily correlate with biological age The variation in biological fitness in a specific age cohort increases with rising age, but the ‚biology‘ of myeloma cells does not vary with age All three individuals are 70 years old Fit Minor morbidity significant morbidity

5 Ludwig © 2013 Assess fraility FitUnfitFrail Full go Slow go Very slow go 2 or 3 drug regimen reduce dose 2 (3) drug regimen further dose reduction MP, CTX-P VD, Ld Treatment of patients with multiple myeloma not eligible for transplantation

6 H. Ludwig 2013 Instruments for assessing fraility and allocation to treatment groups FitUnfitFrail Age <80 yrFit >80 yrUnfit >80 yr ADL 6 IADL 8 Charlson 0 ADL 5 IADL 6-7 Charlson 1 ADL ≤4 IADL ≤5 Charlson ≥2 Go-goModerate-goSlow-go Full-dose regimens Dose level 0 Reduced-dose regimens Dose level -1 Reduced-dose Palliative approach Dose level -2 Palumbo A et al. IMW 2013 Assess  Age  ADL  IADL  Charlson comorbidity score

7 H. Ludwig 2013 Adaptation of dose according to risk factors AgentDose level 0Dose level-1Dose level - 2 Dexamethasone40 mg20 mg10 mg Melphalan 0.25 mg/kg or 9 mg/m mg/kg or 7.5 mg/m mg/kg or 5 mg/m 2 Thalidomide100 mg50 mg50 mg/qod Lenalidomide25 mg15 mg10 mg Bortezomib 1.3 mg twice weekly, sc 1.3 mg weekly, sc 1.0 mg weekly, sc Prednisone60 mg/m 2 30 mg/m 2 15 mg/m 2 Cyclophosphamide100 mg50 mg50 mg/qod Palumbo et al.,BLOOD 2011

8 H. Ludwig 2013 Polyneuropathy Avoid bortezomib (or use once weekly sc) Renal impairment Consider dose adaptations when using lenalidomide Bone marrow insufficiency Careful dosing of cytoreductive drugs, consider single agent dexamethasone Cardiac arrhythmias/ dysfunction Cave: Thalidomide & high dose dexamethasone Immune system Careful dosing of cytoreductive drugs Diabetes Cave: high dose dexamethasone Cognitive function/ compliance Consider iv regimens Comorbidities relevant for treatment selection in myeloma

9 H. Ludwig 2013 Higher risk of mortality in patients ≥ 75 years of age Median follow up 33 months Median OS in total population 50 months Estimated 3-year OS 68% in patients < 75 years of age vs 57% in patients ≥ 75 years of age (HR 1.44, CI , p < 0.001) Bringhen S, et al. Haematologica. 2013;98: Retrospective meta-analysis of 4 EU phase III trials (N = 1,435) with MP, MPT, VMP, and VMPT HR (95% CI)p value All1.44 (1.20–0.72)< MP1.21 (0.90–1.64)0.21 MPT1.12 (0.81–1.56)0.49 VMP1.62 (1.04–2.52)0.03 VTP/VMPT3.02 (1.86–4.90)< Higher mortality in patients ≥ 75 years of age Higher mortality in patients < 75 years of age

10 Ludwig © 2013 n=1435 (≥ 65 yrs ): MPT vs MP, VMP vs MP, VMP vs VMPT-VT Bringhen et al. Haematologica 2013;98(6): Age and Organ Damage Correlate with Poor OS: Meta-analysis of 4 Randomized Trials

11 H. Ludwig 2013 New Regimen ComparatorOutcome MPT (6 Trials)*vs.MP MPT  PFS 5/6,  OS 2/6 CTDavs.MP CTDa  ORR VMPvs.MP VMP  PFS,   OS VMPT  VT vs.VMP VMPT  VT   PFS.   OS VMP  VT or VPVDT  VT or VP ns MPR  R vs.MPR or MP MPR  R   PFS LDvs.Ld Ld  PFS,   OS LD continousvs.Ld x 18, vs MPT x 12 Ld cont  PFS,   OS * Meta-analysis of the 6 trials:  PFS  (  ) OS Phase III studies incorporating novel agents in the non-transplant setting

12 H. Ludwig 2013 MPT vs MP: Meta-analysis of 1685 individual-patient data of 6 randomized trials Fayers et al. Blood 2011, accepted for publication 30 May months Median 32.7 mos ( ) Median 39.3 mos ( ) HR=0.83 in favor of MPT, p=0.005* OS *Cox model for treatment, with analysis stratified by study using a random effects (frailty) model MP MPT

13 H. Ludwig 2013 MPT: Pros and Cons Pros  Survival benefit  Oral regimen  Not expensive Cons  Thalidomide toxicity  Suboptimal in cytogenetic high risk group  Shorter survival after relapse

14 H. Ludwig 2013 MP vs. VMP (VISTA) Final updated OS analysis Median follow-up 60.1 months 31% reduced risk of death Median OS benefit: 13.3 months 5-year OS rates: 46.0% vs 34.4% Patients alive (%) Time (months) GroupNEventMedianHR (95% CI)P-value M VMP (0.567, 0.852) San Miguel et al. JCO 2013

15 H. Ludwig 2013 San Miguel et al., JCO 2013 Overall survival in different subgroups: VMP vs. MP

16 H. Ludwig 2013 Time to next therapyTime to progression Treatment-free interval Overall survival Harousseau JL et al., BLOOD 2010 VMP induced CR is associated with improved outcome

17 H. Ludwig 2013 VD vs. VTD vs. VMP followed by bortezomib maintenance therapy Niesvitzky R. et al., BLOO, Para- meter VDVTDVMP >VGPR36%44%40% ORR68%78%71% PNP G3-4 15%26%20% PFS (mos)

18 H. Ludwig 2013 Global QoL during VD, VTD and VMP induction therapy Niesvizky R et al., ASH 2011 VD vs. VTD or VMP: shorter PFS, similar OS, better tolerance

19 H. Ludwig 2013 Treatment schedule

20 H. Ludwig 2013 Palumbo A et al. ASH 2012 Progression free survival Overall survival landmark analysis PFS and OS: VMP vs VMPT –VT

21 H. Ludwig 2013 Overall survival, Landmark analysis

22 H. Ludwig 2013 Palumbo et al. ASH 2012 (Abstract 200) Overall survival from relapse

23 H. Ludwig 2013 VMPT-VT versus VMP in newly diagnosed elderly patients Significant OS benefit in patients – 75 years) –With stage ISS 1-2 (tendency for  OS in stage ISS 3) –With CR (none in pts with VGPR/PR) Benefit in ‚good risk‘ patients with CR only Grade 3- 4 adverse events during VT maintenance –PN 7% –Hematological toxicity 5% –Infection 3% –Discontinuation due to AEs 12% Palumbo et al. ASH 2012 (Abstract 200), oral presentation

24 H. Ludwig 2013 How to reduce toxicity of Bortezomib and and maintain efficacy?  Bortezomib once weekly  longer duration of therapy  similar cumulative dose  similar efficacy  less toxicty (G3/4 neurotoxicity)  Bortezomib subcutaneously  10 times lower serum peak concentration  similar area under the curve  less neurotoxicity  similar efficacy

25 H. Ludwig 2013 MPR-R vs. MPR vs. MP (MM015 trial)

26 H. Ludwig 2013 Progression-free and overall survival

27 H. Ludwig 2013 PFS and OS with MPR-R and MPR patients aged years

28 H. Ludwig 2013 FIRST: Phase 3 trial of Lenalidomide + low-dose Dex vs MPT (IFM 07-01; MM-020) Inclusion criteria N = 1,623 Previously untreated MM Age  65 years or not eligible for a transplant No neuropathy of grade > 2 Rd (28-day cycle; until disease progression) Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22 Rd (28-day cycle; until disease progression) Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22 Rd (28-day cycle; up to 18 cycles) Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22 Rd (28-day cycle; up to 18 cycles) Lenalidomide 25 mg/day, days 1–21 Dexamethasone* 40 mg/day, days 1, 8, 15, and 22 Centres in EU, Switzerland, APAC, USA, and Canada *In patients aged > 75 years: Dex 20 mg/day, melphalan 0.20 mg/kg/day, thalidomide 100 mg/day MPT (6-week cycle; up to 12 cycles ) Melphalan* 0.25 mg/kg/day, days 1–4 Prednisone 2.0 mg/kg/day, days 1–4 Thalidomide* 200 mg/day MPT (6-week cycle; up to 12 cycles ) Melphalan* 0.25 mg/kg/day, days 1–4 Prednisone 2.0 mg/kg/day, days 1–4 Thalidomide* 200 mg/day Primary end-point: PFS NCT Available from: RANDOMIZATIONRANDOMIZATION

29 H. Ludwig 2013 Trials & duration of therapy (months) VMP (Vista)12 MPT trials CTDa6-9 MPR-R9, R untill PD VMPT-VT12.5, VT maintenance: 2 years LD (MM20)Continously until PD/intolerance Duration of therapy: minimally 6, maximally 12 months Most experts recommend ≈ 9 months What is the optimal duration of first line therapy?

30 H. Ludwig 2013 CR rate (%)Median PFS (months)Median OS (months) MP 1,2 rare11– BP 2 -14*32 MPT CTDa VMP – MPR-R % (4-yr OS) VMP-VT/VP % (5-yr OS) VMPT-VT 8, % (5-yr OS) LD continuous 10 ≥PR 75% vs. 62% 28% ↓ risk for PD22% ↓ risk for death 1 MTCG. J Clin Oncol 1998;16(12): Ludwig et al., BLOOD Pönisch et al. J Cancer Res Clin Oncol. 2006;132: Fayers et al. Blood 2011; 118(5): Morgan et al. Blood 2011;118: San Miguel et al. JCO 2013; 31(4): Palumbo et al. N Engl J Med 2012;366(19): Mateos et al. Blood 2012; 120: Palumbo et al. ASH 2012 (Abstract 200), oral presentation 9 Palumbo et al. ASH 2011 (Abstract 653), oral presentation 10 Facon et al. ASH 2013 (Abstract 2), oral presentation Outcome with novel combinations

31 H. Ludwig 2013 Gay et al. Blood 2011; 117(11): Retrospective analysis: 3 randomized European trials of GIMEMA and HOVON groups (N=1175) First-line treatment MP (n=332), MPT (n=332), VMP (n=257), VMPT-VT (n=254) Significant benefit also seen when analysis is restricted to patients >75 years old PFS OS P<0.001 CR VGPR PR CR VGPR PR Probability Hematologic CR correlates with long PFS and OS in elderly patients treated with novel agents

32 H. Ludwig PFS Immunophenotypic CR 90% at 3y “Stringent CR”38% at 3y Conventional CR57% at 3y PR (≥70% reduction) 28% at 3y Paiva et al; J Clin Oncol. 2011;29(12): Immunophenotypc CR correlates with OS GEM2005 >65y

33 H. Ludwig 2013 Cytogenetic abnormalities are a major prognostic factor in elderly patients with MM: IFM experience 1,890 patients (median age 72, range 66–94), including 1,095 patients with updated data on treatment modalities and survival Whatever the treatment, t(4;14) and del(17p) were associated with shorter PFS and OS; similar results were achieved in the subgroup of 335 patients > 75 years 1. Avet-Loiseau H, et al. J Clin Oncol (22): Hulin et al. Blood 2012:[abstract 204] Probability of OS Time (years) OS according to t(4:14) t(4:14) neg t(4:14) pos Probability of OS Time (years) OS according to del(17p) del(17p) < 60 del(17p) ≥ 60 p < 10.4p < 10.6

34 H. Ludwig 2013 The challenge of high-risk CA [t(4;14), del(17p), t(14;16)] in NDMM elderly patients Study No of pts with high-risk CA Outcome of high-risk CA patients MPT/MP 1 NR CTDa/MP 1 (MRC Myeloma IX) NR CTDa does not overcome the effect of high-risk CA and is not significantly better than MP in high-risk CA RD/Rd 2 (E4A03)212y OS=76% for high-risk CA vs 91% VMP/MP 3 (VISTA)46 Absence of OS benefit, median OS 44.1mo. VMP vs 50.6 mo., MP VMP/VTP – VT/VP 4 (GEM-05) 44 Adverse prognosis of both t(4;14) and del (17p) regardless of induction and maintenance. Median OS t(4;14)=29 mo., del(17p) = 27mo. First generation novel agents only partly overcome the negative prognosis of high-risk CA in newly diagnosed elderly patients with MM 1. Bergsagel PL, et al. Blood. 2013;121: Rajkumar SV, et al. Lancet Oncol. 2010;11: San Miguel J, et al. J Clin Oncol. 2013;31: Mateos MV, et al. Blood. 2011;118:

35 H. Ludwig 2013 Thalidomide  PFS no improvement in OS  Reduced OS after relapse Negative impact on high risk pts Clinical practice recommendations 50 mg for ≈ 12 mos may be considered Lenalidomide  PFS -no improvement in OS -increased risk for SPM Bortezomib-thalidomide Tendency for  PFS and  OS but not significant superior over VP Maintenance studies - summary

36 H. Ludwig 2013 Summary: Treatment results in elderly patients  MPT,  PFS, +/-  OS, can be toxic in elderly pts  VMP,  PFS  OS, may induce severe PNP  Ld,  PFS,  OS, low dose Dex recommended  Thal-Dex, an option for fit pts  CTDa vs MP,  overall response rate,  CR, VGPR  Bendamustine-Pred, approved for first line TX  Thalidomide maintenance  PFS, but not OS  MPR with Lenalidomide maintenance  PFS, but not OS  VT maintenance  not significantly better than VP

37 H. Ludwig 2013 Maintenance The natural course of multiple myeloma

38 H. Ludwig 2013 Treatment of relapsed/refractory MM General considerations Components of initial therapy –Alkylating-based –Dexamethasone-based –IMiD-based –Bortezomib-based Efficacy of initial therapy –Quality of response –Tolerance of tretament –Duration of respose Patient status and type of relapse –Age, performance status, glucose metabolism –Aggressive vs non-aggressive relapse –Bone marrow reserve –Renal function impairment –Pre-existing peripheral neuropathy –Oral vs. iv therapy IMiD, immunomodulatory derivative; MM, multiple myeloma

39 H. Ludwig 2013 Frontline Therapy successful? Yes No Long duration of response Select other TX (Class switch) Yes No Repeat first line TX Select other TX Bortezomib based frontline TX: IMiD based frontline TX IMiD-based TD MPT CTD Rd (MPR) Bort-based VD VMP VTD Treatment of Relapsed/Refractory Myeloma Old Type MP DCEP M ASCT Ludwig et al. The Oncologist 2011 Pomalidomide

40 H. Ludwig 2013 Retreatment with bortezomib: a meta-analysis including 23 studies 23 trials, 1051 patients Patients refractory or not refractory to bortezomib 11 studies including bortezomib-refractory pts 6 studies excluding bortezomib-refractory pts 6 studies missing information on bortezomib-refractory pts Combinations Bortezomib ± Dex: 4 studies Bortezomib + combination therapy: 19 studies Knopf et al. IMW 2013 (Abstract P-228), poster presentation

41 H. Ludwig 2013 Results of meta-analysis of retreatement with bortezomib in different risk groups VariableORR TTP (months) OS (months) Relapsed57% Relapsed/>refractory19% ≤ 4 prior TX lines43% > 4 prior TX lines29% Boz + Dex51% Combination36% Pooled analysis51% Knopf et al., IMW 2013

42 H. Ludwig 2013 Carfilzomib a second generation proteasome inhibitor

43 H. Ludwig 2013 Single agent Carfilzomib in relapsed/refractory patients Response category All patients (n=267) High risk cytogenetics (n=71) CR0.4%0 VGPR5.1%4.2% PR18.3%25.4% MR13.2%4.2% ORR37%29.5% PFS(median)3.7 mos3.6 mos DOR (median)7.8 mos6.9 mos Progressive disease at enrollment, Relapsed from  2 prior TX lines, Must include bortezomib Must include thalidomide or lenalidomide, Refractory to last line Siegel D et al., BLOOD 2012

44 H. Ludwig 2013 Patients with relapsed/refractory myeloma (N = 455) POM + LoDex Pomalidomide 4 mg on Days Dexamethasone 40 mg (if ≤ 75 yrs) or 20 mg (if > 75 yrs) on Days 1, 8, 15, 22 (n = 302) HiDex Dexamethasone 40 mg (if ≤ 75 yrs) or 20 mg (if > 75 yrs) on Days 1-4, 9-12, (n = 153) 28-day cycles Stratified by age (≤ 75 vs > 75 yrs), number of previous treatments (2 vs > 2), disease population (refractory vs relapsed/refractory vs intolerant/refractory) Until PD* Companion trial MM-003C: Pomalidomide 21/28 days Follow-up for OS and SPM until 5 yrs Post enrollment Until PD* San Miguel JF, et al. ASCO Abstract Pomalidomide + LoDex vs HiDex (MM-003): Phase III Trial Design Primary endpoint: PFS Secondary endpoints: OS, ORR, DOR, safety *Independently adjudicated in real time. Thromboprophylaxis indicated for patients receiving pomalidomide or with history of DVT.

45 H. Ludwig 2013 Pomalidomide + LoDex vs HiDex: Key Criteria for Pts With Relapsed/Refractory MM All patients –Refractory to last therapy –≥ 2 previous therapies ≥ 2 consecutive cycles of lenalidomide and bortezomib (alone or in combination) or adequate previous alkylator therapy –Failed bortezomib and lenalidomide Progression within 60 days; PR with progression within 6 mos, and/or bortezomib intolerant after ≥ 2 cycles and achieving ≤ MR –Refractory or relapsed/refractory Primary refractory (never achieved better than PD to any therapy) or relapsed and refractory (relapsed after having ≥ SD for ≥ 2 cycles of therapy to ≥ 1 previous regimen and then developed PD ≤ 60 days of completing their last treatment) San Miguel JF, et al. ASCO Abstract 8510.

46 H. Ludwig 2013 Mos Pomalidomide + LoDex vs HiDex (MM-003) PFS (ITT Population)OS (ITT Population) Mos San Miguel JF, et al. ASCO Abstract 8510.

47 H. Ludwig 2013 Pomalidomide + LoDex vs HiDex Adverse Events (MM-003) AE, %POM + LoDex (n = 300) HiDex (n = 150) Grade 3/4 hematologic AEs  Neutropenia 4816  Anemia 3337  Thrombocytopenia 2226 Grade 3/4 nonhematologic AEs  Infections 3024 – Pneumonia 138  Bone pain 75  Fatigue 56  Asthenia 46 Grade 3/4 AEs of interest  DVT/PE 10  Peripheral neuropathy* 11 Discontinuation due to AEs 910 *Includes hyperesthesia, peripheral sensory neuropathy, paraesthesia, hypoesthesia, and polyneuropathy. San Miguel JF, et al. ASCO Abstract 8510.

48 H. Ludwig 2013 Zoledronic Acid vs Clodronate in Newly Diagnosed MM: SREs Morgan GJ, et al. ASH Abstract 311. Significantly reduced incidence of SREs* with zoledronic acid vs clodronate –Regardless of presence of bone lesions at baseline HR: 0.74 (P =.0004) *SREs defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic bone lesions. Patients at Risk, n ZOL Patients With an SRE (%) CLO ZOL Time From Randomization (Mos) CLO % 27.0%

49 H. Ludwig 2013 Planned and/or ongoing studies VD vs VTD vs VMP + V maintenance (UPFRONT study) VRd vs Rd + Rd maintenance (SWOG S0777) Rd vs MPT vs Rd + Rd maintenance (MM20/IM(FIRST trial) Rd vs MPR vs CRP + maintenance R vs RP (EMNTG) MPT+T vs MPR+R (HOVON 87-NMSG 18, ECOG EA1A06) CTDa vs RCD +/- R maintenance (MRC Myeloma XI) VP vs VMP vs VCP + VP maintenance (EMNTG) ( Carfilzomib + MP (CARMYSAP trial): ORR of 92% (40% VGPR). EHA 2012 MLN9708 plus LD and MLN9708 plus MP: EHA 2012 Rd vs MEL140 (DSMM XIII) Pomalidomide + Dex vs Dexamethasone: MM 005 Alternating treatment with different regimens: VMP and RD (PETHEMA/GEM) Bortezomib + Bendamustine + Prednisone (PETHEMA/GEM)

50 H. Ludwig 2013 New drugs in clinical evaluation AgentMechanism of action Panobinostat, Vorinostat, Givinostat, Romidepsin HDAC inhibitor Perifosine, GSK Akt inhibitor Temsirolismus, Everolismus mTOR inhibitor SelumetinibMEK/ERK inhibitor Plitidepsin (aplidin) Jun N-terminal Kinase (JNK) activator, anti-angiogenic activity DinaciclibCDK inhibitor MLN8237Aurora kinase inhibitor ARRY-520Kinesin spindle protein (KSP) inhibitor Elotuzumabanti-CS1 Daratumumabanti-CD38 BHQ880anti-DKK1 BT062anti-CD138 TabalumabAnti-B cell activiating factor (BAFF) BI-505Anti-intercellular adhesion molecule 1 (ICAM-1)

51 H. Ludwig 2013  Assess - comorbidities - degree of functional impairment  Select most appropriate drug regimen  Adapt dose if required  Consider the increased risk of infections within first weeks/months of therapy  Optimize supportive care -Antibiotics, antivirals, growth factors, anti-thrombotics Recommendations for clinical practice

52 H. Ludwig 2013 Thank you for your attention The future looks bright for elderly myeloma patients

53 H. Ludwig 2013

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