What we know about myeloma in elderly patients from trials and observational studies? Heinz Ludwig Department of Medicine I Center for Oncology, Hematology and Palliative Care Wilhelminenhospital, Vienna, Austria Ludwig© 2013
Goals of therapy in elderly patients Ø Rapid symptom control Ø Optimal quality of life Ø Few and acceptable side effects Ø Best possible quality of response Ø Long PFS Ø Long OS Ø Cure ? Ludwig© 2013
Drug combinations for elderly patients Possible options 1 -drug* 2 - drugs 3 - drugs 4 - drugs Dex Bendamustine +P MPT VMPT Thal VD VMP MP* CTD Thal-Dex VTD L-ld. Dex *only exceptional cases Most commonly used combinations contain 2 -3 drugs Ludwig© 2013
Characteristics of the Elderly Patient Chronological age does not necessarily correlate with biological age All three individuals are 70 years old Fit Minor morbidity significant morbidity 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 H. Ludwig 2013
Treatment of patients with multiple myeloma not eligible for transplantation Assess fraility Fit Unfit Full go Slow go Very slow go reduce dose 2 (3) drug regimen further dose reduction MP, CTX-P VD, Ld 2 or 3 drug regimen Ludwig© 2013 Frail
Instruments for assessing fraility and allocation to treatment groups Fit Age <80 yr Fit >80 yr Unfit >80 yr ADL 6 ADL 5 ADL ≤ 4 IADL 8 IADL 6 -7 IADL ≤ 5 Charlson 0 Charlson 1 Charlson ≥ 2 Go-go Moderate-go Slow-go Full-dose Reduced-dose regimens Palliative Dose level 0 §Age §ADL §IADL §Charlson comorbidity score Frail regimens Assess Unfit Dose level -1 approach Dose level -2 Palumbo A et al. IMW 2013 H. Ludwig 2013
Adaptation of dose according to risk factors Agent Dose level 0 Dose level-1 Dose level - 2 Dexamethasone 40 mg 20 mg 10 mg Melphalan 0. 25 mg/kg or 9 mg/m 2 0. 18 mg/kg or 7. 5 mg/m 2 0. 13 mg/kg or 5 mg/m 2 Thalidomide 100 mg 50 mg/qod Lenalidomide 25 mg 10 mg Bortezomib 1. 3 mg twice weekly, sc 1. 3 mg weekly, sc 1. 0 mg weekly, sc Prednisone 60 mg/m 2 30 mg/m 2 15 mg/m 2 Cyclophosphamide 100 mg 50 mg/qod H. Ludwig 2013 Palumbo et al. , BLOOD 2011
Comorbidities relevant for treatment selection in myeloma 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 H. Ludwig 2013
Higher risk of mortality in patients ≥ 75 years of age Retrospective meta-analysis of 4 EU phase III trials (N = 1, 435) with MP, MPT, VMP, and VMPT • 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 1. 20 -1. 72, p < 0. 001) HR (95% CI) p value All 1. 44 (1. 20– 0. 72) < 0. 001 MP 1. 21 (0. 90– 1. 64) 0. 21 MPT 1. 12 (0. 81– 1. 56) 0. 49 VMP 1. 62 (1. 04– 2. 52) 0. 03 VTP/VMPT 3. 02 (1. 86– 4. 90) < 0. 001 0. 1 Higher mortality in patients < 75 years of age H. Ludwig 2013 1 10 Higher mortality in patients ≥ 75 years of age Bringhen S, et al. Haematologica. 2013; 98: 980 -7.
Age and Organ Damage Correlate with Poor OS: Meta-analysis of 4 Randomized Trials • n=1435 (≥ 65 yrs ): MPT vs MP, VMP vs VMPT-VT Ludwig© 2013 Bringhen et al. Haematologica 2013; 98(6): 980 -987
Phase III studies incorporating novel agents in the non-transplant setting New Regimen Comparator Outcome MPT (6 Trials)* vs. MP MPT PFS 5/6, OS 2/6 CTDa vs. MP CTDa ORR VMP vs. MP VMP PFS, OS VMPT VT vs. VMPT VT PFS. OS VDT VT or VP ns VMP VT or VP MPR R vs. MPR or MP MPR R PFS LD vs. Ld Ld PFS, OS LD continous vs. Ld x 18, vs MPT x 12 Ld cont PFS, OS *Meta-analysis of the 6 trials: H. Ludwig 2013 PFS ( ) OS
MPT vs MP: Meta-analysis of 1685 individual-patient data of 6 randomized trials OS PFS Median 39. 3 mos 0. 8 MPT MP 1. 0 HR=0. 83 in favor of MPT, p=0. 005* (35. 6 -44. 6) Median 32. 7 mos 0. 4 (18. 8 -21. 6) (30. 5 -36. 6) 0. 2 Median 14. 9 mos 0. 2 MPT MP 0. 6 Median 20. 3 mos (14. 0 -16. 6) 0. 0 Survival proportion 1. 0 HR=0. 67 in favor of MPT, p<0. 0001 0 12 24 months 36 48 *Cox model for treatment, with analysis stratified by study using a random effects (frailty) model Fayers et al. Blood 2011, accepted for publication 30 May 2011 H. Ludwig 2013
MPT: Pros and Cons Pros Cons §Survival benefit §Thalidomide toxicity §Oral regimen §Suboptimal in cytogenetic high risk §Not expensive group §Shorter survival after relapse H. Ludwig 2013
MP vs. VMP (VISTA) Final updated OS analysis Median follow-up 60. 1 months • 31% reduced risk of death 100 Patients alive (%) 90 Median OS benefit: 13. 3 months 5 -year OS rates: 46. 0% vs 34. 4% 80 70 60 50 40 30 Group N Event Median M 338 211 VMP 344 176 56. 4 0. 0004 20 10 0 0 H. Ludwig 2013 6 12 18 24 30 HR (95% CI) P-value 43. 1 0. 695 (0. 567, 0. 852) 36 42 48 Time (months) 54 60 66 72 78 San Miguel et al. JCO 2013
Overall survival in different subgroups: VMP vs. MP H. Ludwig 2013 San Miguel et al. , JCO 2013
VMP induced CR is associated with improved outcome Time to progression Treatment-free interval Time to next therapy Overall survival Harousseau JL et al. , BLOOD 2010 H. Ludwig 2013
VD vs. VTD vs. VMP followed by bortezomib maintenance therapy Parameter VD VTD VMP >VGPR 36% 44% 40% ORR 68% 71% PNP G 3 15% -4 26% 20% PFS (mos) 18. 4 17. 3 13. 8 H. Ludwig 2013 Niesvitzky R. et al. , BLOO, 116 2010
Global Qo. L during VD, VTD and VMP induction therapy VD vs. VTD or VMP: shorter PFS, similar OS, better tolerance H. Ludwig 2013 Niesvizky R et al. , ASH 2011
Treatment schedule H. Ludwig 2013
PFS and OS: VMP vs VMPT –VT Progression free survival landmark analysis H. Ludwig 2013 Overall survival Palumbo A et al. ASH 2012
Overall survival, Landmark analysis H. Ludwig 2013
Overall survival from relapse H. Ludwig 2013 Palumbo et al. ASH 2012 (Abstract 200)
VMPT-VT versus VMP in newly diagnosed elderly patients • Significant OS benefit in patients – < 75 years of age (none in pts > 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% H. Ludwig 2013 Palumbo et al. ASH 2012 (Abstract 200), oral presentation
How to reduce toxicity of Bortezomib and maintain efficacy? q Bortezomib once weekly q q similar cumulative dose q similar efficacy q q longer duration of therapy less toxicty (G 3/4 neurotoxicity) Bortezomib subcutaneously q q similar area under the curve q less neurotoxicity q H. Ludwig 2013 10 times lower serum peak concentration similar efficacy
- MPR-R vs. MP (MM 015 trial) N = 459, 82 centers in Europe, Australia, and Israel Open-Label Extension Phase Double-blind Treatment Phase Cycles (28 -day) 1 -9 RANDOMIZATION MPR-R M: 0. 18 mg/kg, days 1 -4 P: 2 mg/kg, days 1 -4 R: 10 mg/day po, days 1 -21 Cycles 10+ Maintenance Lenalidomide 10 mg/day days 1 -21 MPR M: 0. 18 mg/kg, days 1 -4 P: 2 mg/kg, days 1 -4 R: 10 mg/day po, days 1 -21 Placebo MP M: 0. 18 mg/kg, days 1 -4 P: 2 mg/kg, days 1 -4 PBO: days 1 -21 • • Disease Progression Lenalidomide (25 mg/day) +/Dexamethasone Placebo Stratified by age (<75 years vs > 75 years) and stage (ISS I/II vs III) - ISS, International Staging System; MP, melphalan prednisone; MPR, , melphalan prednisone, lenalidomide MPR-R, melphalan prednisone, lenalidomide , ; , with lenalidomide maintenance; PBO, placebo. H. Ludwig 2013
Progression-Free and Overall Survival Progression-free and overall survival All Patients Median PFS 4 -year OS MPR-R 59% MPR 14 months MPR 58% MP 100 31 months 13 months MP 58% 100 HR 0. 395 50 P <. 001 HR 0. 796 25 P =. 135 0 HR 0. 898 75 0 10 20 Time (Months) 30 40 Patients (%) 75 P =. 579 50 HR 1. 089 P =. 648 25 0 0 10 20 30 40 Time (Months) • TTP HR advantages were similar: MPR-R vs MP = 0. 337; MPR vs MP = 0. 826 HR, hazard ratio; MP, melphalan prednisone; MPR, , melphalan prednisone, lenalidomide ; MPR -R, melphalan prednisone, , , lenalidomide with lenalidomide maintenance; OS, overall survival; PFS, progression free survival; TTP, time to progression. H. Ludwig 2013 50 60
PFS and OS with MPR-R and MPR patients aged 65 -75 years H. Ludwig 2013
FIRST: Phase 3 trial of Lenalidomide + low-dose Dex vs MPT (IFM 07 -01; MM-020) Centres in EU, Switzerland, APAC, USA, and Canada Inclusion criteria N = 1, 623 • Previously untreated MM • Age 65 years or not eligible for a transplant • No neuropathy of grade > 2 Primary end-point: PFS R A N D O M I Z A T I O N 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 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 *In patients aged > 75 years: Dex 20 mg/day, melphalan 0. 20 mg/kg/day, thalidomide 100 mg/day H. Ludwig 2013 NCT 00689936. Available from: www. clinicaltrials. gov.
What is the optimal duration of first line therapy? Trials & duration of therapy (months) VMP (Vista) 12 MPT trials 6 -18. 5 CTDa 6 -9 MPR-R 9, R untill PD VMPT-VT 12. 5, VT maintenance: 2 years LD (MM 20) Continously until PD/intolerance Duration of therapy: minimally 6, maximally 12 months Most experts recommend ≈ 9 months H. Ludwig 2013
Outcome with novel combinations CR rate (%) Median PFS (months) Median OS (months) rare 11– 20 29 - 43. 45 - 49. 42 - 14* 32 MPT 3 10 20. 3 39 CTDa 4 13 13 33 VMP 5 30 21. 7– 27. 4 56. 4 MPR-R 6 10 31 59% (4 -yr OS) VMP-VT/VP 7 42 35 58% (5 -yr OS) VMPT-VT 8, 9 42 35. 3 59. 3% (5 -yr OS) ≥PR 75% vs. 62% 28% ↓ risk for PD 22% ↓ risk for death MP 1, 2 BP 2 LD continuous 10 1 MTCG. J Clin Oncol 1998; 16(12): 3832 -42 2 Ludwig et al. , BLOOD 2009 2 Pönisch et al. J Cancer Res Clin Oncol. 2006; 132: 205 -12. 3 Fayers et al. Blood 2011; 118(5): 1239 -1247 4 Morgan et al. Blood 2011; 118: 1231 -8 H. Ludwig 2013 5 San Miguel et al. JCO 2013; 31(4): 448 -455 et al. N Engl J Med 2012; 366(19): 1759 -69 7 Mateos et al. Blood 2012; 120: 2581 -2588 8 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 6 Palumbo
Hematologic CR correlates with long PFS and OS in elderly patients treated with novel agents • 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) OS PFS CR VGPR P<0. 001 PR VGPR Probability CR PR P<0. 001 Significant benefit also seen when analysis is restricted to patients >75 years old H. Ludwig 2013 Gay et al. Blood 2011; 117(11): 3025 -31
Immunophenotypc CR correlates with OS GEM 2005 >65 y 100 PFS 60 40 Immunophenotypic CR 90% at 3 y “Stringent CR” 80 38% at 3 y Conventional CR 57% at 3 y PR (≥ 70% reduction) 28% at 3 y 20 Paiva et al; J Clin Oncol. 2011; 29(12): 1627 -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 OS according to t(4: 14) 1. 00 OS according to del(17 p) 1. 00 p < 10. 6 0. 75 Probability of OS p < 10. 4 0. 50 0. 25 0. 75 0. 50 0. 25 t(4: 14) neg t(4: 14) pos 0. 00 0 1 del(17 p) < 60 del(17 p) ≥ 60 2 3 Time (years) 4 5 0. 00 0 1 2 3 Time (years) 4 5 Whatever the treatment, t(4; 14) and del(17 p) were associated with shorter PFS and OS; similar results were achieved in the subgroup of 335 patients > 75 years H. Ludwig 2013 1. Avet-Loiseau H, et al. J Clin Oncol. 2013 31(22): 2806 -9. 2. Hulin et al. Blood 2012: [abstract 204].
![The challenge of high-risk CA [t(4; 14), del(17 p), t(14; 16)] in NDMM elderly](https://present5.com/presentation/913268d6230970d2529ad52075269eea/image-34.jpg "The challenge of high-risk CA [t(4; 14), del(17 p), t(14; 16)] in NDMM elderly")
The challenge of high-risk CA [t(4; 14), del(17 p), t(14; 16)] in NDMM elderly patients Study MPT/MP 1 No of pts with high-risk CA Outcome of high-risk CA patients NR 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 (E 4 A 03) 21 2 y OS=76% for high-risk CA vs 91% VMP/MP 3 (VISTA) 46 Absence of OS benefit, median OS 44. 1 mo. VMP vs 50. 6 mo. , MP 44 Adverse prognosis of both t(4; 14) and del (17 p) regardless of induction and maintenance. Median OS t(4; 14)=29 mo. , del(17 p) = 27 mo. VMP/VTP – VT/VP 4 (GEM-05) First generation novel agents only partly overcome the negative prognosis of high-risk CA in newly diagnosed elderly patients with MM H. Ludwig 2013 1. Bergsagel PL, et al. Blood. 2013; 121: 884 -91. 2. Rajkumar SV, et al. Lancet Oncol. 2010; 11: 29 -37. 3. San Miguel J, et al. J Clin Oncol. 2013; 31: 448 -55. 4. Mateos MV, et al. Blood. 2011; 118: 4547 -53.
Maintenance studies - summary 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 Bortezomib-thalidomide H. Ludwig 2013 PFS -no improvement in OS -increased risk for SPM Tendency for PFS and OS but not significant superior over VP
Summary: Treatment results in elderly patients Ø MPT, PFS, +/- OS, can be toxic in elderly pts Ø VMP, PFS OS, may induce severe PNP Ø Ld, PFS, OS, low dose Dex recommended Ø Thal-Dex, an option for fit pts Ø CTDa vs MP, overall response rate, CR, VGPR Ø Bendamustine-Pred, approved for first line TX Ø Thalidomide maintenance PFS, but not OS Ø MPR with Lenalidomide maintenance PFS, but not OS Ø VT maintenance not significantly better than VP H. Ludwig 2013
The natural course of multiple myeloma Maintenance H. Ludwig 2013
Treatment of relapsed/refractory MM General considerations Components of initial therapy – Alkylating-based – Dexamethasone-based – IMi. D-based – Bortezomib-based Patient status and type of relapse – Age, performance status, glucose metabolism – Aggressive vs non-aggressive relapse – Bone marrow reserve Efficacy of initial therapy – Quality of response – Tolerance of tretament – Renal function impairment – Pre-existing peripheral neuropathy – Oral vs. iv therapy – Duration of respose IMi. D, immunomodulatory derivative; MM, multiple myeloma H. Ludwig 2013
Treatment of Relapsed/Refractory Myeloma Frontline Therapy successful? Yes No Long duration of response Yes Select other TX (Class switch) No Repeat first line TX Select other TX Bortezomib based frontline TX: IMi. D based frontline TX Pomalidomide H. Ludwig 2013 IMi. D-based TD MPT CTD Rd (MPR) Old Type MP DCEP M-100 + ASCT Bort-based VD VMP VTD Ludwig et al. The Oncologist 2011
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 H. Ludwig 2013 Knopf et al. IMW 2013 (Abstract P-228), poster presentation
Results of meta-analysis of retreatement with bortezomib in different risk groups ORR TTP (months) OS (months) Relapsed 57% 8. 5 19. 7 Relapsed/>refractory 19% 5. 9 20. 4 ≤ 4 prior TX lines 43% 8. 2 13. 3 > 4 prior TX lines 29% 7. 1 20. 0 Boz + Dex 51% 7. 9 19. 2 Combination 36% 7. 1 16. 2 Pooled analysis 51% 8. 4 19. 2 Variable H. Ludwig 2013 Knopf et al. , IMW 2013
Carfilzomib a second generation proteasome inhibitor H. Ludwig 2013
Single agent Carfilzomib in relapsed/refractory patients Progressive disease at enrollment, Relapsed from 2 prior TX lines, Must include bortezomib Must include thalidomide or lenalidomide, Refractory to last line Response category All patients (n=267) High risk cytogenetics (n=71) CR 0. 4% 0 VGPR 5. 1% 4. 2% PR 18. 3% 25. 4% MR 13. 2% 4. 2% ORR 37% 29. 5% PFS(median) 3. 7 mos 3. 6 mos DOR (median) 7. 8 mos 6. 9 mos Siegel D et al. , BLOOD 2012 H. Ludwig 2013
Pomalidomide + Lo. Dex vs Hi. Dex (MM-003): Phase III Trial Design Stratified by age (≤ 75 vs > 75 yrs), number of previous treatments (2 vs > 2), disease population (refractory vs relapsed/refractory vs intolerant/refractory) Patients with relapsed/refractory myeloma (N = 455) • 28 -day cycles POM + Lo. Dex Pomalidomide 4 mg on Days 1 -21 + Dexamethasone 40 mg (if ≤ 75 yrs) or 20 mg (if > 75 yrs) on Days 1, 8, 15, 22 (n = 302) Hi. Dexamethasone 40 mg (if ≤ 75 yrs) or 20 mg (if > 75 yrs) on Days 1 -4, 9 -12, 17 -20 (n = 153) Until PD* Follow-up for OS and SPM until 5 yrs Post enrollment Companion trial MM-003 C: Pomalidomide 21/28 days Primary endpoint: PFS • Secondary endpoints: OS, ORR, DOR, safety San Miguel JF, et al. ASCO 2013. Abstract 8510. H. Ludwig 2013 *Independently adjudicated in real time. Thromboprophylaxis indicated for patients receiving pomalidomide or with history of DVT.
Pomalidomide + Lo. Dex vs Hi. Dex: 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 2013. Abstract 8510. H. Ludwig 2013
Pomalidomide + Lo. Dex vs Hi. Dex (MM-003) PFS (ITT Population) Mos H. Ludwig 2013 OS (ITT Population) Mos San Miguel JF, et al. ASCO 2013. Abstract 8510.
Pomalidomide + Lo. Dex vs Hi. Dex Adverse Events (MM-003) AE, % POM + Lo. Dex (n = 300) Hi. Dex (n = 150) § Neutropenia 48 16 § Anemia 33 37 § Thrombocytopenia 22 26 30 24 13 8 § Bone pain 7 5 § Fatigue 5 6 § Asthenia 4 6 § DVT/PE 1 0 § Peripheral neuropathy* 1 1 Discontinuation due to AEs 9 10 Grade 3/4 hematologic AEs Grade 3/4 nonhematologic AEs § Infections – Pneumonia Grade 3/4 AEs of interest *Includes hyperesthesia, peripheral sensory neuropathy, paraesthesia, hypoesthesia, and polyneuropathy. H. Ludwig 2013 San Miguel JF, et al. ASCO 2013. Abstract 8510.
Zoledronic Acid vs Clodronate in Newly Diagnosed MM: SREs • Significantly reduced incidence of SREs* with zoledronic acid vs clodronate – Regardless of presence of bone lesions at baseline Patients With an SRE (%) HR: 0. 74 (P =. 0004) CLO 40 30 ZOL 20 35. 3% 27. 0% 10 0 0 18 24 30 36 42 6 12 Time From Randomization (Mos) Patients at Risk, n ZOL 981 663 506 390 284 201 138 97 CLO 979 629 465 337 256 173 112 74 *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. Morgan GJ, et al. ASH 2010. Abstract 311. H. Ludwig 2013
Planned and/or ongoing studies VD vs VTD vs VMP + V maintenance (UPFRONT study) VRd vs Rd + Rd maintenance (SWOG S 0777) Rd vs MPT vs Rd + Rd maintenance (MM 20/IM(FIRST trial) Rd vs MPR vs CRP + maintenance R vs RP (EMNTG) MPT+T vs MPR+R (HOVON 87 -NMSG 18, ECOG EA 1 A 06) 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 MLN 9708 plus LD and MLN 9708 plus MP: EHA 2012 Rd vs MEL 140 (DSMM XIII) Pomalidomide + Dex vs Dexamethasone: MM 005 Alternating treatment with different regimens: VMP and RD (PETHEMA/GEM) Bortezomib + Bendamustine + Prednisone (PETHEMA/GEM) H. Ludwig 2013
New drugs in clinical evaluation Agent Mechanism of action Panobinostat, Vorinostat, Givinostat, Romidepsin HDAC inhibitor Perifosine, GSK 2110183 Akt inhibitor Temsirolismus, Everolismus m. TOR inhibitor Selumetinib MEK/ERK inhibitor Plitidepsin (aplidin) Jun N-terminal Kinase (JNK) activator, anti-angiogenic activity Dinaciclib CDK inhibitor MLN 8237 Aurora kinase inhibitor ARRY-520 Kinesin spindle protein (KSP) inhibitor Elotuzumab anti-CS 1 Daratumumab anti-CD 38 BHQ 880 anti-DKK 1 BT 062 anti-CD 138 Tabalumab Anti-B cell activiating factor (BAFF) BI-505 Anti-intercellular adhesion molecule 1 (ICAM-1) H. Ludwig 2013
Recommendations for clinical practice Ø Assess - comorbidities - degree of functional impairment Ø Select most appropriate drug regimen Ø Adapt dose if required Ø Consider the increased risk of infections within first weeks/months of therapy Ø Optimize supportive care -Antibiotics, antivirals, growth factors, anti-thrombotics H. Ludwig 2013
The future looks bright for elderly myeloma patients Thank you for your attention H. Ludwig 2013
H. Ludwig 2013
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