Consolidation and maintenance therapy for transplant eligible myeloma patients Teeraya Puavilai, M.D. Division of Hematology, Department of Medicine Faculty of Medicine Ramathibodi Hospital Mahidol University
Outlines Consolidation Maintenance Minimal residual disease
Definition and aim of consolidation and Consolidation therapy Short period: 2-4 cycles maintenance therapy Single agent or combination therapy or 2 nd ASCT Aim to increase the depth of response Maintenance therapy Longer period: 2-3 years or until disease progression Less intensive Aim to suppress any MRD with clinical objectives of prolonging response duration, PFS, and OS while minimizing toxicity
Consolidation therapy
What is the impact of consolidation therapy after ASCT? Post ASCT novel agent based consolidation therapy 2-4 cycles after ASCT To intensify therapy and improve depth of response 1 Spencer A et al. Lancet Haematology 2014;1(3):112-9
Post ASCT novel agent based consolidation therapy Reference Type of trial Treatment No. of patients Response rate EFS or PFS OS Bortezomib-based Cavo M et al 1 Phase III VTD vs TD 160 vs 161 CR/nCR pre consolidation: 63% vs 55% (P=NS) CR/nCR post consolidation: 73% vs 61% (P=0.02) Mellqvist UH et al 2 Phase III Bortezomib vs no consolidation Leleu X et al 3 Retrospective VTd vs no consolidation Ladetto M et al 4 Phase II VTD comsolidation 187 vs 183 VGPR pre consolidation: 40% vs 39% (P=NS) VGPR post consolidation: 71% vs 57% (P=0.009) 121 vs 96 CR post consolidation: 52% vs 30% (P=0.001) 39 CR pre VTD: 15% CR post VTD: 49% Tacchetti P et al 5 Phase III VTD vs TD 117 vs 117 CR/nCR post consolidation: 73% vs 61% P=0.012 Straka C et al 6 Phase III Bortezomib vs no consolidation 1 Cavo M et al. Blood 2012;120(1):9-19 2 Mellqvist UH et al. Blood 2013;121(23):4647-54 3 Leleu X et al. Leukemia 2013;27(11):2242-4 186 vs 185 VGPR pre consolidation: 55% vs 59% VGPR post consolidation: 62% vs 48% Median PFS for pts with <VGPR: 33% vs 25% P=0.009 Median PFS for high risk cytogenetic: 31% vs 24% P= 0.074 3-yr PFS: 60% vs 48% P=0.042 Median PFS: 27 m vs 20 m P=0.05 Median TTP: NR vs 25 m P=0.005 Median PFS: 60 m Median PFS: 65 m vs 57 m P=0.001 Median PFS: 34 m vs 28 m P=0.0058 3-yr OS: 90% vs 88% P=NS 3-yr OS: 80% vs 80% P=NS 4-yr OS: 84% vs 91% P=NS 3-yr OS: 89% 5-yr OS: 80% vs 73% P=NS Median OS: NR vs NR 4 Ladetto M et al. J Clin Oncol 2010;28(12):2077-84 5 Tcchetti P et al. GMMY 3006 study ASH Ann Meet Abstr. 2014;124(21):196 6 Straka C et al. J Clin Oncol 2015;33(suppl):Abstrc 8511
Post ASCT novel agent based consolidation therapy Reference Type of trial Treatment No. of patients Response rate EFS or PFS OS Lenalidomide-based Attal et al 1 Phase III Len consolidation + len maintenance vs Len consolidation + placebo 307 vs 307 CR pre consolidation: 58% CR post consolidation: 69%% (P<0.001) Roussel et al 2 Phase II RVD consolidation 31 scr/cr pre VRD: 47% scr/cr post VRD: 50% NR after consolidation NR after consolidation 3-yr PFS: 77% 3-yr OS: 100% Ongoing trials IFM-Dana-Farber group Arm A: RVD 8 cycles then len maintenance 1 year Arm B: RVD 3 cycles then ASCT with melphalan 200 mg/m2 then RVD consolidation 2 cycles and len maintenance 1 year 3-yr PFS: 48% vs 61% P<0.0002 CR rate: 46% vs 58% P<0.01 Median OS at 3 year: similar US trial using similar design but with len until progression 1 Attal et al N Engl J Med 2012;336:1782-91 2 Roussel et al IFM 2008 ASH Ann Meet Abstrc 2011;118(21):1872
Summary of studies examining impact of cytogenetics on outcomes after ASCT N. Shah et al. Biol Blood Marrow Transplant 21 (2015) 1155-66
Progression free survival from the landmark of starting consolidation therapy according to the presence or absence of cytogenetic abnormalities No cytogenetic abnormality or with del(13q) positivity but lack of t(4;14) and del(17p) t(4;14) and/or del(17p) positivity Mansour ZA and Ramanathan M. Advances in Hematology 2014
Maintenance therapy
What is the impact of maintenance therapy after ASCT? To achieve long term disease control To reduce risk of progression or relapse and to prolong OS Consist of a gentle treatment for a prolonged period with long term safety Several concerns: long term safety, financial burden, selection of treatment resistant clones, and consistent overall survival benefit remain Nathwami N et al. Curr Hematol Malig Res 2016;11:127-36
Thalidomide trials in the post ASCT PFS setting OS Patients with adverse cytogenetics [t(4;14),t(14;16),t(14;20),del17p,del1p32,gain 1q21]attained a similar PFS(9 v 12 months, P =.49) but a worse OS(P=.009). Mansour ZA and Ramanathan M. Advances in Hematology 2014
Meta analysis and systematic review showed collective data from thalidomide trials favoring maintenance Mansour ZA and Ramanathan M. Advances in Hematology 2014
Thalidomide maintenance A recent meta-analysis including 6 post-transplantation thalidomide studies confirmed similar findings of the clear PFS benefit of thalidomide maintenance (HR=0.67; p<0.001) but did not translate into an OS benefit (HR=0.90; p=0.343) The side effects of thalidomide limited long-term use, with the median duration of thalidomide maintenance varying from 7 24 months.(venous thrombosis and peripheral neuropathy) Wang Y et al J Natl Cancer Inst 2016 Mar;108(3)
Systematic review and meta-analysis Lenalidomide maintenance
Demographic & disease related characteristics at diagnosis: intention to treat population J Clin Oncol 35:3279-3289
Demographic & disease related characteristics at diagnosis: intention to treat population J Clin Oncol 35:3279-3289
Duration of maintenance therapy (safety population) Safety population includes patients who received at least one dose of study drug. J Clin Oncol 35:3279-3289
Progression-free survival (PFS) analysis (intent-to-treat population) J Clin Oncol 35:3279-3289
Hazard ratio for PFS by subgroup J Clin Oncol 35:3279-3289
Overall survival J Clin Oncol 35:3279-3289
Overall survival Hazard ratios (HRs) for OS by subgroup HRs for OS by prior induction subgroup J Clin Oncol 35:3279-3289
Cumulative incidence curve of time to hematologic second primary malignancy (SPM) and solid tumor SPM onset (as-treated population) J Clin Oncol 35:3279-3289
Cumulative incidence curves of time to disease progression and time to invasive SPM onset before disease progression J Clin Oncol 35:3279-3289
Kaplan-Meier (KM) curve of time to death by cause of death J Clin Oncol 35:3279-3289
Bortezomib maintenance trials In high-risk patients presenting with creatinine > 2 mg/dl and/or poor risk cytogenetic (deletion 17p13, t(4;14), and amplification of 1q21) bortezomib significantly improved both PFS and OS. Study Median FU Number Treatment Outcome HOVON 65 MM/ GMMG-HD4 41 months 413 414 PAD/HDM/BORT q 2 wk for 2 yrs vs VAD/HDM/THAL 50 mg daily for 2 yrs PFS 35 months 28 months P < 0.001 OS Median not reached HR = 0.77(0.60-1.00) P = 0.049 PETHEMA/GEM 34.9 months 89 87 90 VT THAL Interferon-α2b Significant PFS benefit for VT P < 0.0009 OS not significantly different between arms Induction regimen with VTD, TD or VBMCP/VBAD + V then ASCT Mohty M and Harousseau JL. Haematologica 2014;99(3):408-16
Bortezomib-based vs non-bortezomib-based post transplantation treatment in multiple myeloma patients: systematic review and meta-analysis of phase III RCT Flow diagram of study selection Liu et al. Onco Targets and Therapy 2015;8:1459-69
Patient demographics and baseline disease characteristics Liu et al. Onco Targets and Therapy 2015;8:1459-69
Bortezomib-based therapy of the included studies Systematic review and meta-analysis of phase III RCT Liu et al. Onco Targets and Therapy 2015;8:1459-69
Traditional and cumulative meta-analysis of response rates with bortezomib-based post-transplantation therapy ORR rate with bortezomib-based post-transplantation therapy CR/nCR rate with bortezomib-based post-transplantation therapy Liu et al. Onco Targets and Therapy 2015;8:1459-69
Traditional and cumulative meta-analysis of the outcomes Progression Free Survival (PFS) Overall Survival (OS) PFS: 27% reduction in risk of disease progression or death With bortezomib based therapy after ASCT OS: No statistical difference Liu et al. Onco Targets and Therapy 2015;8:1459-69
Traditional and cumulative meta-analysis of the frequency of grade 3 or 4 peripheral neuropathy Liu et al. Onco Targets and Therapy 2015;8:1459-69
Phase 3 trials evaluating novel agent-based maintenance therapy after ASCT Study Regimen Comparator Increased PFS? Increased OS? Lenalidomide Attal et al McCarthy et al Palumbo et al Thalidomide Attal et al Barlogie et al Spencer et al Lokhorst et al Morgan et al Stewart et al Bortezomib Sonneveld et al Rosinol et al LEN LEN LEN THAL + PAM THAL + IFNa + DEX THAL + pred THAL THAL THAL + pred PAD BORT BORT + THAL Placebo Placebo No maintenance PAM or no maintenance IFNa + DEX Pred IFNa No maintenance No maintenance VAD THAL THAL or IFNa Yes Yes (TTP and EFS) Yes Yes (EFS) Yes (EFS) Yes Yes (EFS) Yes Yes Yes Yes No Yes No No Yes Yes No No No No No Facon T. Hematology 2015;279-85
Conclusion.
Consolidation to maintenance therapy Goal to achieve deep response Maintained with less intense therapy
Recommendations for therapy after ASCT Consolidation after auto-hct is not routinely recommended but can be considered in the setting of a clinical trial. Maintenance with an immunomodulatory drug (thalidomide or lenalidomide) is recommended unless a contraindication exists (grade A). In most cases, lenalidomide is preferred because of improved survival data in the era of novel agents. In patients with high-risk disease with renal failure or adverse chromosome changes, post auto-hct bortezomib consolidation and maintenance may be considered (grade D). N. Shah et al. Biol Blood Marrow Transplant 21 (2015) 1155-66
Current approaches to consolidation and maintenance for transplant eligible patients Mayo clinic use FISH-based risk stratification model termed msmart (Mayo Stratification of Myeloma and Risk-Adapted therapy) Intermediate risk [t(4;14) or 1q gain] VRd for 4 cycles followed by ASCT then bortezomibbased maintenance for 1 year High-risk patients [t(14;16), t(14;20), 17p deletion, or high-risk gene expression profile], bortezomib or carfilzomib-based maintenance following KRd (carfilzomib, lenalidomide, dexamethasone) induction for a minimum of 1 year after ASCT Standard-risk patients[trisomies, t(11;14), t(6;14)] 2 cycles of Rd consolidation followed by lenalidomide maintenance of limited duration (12 24 months) if VGPR has not been achieved following consolidation.
Current approaches to consolidation and maintenance for transplant eligible patients HOVON-65/GMMGHD4 trial, del(17p) treated with bortezomib induction and maintenance had a median PFS of 26.2 months versus 12 months in patients treated without bortezomib. VTd consolidation: PFS benefit; however, the high rates of peripheral neuropathy and treatment discontinuation remain a limitation. Retrospective study of 45 high-risk patients at Emory University, VRd was administered after ASCT on a 28-day cycle up to 3 years, then lenalidomide 10 mg/day single agent therapy thereafter. Median PFS was 32 months with a 3-year OS of 93 %, which significantly exceeds the median OS of 3 years in many studies of high-risk patients.
Minimal residual disease
The natural history of myeloma MGUS Smoldering Myeloma Early Myeloma Late Myeloma Plasma Cell Leukemia M-PROTEIN 100 Asymptomatic Symptomatic Active myeloma 2 ND RELAPSE 50 1 ST RELAPSE 20 Induction and ASCT 1 st line PLATEAU REMISSION Operational cure TIME
MRD modality and sensitivity of detection Bone Marrow Transplantation (2016) 51, 2 12
Flow cytometry testing for MRD in patients with treated MM Key characteristics distinguish malignant plasma cells from normal plasma cells: CD19 (all panels); expression of less CD38; a. CD45 b. CD56+ c. CD117+ d. CD27 e. CD81
Effect of sample size on flow cytometry testing for MRD in treated patients with MM All panels depict healthy (black) and malignant (green) plasma cells in a bone marrow sample obtained from the same patient. a. 84 malignant plasma cells were detected by analysing 3,000,000 events. b. 30 cells were detected in 1,000,000 events. c. 14 malignant cells were detected in 500,000 events. d. Only 6 malignant cells were detected in 100,000 events.
Allele-specific oligonucleotide-quantitative PCR (ASOqPCR) method to detect MRD J. Clin. Med. 2017, 6(10), 91
Next-generation sequencing method to detect minimal residual disease (MRD) J. Clin. Med. 2017, 6(10), 91
Prognostic value of MRD in post-asct BM samples for patients with MM according to MRD level as determined by deep sequencing (threshold: 10 6 ) PFS OS PFS Patients achieving conventional CR from ASCT PFS OS PFS Patients achieving conventional CR from BM MRD assessment Annals of Oncology 28: 2503 2510, 2017
Patients who did not receive post-asct treatment Correlation between NGS-based MRD assessment in autografts and clinical outcome Patients who receive post-asct treatment Annals of Oncology 28: 2503 2510, 2017
Influence of high-risk chromosomal abnormalities (HRCA) and MRD levels by NGS on prognosis of MM BM BM Autograft Autograft Annals of Oncology 28: 2503 2510, 2017
Comparison of MRD assays in multiple myeloma J. Clin. Med. 2017, 6(10), 9