1 / 22

Methodology Overview Paul G. Richardson, MD Associate Professor, Harvard Medical School

Methodology Overview Paul G. Richardson, MD Associate Professor, Harvard Medical School Clinical Director, Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute Boston MA. Common clinical endpoints. Response rates Response criteria M-protein reduction alone EBMT

aya
Download Presentation

Methodology Overview Paul G. Richardson, MD Associate Professor, Harvard Medical School

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Methodology Overview Paul G. Richardson, MD Associate Professor, Harvard Medical School Clinical Director, Jerome Lipper Multiple Myeloma Center Dana-Farber Cancer Institute Boston MA

  2. Common clinical endpoints • Response rates • Response criteria • M-protein reduction alone • EBMT • IMW Uniform criteria • Response criteria by different trial groups • Time to event measures • Duration of response • TTP: time to progression • PFS: progression free survival • EFS: event free survival • OS: overall survival • Time to next therapy • Treatment free interval

  3. Response rates • First evidence of clinical activity Response Criteria • M-protein reduction alone • EBMT response criteria • Developed by Bladé et al 1998 for transplant trials • Millennium is the first to adopt this criteria in MM trials (SUMMIT) • IMWG uniform criteria • Durie et al 2006 • Attempt to standardize response assessment • Response criteria by different trial groups • SWOG criteria • ECOG criteria • IFM criteria

  4. Measuring CR: EBMT vs Uniform Criteria *IHC: immunohistochemistry; IFR: immunofluorescence. †Presence/absence of clonal cells based on k/l ratio (abnormal ratio is k/l of >4:1 or <1:2). Bladé et al. Br J Haematol 1998;102:1115-23 Durie et al., Leukemia 2006

  5. Measuring progression: EBMT vs Uniform Criteria *IHC: immunohistochemistry; IFR: immunofluorescence. †Presence/absence of clonal cells is based on k/l ratio (abnormal ratio is k/l of >4:1 or <1:2). Bladé et al. Br J Haematol 1998;102:1115-23 Durie et al., Leukemia 2006

  6. Time to Event: Definitions Durie et al: “Intl Uniform Response Criteria for MM” Leukemia 2006

  7. PD from CR  PD from PR: An illustration based on APEX M-protein ≥ 25%/+5 g/L TNT TNT 50-100% M-protein 0 - Immunofixation + Immunofixation *TNT: Time to Next Therapy Niesvizky et al., IMW 2007 Richardson et al, JNCI 2008

  8. Time to event measures: TTP alone may not truly reflect overall clinical benefit • CR penalty: progression from CR ≠ progression from PR (≥25% M protein increase that must also be ≥ 5g/L) • Sensitive definition of relapse from CR by EBMT may lead to paradoxically shorter duration of remission • Subset analysis of a large phase 3 APEX study (Niesviezky et al., IMW 2007) showed patients with CR had comparable TTP to those with PR (9.7m vs 9.5m), but much longer TNT* (27m vs 14m) • Definition: typically defined from randomization or first dose to progression • Measuring from diagnosis may lead to longer TTP • Assessment schedule: longer TTP if measured less frequently • Measuring less frequently may lead to longer TTP • Stringent criteria/centralized laboratory/algorithm based analysis • More stringent assessment may lead to shorter TTP • Type of analysis: intent-to-treat (ITT) is the most robust analysis • Excluding certain patient groups may lead to bias • Other factors • Patient baseline characteristics: age, ISS staging, renal function, cytogenetics, etc. • Length of treatment (defined treatment duration vs treating to progression, maintenance) Bladé et al. BJH 1998 Richardson et al, JNCI 2008 *TNT: Time to Next Therapy

  9. Long term F/U matters: CREST example 1.0 mg/m2 (N=28) 1.3 mg/m2 (N=26) Jagannath et al. ASH 2007

  10. Methodological considerations: Summary • Long-term survival is the ultimate goal of treatment • Interpretation of survival needs to be based on mature data with longer follow-up • CR can be considered a surrogate endpoint for survival • Strong association with prolonged survival • First step towards potential cure • PFS/EFS/TTP are highly sensitive to definition and measurements, thus caution should be exercised when comparing PFS/EFS/TTP across studies • Clinicians should be aware that shorter-than-expected TTP may in fact be associated with longer TNT* or TFI**; the latter measures better reflect patient benefit • OS is a hard endpoint and precise end point, not subject to bias • CR now can be more consistently defined and objectively measured, as such, it can be considered a more reliable endpoint similar to OS *TNT: time to next therapy **TFI: treatment-free interval

  11. SD MR PR VGPR CR What is CR? • NCI: The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured • In multiple myeloma: there is heterogeneity in response criteria. CR is generally defined as the absence of M-protein in serum and urine, disappearance of soft tissue plasmacytomas, no evidence of progression in bone lesions, and in most cases documentation of <5% clonal plasma cells in a bone marrow sample

  12. Path to cure Ineffective treatment Dexamethasone Alkylators Tumor Volume → High-Dose Therapy Limit ofdetection Goal of newertherapy options Time → Ultimate goal: Cure

  13. CR in SCT setting • Outcomes of 4990 HDT/SCT pts (21 studies) according to best response were reported • Majority of studies show correlation between maximal response (CR/nCR/VGPR), long-term outcomes (OS & EFS/PFS) • Two meta-analyses: both show highly significant associations • One based on p-values • One based on primary response, outcome data van de Velde et al. Haematologica 2007

  14. + Median not available, OS calculated from 2yr (San Miguel), 3yr (Palumbo) and 5yr (Zervas) estimates CR in non-transplant setting • Medline/OVID search from 1980 – Mar 2008 • 13 studies (4396 pts) meeting the criteria: randomized comparative trials in newly diagnosed MM reporting CR or CR/nCR, survival (either median survival or survival rate) • Percent improvement in survival for each percent increase in CR/nCR rate was calculated for each study • 5 of 13 studies failed to show association: primarily due to the confounding effect of a therapy that generates high CR and is simultaneously too toxic • Two polarizing impact of a therapy on survival (higher CR leading to longer survival vs higher toxicity leading to shorter survival) confounds analysis

  15. PD from CR  PD from PR: An illustration based on APEX M-protein ≥ 25%/+5 g/L TNT TNT 50-100% M-protein 0 - Immunofixation + Immunofixation *TNT: Time to Next Therapy Niesvizky et al., IMW 2007

  16. CR PR VGPR All Pts MR NR CR (n=27) VGPR (n=31) PR (n=77) MR (n=21) NR (n=159) All Bz Pts (n=315) CR in APEX Niesviezky et al. IMW 2007

  17. VISTA: highest CR reported in phase III setting • VISTA confirms high CR rate reported in ph I/II VMP study (IF- CR 32%) • 3 year survival for VMP ph I/II study was 85%, highest reported in non-transplant setting 1 Blade et al, BJH 1998; San Miguel et al., ASH 2007 Mateos et al., Haematologica 2008 *measured in serum or urine by centralized laboratory

  18. Why some studies fail to show correlation • Small sample size • Small difference to date • Low CR/nCR rates (most <10%) with older/conventional therapies (≥20% CR in transplant setting) make it harder to detect meaningful difference • Contribution to survival by CR (quality of response) is relatively small, leading to inconsistent findings • Confounding factors • Some therapies have two polarizing effect: they generate higher CR (leading to longer survival) but are also associated with higher toxicity (leading to shorter survival) • Subsequent therapies: studies stopping early or cross-over studies reduce or confound the impact of experimental therapies; patients from comparator arm receive different subsequent therapies • Unidentified confounding factors: heterogeneity of myeloma as a disease (MGUS, subset of myeloma with more indolent course of disease, tumor stem cells) Bottom Line • Survival is a multi-factorial measure, confounded by numerous factors, including baseline patient and disease characteristics, study design, type of therapies, and subsequent therapies • All things being equal, it’s better to have CR

  19. CRs are better • “ASH/FDA Workshop on Clinical Endpoints in Multiple Myeloma” held in October 2006, published in 2007 (Anderson et al, Leukemia 2007) • CR rate is recommended as an additional registration endpoint • NCCN MM guideline • Attainment of CR is important for survival benefit • CR associated with better outcomes such as longer PFS/EFS and OS in both transplant and non-transplant setting • Growing body of evidence, both in the transplant and non-transplant setting, demonstrate CR is associated with greater clinical benefit, including prolonged survival • Higher CR associated with improved OS with high-dose therapy/stem cell transplantation • Higher CR associated with improved OS with novel therapies (eg MPT, VMP) • Landmark analysis, retrospective analysis show improved OS in CR pts • Evidence provides strong support for the association; only a minority of studies fail to show the correlation • Negative studies are primarily due to the polarizing effect of a specific therapy that generates higher CR and is simultaneously too toxic • From a statistical point, even on tried and true facts, there will be small number of studies with disparate results, either due to insufficient sample size and/or chance

  20. TTP Subgroup Analysis Favors MP Favors VMP VISTA: highest level of evidence and consistency of results • Largest MM study ever conducted • Highest CR rate reported in phase III setting • Rapid and durable responses for all responding patients • Duration of response: 19.9 mos (24 mos for CR) • Consistency of results: CR similar to phase I/II rate (phase I/II study had highest 3-yr survival rate reported in non-transplant setting) *Odds ratio

  21. Summary • Comprehensive literature review of large randomized studies, both in transplant and non-transplant, demonstrate strong association of CR with prolonged survival • Small number of studies fail to show association, primarily due to polarizing effect of a therapy that generates high CR and is simultaneously too toxic • All things being equal, CR preferred • High level of evidence and consistency of evidence with bortezomib-based therapies • Unprecedented CR • Rapid and durable responses • Associated extended survival (Mateos et al: VMP ~ highest 3-yr survival rate of 85% reported in non-transplant setting)

  22. Key references • Attal M, Harousseau J-L, Facon T, et al. Single verses double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349:2495-2502. • Attal M, Harousseau J-L, Stoppa A-M, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;335:91-97. • Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875-1883 • Harousseau J-L, Attal M, Divine M, et al. Autologous stem cell transplantation after first remission induction treatment in multiple myeloma: a report of the French registry on autologous transplantation in multiple myeloma. Blood. 1995;85:3077-3085. • Kyle RA, Leong T, Li S, et al. Complete response in multiple myeloma. Cancer. 2006;106:1958-1966 • Van del Velde HJK, Liu X, Chen G, et al. The correlation between complete response and long-term survival and progression-free survival in patients treated with high-dose therapy for multiple myeloma. Haematologica. 2007;92:1399-1406 • Cavo M, Tosi P, Zamagni E, et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007; 25:2434-2441 • Pineda-Roma M, Zangari M, Haessler J, et al. Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2. British Journal of Haematology. 2008;140:625-634 • Niesviezky R, Richardson PG, Rajkumar SV, et al. Relationship between quality of response to bortezomib and clinical benefit in the APEX trial. IMW 2007

More Related