A Matching-Adjusted Indirect Treatment Comparison of Daratumumab-Bortezomib-Melphalan-Prednisone Versus Lenalidomide-Dexamethasone Continuous, Lenalidomide-Dexamethasone 18 Months, and Melphalan-Prednisone-Thalidomide
Authors: Dimopoulos Meletios A , Cavo Michele , Mateos Maria-Victoria , Facon Thierry , Heeg Bart , van Beekhuizen Sophie , Nair Sandhya , Pisini Marta , Lam Annette , Slavcev Mary 
Published: October 2019

Abstract

Introduction: Daratumumab-bortezomib-melphalan-prednisone (D-VMP) is a novel treatment regimen for newly diagnosed multiple myeloma patients who are ineligible for autologous stem cell transplantation (ASCT). D-VMP is currently being investigated and compared to bortezomib-melphalan-prednisone (VMP) in the ALCYONE trial, and demonstrated a significant benefit for D-VMP over VMP in terms of progression-free survival (PFS) [1]. Recently, a systematic literature review and a network meta-analysis (NMA) were conducted to compare D-VMP against all other available treatments in that indication. However, the reliability of an NMA on overall survival (OS) may be limited due to several factors. First, OS data from the ALCYONE trial is still immature. Second, within the OS network of evidence, four MP trials showed similar PFS, yet large differences were observed in OS for MP. This is an indication of effect modification due to subsequent therapies and thus violation of the similarity assumption. The four MP trials are a bridge to key approved comparators lenalidomide-dexamethasone (Rd) and melphalan-prednisone-thalidomide (MPT), which have been investigated in the FIRST trial. To overcome these challenges faced in the OS NMA, an unanchored matching-adjusted treatment comparison (MAIC) was conducted to assess the relative OS between D-VMP and Rd continuous, Rd 18, and MPT. In addition, the analysis was extended to also include PFS.
Methods: Individual patient data from the ALCYONE trial were adjusted to match the aggregated baseline characteristics of the FIRST trial. Patient level OS and PFS data of FIRST trial were generated based on the Guyot algorithm. The considered baseline characteristics were median age, male (%), ECOG status (%), ISS state (%), IgG serum (%), creatinine clearance (%), and high-risk cytogenetic profile. After matching patients, a Cox proportional hazard model was fitted. In both analyses, the null hypothesis of no difference in relative treatment effect in OS and PFS between D-VMP and each of the three treatment arms of the FIRST trial was tested using the log-rank test. To assess the impact of matching patients, a naïve unanchored comparison between D-VMP and FIRST treatments arms was conducted in addition to the MAIC.
Results: The results of the MAIC are summarized in Table 1. Significant results are denoted with an asterisk. OS for D-VMP is significantly longer than for both MPT and Rd 18. When comparing OS for D-VMP with Rd continuous, there is a trend in favour of D-VMP. D-VMP performs significantly better than the three comparator treatments in terms of PFS. In all analyses, the HR point estimates are in favour of D-VMP.
Conclusion: This MAIC showed a significant OS benefit for D-VMP compared to Rd 18 and MPT, and a trend favouring D-VMP vs Rd continuous in newly diagnosed multiple myeloma patients who are ineligible for ASCT. Additionally, this analysis supports a previously conducted NMA on PFS and suggests that D-VMP provides a consistent and statistically significant PFS benefit relative to Rd continuous, Rd 18, and MPT. Since ALCYONE is a more recent trial than FIRST, a potential limitation is that the OS results might be biased by better subsequent therapies being available in ALCYONE. However, the impact of this is expected to be limited due to the immaturity of survival data and the large proportion of patients in the D-VMP arm of ALCYONE who had not yet progressed at the time of the datacut. This MAIC, which provides a more robust method to compare OS outcomes than an NMA, shows OS benefits and confirms PFS benefits for D-VMP compared to Rd continuous, Rd 18 and MPT.
[1] Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528.

Disclosures
Dimopoulos: Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Cavo:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mateos:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Heeg:Ingress-health Nederland BV: Employment, Equity Ownership, Research Funding. van Beekhuizen:Ingress Health: Consultancy. Nair:Janssen Research & Development, LLC: Employment. Pisini:Janssen Research & Development, LLC: Employment. Lam:Janssen Global Services, LLC: Employment. Slavcev:Janssen Global Services, LLC: Employment.