Celgene: Therapies for Relapsed and/or Refractory Multiple Myeloma: an updated meta-analysis

Jose Miguel Fernandez Santos

Universidad Pompeu Fabra




Until relatively recently, treatment for multiple myeloma (MM) consisted of either single agent or combination regimens of chemotherapydrugs such as melphalan, doxorubicin and vincristine, and the glucocorticosteroids prednisone and dexamethasone. The introduction of stem cell transplantation (SCT) for certain subgroups also led to further improvements in disease-free and overall survival. More recently, the clinical development of targeted agents such as the immunomodulatory drugs (lenalidomide, pomalidomide) and proteasome inhibitors treatment has considerably expanded therapeutic options for myeloma patients; especially in the relapsed/refractory setting.Our overall objectives are to perform a systematic review of maintenance therapies amongst patients with Relapsed and/or Refractory Multiple Myeloma (rrMM) to assess benefits (OS, PFS, response, and quality of life) and harms (adverse events and treatment-related mortality) . Furthermore, if maintenance/salvage therapy is beneficial, which regimen is the most optimal.

This is a Systematic Review, leading to a further Mixed Treatment Comparison, which includes treatments for rrMM marketed since 2000. It will be conducted according to the Cochrane Library’s Database of Systematic Review standards, and commisioned solely for research purposes by the Haematological Malignancies Group.Only Phase III, Randomized Controlled Trials -with an active comparator- will be included; after a peer review and assessment of bias.Findings will be published in the Cochrane Library of Systematic Review and publicly available by end of 2016.

A systematic review and meta-analysis of relevant and similar trials will therefore analyse overall survival (OS), while analysis of combined data from similar RCTs will also enable greater precision in making an unbiased estimation of the effects of treatment.Patients of any age, gender or ethnic origin and with any diagnosis of multiple myeloma (according to either the Durie-Salmon staging system or International Staging System (ISS).RCTs that investigate the following comparisons will be included:• Bortezomib, Carfilzomib, Thalidomide, Pomalidomide, Dexamethasone (high and low dose), Prednisone, Doxorubicin (PLD), Panobinostat, Elotuzumab, Daratumumab; alone or in combination amongst them -if marketed for the rrMM indication-, with at least 2 previous lines (including SCT) of previous treatments, with/out relapsing to the last one.

SAP:Will be HR comparison for OS and PFS, ORR for the dychotomous variables.Bias control: Stratification and covariant adjustment (i.e. number of previous therapies), also adjusting for potential cross-oversFixed and Random effects when apply.We will use Kaplan-Meier curves with adjustments to continuous variables when needed, and by covariates. Obviously Fisher tests would be needed for proportions.Handling of missing data . Censoring or adjudication.PSA and OWSA will be performed once pooled, by ECOG performance, number of previous therapies, ASCT existence (y/n), renal impairment, age, sex and geographical spread, amongst other variables.This is a confirmatory and exploratory (depending on the effect size variable) analysis.

Findings will be published in the Cochrane Library of Systematic Review and publicly available by end of 2016.


Dimopoulos et al. 2007

We will assess the effects of therapies, different doses, treatment administration andschedules -if applicab le- , on overall survival (OS), progressionfreesurvival (PFS), response rate (RR), health-related quality oflife (HRQoL), adverse events (AE) and treatment-related deaths.

The publication citation will be added after the research is published.