Background and importance There are studies (subgroup analyses) suggesting a lack of benefit for daratumumab drug combinations in patients with untreated multiple myeloma (MM) and hepatic impairment (HI).

Aim and objectives To conduct a systematic search and methodological interpretation of subset analysis about the use of daratumumab based treatments in patients with untreated MM and HI.

Material and methods A bibliographic review in Pubmed was performed up to 11 October 2020. A review strategy was used in the ‘Clinical Queries/Narrow’ tool: (Therapy/Narrow[filter]) AND (daratumumab AND myeloma). Randomised clinical trials (RCTs) with subset analyses according to baseline hepatic function for overall survival (OS) or progression free survival (PFS) in untreated MM were selected. The rest of the search results were excluded. Two methodologies were applied. One considered statistical interaction among subsets (p<0.1), prespecification, biological support and consistency of subset analyses of similar RCTs.¹ The second methodology was a two part validated tool: preliminary questions to discard subgroup analyses without minimal relevance, and a checklist.² The checklist assigned a recommendation for applicability of subset analysis in clinical practice.

Results A total of 25 results were found in the search and the following were excluded: 10 were not RCTs, 9 studies had a different clinical context, 2 evaluated different drugs and 1 had no subset analysis. Therefore, three RCTs were included. According to the first methodology, statistical interaction among subsets was observed for PFS in one RCT. Subgroup analysis was prespecified in each endpoint of all RCTs. Biological support could be reasoned for outcomes of subgroup analyses in all RCTs. However, no consistency of these subset analyses was found. The second methodology (validated tool) discarded applicability of subgroup analysis in two RCTs. In the remaining RCT, checklist recommended a ‘null’ application of subgroup analysis for PFS because of inconsistency of results.

Conclusion and relevance No differences in OS or PFS according to baseline hepatic function should be considered for daratumumab based combinations in patients with untreated MM. Patients with normal hepatic function and HI could benefit from treatment. Application of subgroup analysis should be considered with caution.

References and/or acknowledgements

1. Sun X, et al. How to use a subgroup analysis: users’ guide to the medical literature. JAMA 2014;311:405–11

2. Gil-Sierra MD, et al. Checklist for clinical applicability of subgroup analysis. J Clin Pharm Ther 2020;45:530–8.

Conflict of interest Corporate sponsored research or other substantive relationships

MDG-S: membership of an advisory board (consultation fees) and lecture for Janssen Pharmaceutica (reimbursement for attending symposia). The other authors have no conflicts of interest to declare