Clinical outcomes of bortezomib-based therapy in myeloma.

Faouzi Djebbari,Karthik Ramasamy,Grant Vallance,Anandagopal Srinivasan,Sally Moore,Jaimal Kothari,Dario Ummarino

doi:10.1371/journal.pone.0208920

Abstract

Bortezomib, a first generation proteasome inhibitor, is used in both newly diagnosed and relapsed myeloma settings. Considerable differences exist in the usage of bortezomib therapy in the clinical practice setting in comparison to clinical trial setting as well manufacturer’s recommendations. These differences include route of administration (intravenous (iv) vs. subcutaneous (sc)), frequency from twice to once weekly, choice of alkylating agent used in combination with bortezomib (melphalan or cyclophosphamide), and choice of glucocorticoids (dexamethasone or prednisolone). We reviewed data from 272 consecutive bortezomib-treated myeloma patients, who received therapy within the regional Thames Valley Cancer Network for both newly diagnosed myeloma (NDMM, n = 120) and relapsed MM (RMM, n = 152). We investigated the influence of age, sex, transplant, bortezomib combinations (doublet vs. triplet), cumulative bortezomib dose per treatment line (<50mg vs. ≥50mg), and route of administration (iv vs. sc) on time to next treatment (TTNT) and on overall survival (OS). Route of bortezomib administration (iv vs. sc) influenced neither OS (41 vs 35 months, p = 0.5), nor TTNT (14 vs. 19 months, p = 0.052). Our study showed a statistically significant improvement in median OS in patients receiving a cumulative dose ≥50mg compared to <50mg (42 vs. 33months, p = 0.003), although presence of confounders need to be taken into account, such as disease stage, performance status, genetic changes and prior therapies. Median OS was longer using triplet therapies compared to a doublet in the RMM cohort (37 vs. 29 months, p = 0.06), although this did not reach statistical significance. Multivariate Cox Regression analysis showed that cumulative bortezomib dose ≥50mg (p = 0.002, HR = 1.83, 95% CI 1.25–2.67) and autologous transplant (p = 0.002, HR = 2.6, 95% CI 1.41–3.98) were both significant factors associated with improved OS. Our data argues in favour of continuing bortezomib for the recommended duration as per Summary of Product Characteristics (SPC), subject to good tolerability, in order to deepen response or extend the duration of best response.

Highlights

Multiple myeloma (MM) is a haematological malignancy characterised by uncontrolled proliferative behaviour of clonal plasma cells [1, 2]
This study demonstrated that VP, VP plus cyclophosphamide (VCP) and VP plus melphalan (VMP) regimens demonstrated no substantial difference in efficacy
We reviewed records of 272 consecutive MM patients treated with bortezomib-based regimen between 2010 and 2016, either at NDMM or RMM setting

Summary

Introduction

Multiple myeloma (MM) is a haematological malignancy characterised by uncontrolled proliferative behaviour of clonal plasma cells [1, 2]. It remains an incurable disease with a relapsing and remitting course [3]. Bortezomib is NICE-approved to treat NDMM in the transplant non-eligible (TNE) setting (at 1.3mg/m2 (days 1, 4, 8, 11, 22, 25, and 32 of a 35 days cycle during cycles 1–4, and days 1, 8, 15, 22 during cycles 5–9, up to 12 treatment cycles for a total of 52 weeks); in combination with an alkylating agent (melphalan) and a corticosteroid (prednisolone), as per VISTA trial) [5]. Available at: https://www.myeloma.org.uk/wp-content/ uploads/2015/12/An-introduction-to-myeloma-new.pdf (last accessed: 12.03.2018)

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Conclusion