Bortezomib before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in newly diagnosed multiple myeloma: a subgroup analysis from the HOVON-65/GMMG-HD4 trial

Scheid, Christof; Sonneveld, Pieter; Schmidt‐Wolf, Ingo G.H.; Holt, Bronno van der; Jarari, Laila el; Bertsch, Uta; Salwender, Hans; Zweegman, Sonja; Blau, Igor Wolfgang; Vellenga, Edo; Weisel, Katja; Pfreundschuh, Michael; Jie, Kon‐Siong G.; Neben, Kai; Velde, Helgi van de; Duehrsen, Ulrich; Schaafsma, M; Lindemann, Walter; Kersten, Marie José; Peter, Norma; Hänel, Mathias; Croockewit, Sandra; Martin, Hans; Wittebol, Shulamiet; Bos, Gerard M.J.; Marwijk-Kooy, Marinus van; Wijermans, Pierre W.; Goldschmidt, Hartmut; Lokhorst, Henk M.

doi:10.3324/haematol.2013.087585

Cited by 107 publications

(78 citation statements)

References 31 publications

(34 reference statements)

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“…Patients with a baseline serum creatinine 2 mg dL 21 who were randomized in the VAD arm had a significantly shorter 3-year OS (34%) than those in the PAD arm (74%). OS for these latter patients was not influenced by the presence or absence of RI [27].…”

Section: Discussionmentioning

confidence: 87%

Bortezomib‐based therapy combined with high cut‐off hemodialysis is highly effective in newly diagnosed multiple myeloma patients with severe renal impairment

et al. 2015

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Multiple myeloma (MM) is often associated with renal insufficiency (RI) which adversely influences the prognosis. Several studies demonstrated that bortezomib can improve both renal function and outcome. We prospectively evaluated 21 newly diagnosed MM patients with severe renal impairment secondary to tubularinterstitial damage, most of them due to myeloma kidney, who were primarily treated with bortezomib-based therapy combined with high cut-off hemodialysis (HCOD). The median serum creatinine level at baseline was 6.44 mg dL 21 and calculated median estimated glomerular filtration rate (eGFR), according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, was 8 mL/min/1.73 m 2 . Serum free light chain (sFLC) median concentration was 6,040 mg L 21. Post induction and best stringent complete response rates were 19 and 38%, respectively. Responses were fast, occurring within a median of 1.4 months. The combination of bortezomib and HCOD led to a prompt and remarkable (>90%) decrease in sFLC levels. Sixteen patients (76%) became dialysis independent within a median of 32 days. With a median follow up of 17.2 months, the 3-year PFS and OS were 76 and 67%, respectively. No early deaths were observed. This study demonstrates that incorporation of bortezomib into induction therapy combined with HCOD is a highly effective strategy in rescuing renal function and improving outcomes in patients with MM and RI.

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Section: Discussionmentioning

confidence: 87%

Bortezomib‐based therapy combined with high cut‐off hemodialysis is highly effective in newly diagnosed multiple myeloma patients with severe renal impairment

et al. 2015

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“…59,60 The efficacy is further improved when thalidomide is used in triple or even quadruple combinations, including thalidomide with dexamethasone and bortezomib (VTD), dexamethasone and cyclophosphamide (CTD), bortezomib plus melphalan and prednisone (VMPT) or dexamethasone (VMDT), lenalidomide, melphalan and prednisone (RMPT), or VTD with pegylated liposomal doxorubicin. 23,[61][62][63][64][65][66] These regimens have been associated with an ORR of 63-90% with CR being reported in 2-35% of patients.…”

Section: Thalidomidementioning

confidence: 99%

Treatment of relapsed and refractory multiple myeloma

2016

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“…Therefore, an understanding of the impact of RI on the PK of a drug used to treat MM is important to inform appropriate dosing, in order to ensure safe and effective pharmacotherapy. Several subanalyses and studies suggest that treatment with bortezomib‐based therapy is effective and well tolerated in MM patients with RI and can at least partially overcome the negative prognostic impact of RI in these patients (San Miguel et al , 2008; Dimopoulos et al , 2010; Ludwig et al , 2010; Morabito et al , 2011; Scheid et al , 2014). Carfilzomib has also demonstrated clinical efficacy in RRMM patients with varying degrees of RI (CrCl 50–80 ml/min, 30–49 ml/min, <30 ml/min and chronic haemodialysis) in a phase 2 study, and the safety and PK properties of carfilzomib did not appear to be influenced by the level of baseline RI (Badros et al , 2013).…”

Section: Discussionmentioning

confidence: 99%

A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end‐stage renal disease requiring haemodialysis

et al. 2016

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SummaryRenal impairment (RI) is a major complication of multiple myeloma (MM). This study aimed to characterize the single‐dose pharmacokinetics (PK) of the oral proteasome inhibitor, ixazomib, in cancer patients with normal renal function [creatinine clearance (CrCl) ≥90 ml/min; n = 20), severe RI (CrCl <30 ml/min; n = 14), or end‐stage renal disease requiring haemodialysis (ESRD; n = 7). PK and adverse events (AEs) were assessed after a single 3 mg dose of ixazomib. Ixazomib was highly bound to plasma proteins (~99%) in all renal function groups. Unbound and total systemic exposures of ixazomib were 38% and 39% higher, respectively, in severe RI/ESRD patients versus patients with normal renal function. Total ixazomib concentrations were similar in pre‐ and post‐dialyser samples collected from ESRD patients; therefore, ixazomib can be administered without regard to haemodialysis timing. Except for anaemia, the incidence of the most common AEs was generally similar across groups, but grade 3 and 4 AEs were more frequent in the severe RI/ESRD groups versus the normal group (79%/57% vs. 45%), as were serious AEs (43%/43% vs. 15%). The PK and safety results support a reduced ixazomib dose of 3 mg in patients with severe RI/ESRD.

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Bortezomib before and after autologous stem cell transplantation overcomes the negative prognostic impact of renal impairment in newly diagnosed multiple myeloma: a subgroup analysis from the HOVON-65/GMMG-HD4 trial

Cited by 107 publications

References 31 publications

Bortezomib‐based therapy combined with high cut‐off hemodialysis is highly effective in newly diagnosed multiple myeloma patients with severe renal impairment

Bortezomib‐based therapy combined with high cut‐off hemodialysis is highly effective in newly diagnosed multiple myeloma patients with severe renal impairment

Treatment of relapsed and refractory multiple myeloma

A pharmacokinetics and safety phase 1/1b study of oral ixazomib in patients with multiple myeloma and severe renal impairment or end‐stage renal disease requiring haemodialysis

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