Weekly intravenous bortezomib is effective and well tolerated in relapsed/refractory myeloma

Moore, Sally; Atwal, Sangeeta; Sachchithanantham, Sajitha; Streetly, Matthew; Khan, Iftekhar; Percy, Laura; Narat, Santosh; D’Sa, Shirley; Rabin, Neil; Johnston, Rosalynd; Schey, Steve; Yong, Kwee

doi:10.1111/ejh.12070

Cited by 13 publications

(9 citation statements)

References 25 publications

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“…dara 16 mg/m2 + bor1.3 mg/m2 + dex20 mg25118.56421.8432. bor1.3 mg/m2 + dex20 mg2477.2Observational trials Avet-Loiseau et al [40]dex40mg + len25mg2079.66531.744 Chang et al [41]bor1.3 mg/m2659.554> = 21.331 Fukushima et al [72]bor1.3 mg/m2 + dex20mg2216.86922.141 Hou et al [73]dex20/40 mg + len25mg1998.36042.847 Kneppers et al [42]dex40mg + len25mg11710613.52.737 Lacy et al [74]dex40mg + pom2mg344.86241.732 Moore et al [43]bor1.3 mg/m252137212.640 Oehrlein et al [75]Dex < 160-480 mg2611.67122.854Len10-25 mg Pantani et al [76]bor1.3 mg/m2 + dex20mg858.75822.440 Richardson et al [77]bor1.3 mg/m2 + dex40mg + pan20mg555.46141.947 Terpos et al [78]dex40mg + thal200mg3586322.234 Walter-Croneck et al [44]bor1.3 mg/m2708146012.155 bev bevacizumab, bor bortezomib, carf carfilzomib, cyc cyclophosphamide, dara daratumumab, dex dexamethasone, elo elozum...…”

Section: Resultsmentioning

confidence: 99%

The use of single armed observational data to closing the gap in otherwise disconnected evidence networks: a network meta-analysis in multiple myeloma

Schmitz

Maguire

Morris

et al. 2018

BMC Med Res Methodol

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BackgroundNetwork meta-analysis (NMA) allows for the estimation of comparative effectiveness of treatments that have not been studied in head-to-head trials; however, relative treatment effects for all interventions can only be derived where available evidence forms a connected network. Head-to-head evidence is limited in many disease areas, regularly resulting in disconnected evidence structures where a large number of treatments are available. This is also the case in the evidence of treatments for relapsed or refractory multiple myeloma.MethodsRandomised controlled trials (RCTs) identified in a systematic literature review form two disconnected evidence networks. Standard Bayesian NMA models are fitted to obtain estimates of relative effects within each network. Observational evidence was identified to fill the evidence gap. Single armed trials are matched to act as each other’s control group based on a distance metric derived from covariate information. Uncertainty resulting from including this evidence is incorporated by analysing the space of possible matches.ResultsTwenty five randomised controlled trials form two disconnected evidence networks; 12 single armed observational studies are considered for bridging between the networks. Five matches are selected to bridge between the networks. While significant variation in the ranking is observed, daratumumab in combination with dexamethasone and either lenalidomide or bortezomib, as well as triple therapy of carfilzomib, ixazomib and elozumatab, in combination with lenalidomide and dexamethasone, show the highest effects on progression free survival, on average.ConclusionsThe analysis shows how observational data can be used to fill gaps in the existing networks of RCT evidence; allowing for the indirect comparison of a large number of treatments, which could not be compared otherwise. Additional uncertainty is accounted for by scenario analyses reducing the risk of over confidence in interpretation of results.Electronic supplementary materialThe online version of this article (10.1186/s12874-018-0509-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

The use of single armed observational data to closing the gap in otherwise disconnected evidence networks: a network meta-analysis in multiple myeloma

Schmitz

Maguire

Morris

et al. 2018

BMC Med Res Methodol

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“…Our observed rate of treatment emergent PN was also higher than that reported in either the SUMMIT [3] or CREST [4] trials. Newer methods of bortezomib dosing, such as subcutaneous or weekly administrations, appear to significantly lower the rate of PN, but it remains an important issue [11, 12, 35]. These modifications would seem the current best approach in minimizing bortezomib-related PN as the preliminary data from our small study does not support any advantage for the inclusion of ALCAR in this clinical setting.…”

Section: Discussionmentioning

confidence: 92%

Acetyl-l-carnitine (ALCAR) for the prevention of chemotherapy-induced peripheral neuropathy in patients with relapsed or refractory multiple myeloma treated with bortezomib, doxorubicin and low-dose dexamethasone: a study from the Wisconsin Oncology Network

Callander

Markovina

Eickhoff

et al. 2014

Cancer Chemother Pharmacol

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PurposeRetreatment with bortezomib (B) is often considered for patients with relapsed multiple myeloma (MM), but this strategy is hindered by uncertainty of response and emergence of B-induced peripheral neuropathy (PN). We incorporated acetyl-l-carnitine (ALCAR) to prevent PN and allow for adequate dosing. We also investigated the correlation between B-inducible NF-κB activation and response to therapy.MethodsNineteen patients with relapsed/refractory MM received up to 8 cycles of intravenous bortezomib, doxorubicin and oral low-dose dexamethasone (BDD) to evaluate response and toxicity. Thirteen additional patients received prophylactic ALCAR (BDD-A). Patients receiving BDD-A were evaluated by FACT-GOG-TX, FACIT-Fatigue, Neuropathic Pain index (NPI) and Grooved Pegboard (GP) testing. Primary MM cells from 11 patients were tested for B-inducible NF-κB activation.ResultsSeventy-six percent of subjects were refractory to previous treatment, 39 % refractory to bortezomib. Median cycles received were 5. CR + PR for the entire group were 53 % and did not differ between groups. Incidence of ≥3 PN was 32 % in the BDD group versus 15 % in the BDD-A group (p = ns). Patient-reported fatigue and PN measured by FACT-GOG-TX increased throughout the treatment period in the BDD-A group, although time to complete GP testing declined. In a sub-study examining constitutive bortezomib-inducible NF-κB activity in primary subject-specific MM cells, the presence of NF-κB activation correlated with lower likelihood of response.ConclusionsAddition of ALCAR to BDD did not alter the incidence or severity of PN in relapsed MM patients receiving a B-based regimen. Bortezomib-inducible NF-κB activation in patient-derived primary MM cells may be associated with poorer response.

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“…In conclusion, treatment with scBor demonstrated a lower incidence and severity of PN compared with ivBor administration, but did not adversely affect the efficacy of treatment when combined with thalidomide and dexamethasone. Previous studies have indicated that a weekly dose of bortezomib should be used within combinatorial treatments in order to achieve the lowest PN rates (26)(27)(28). However, the most efficient dose schedule of bortezomib under varying ISS stages and patient demographics requires additional research.…”

Section: Discussionmentioning

confidence: 99%

Peripheral neuropathy outcomes and efficacy of subcutaneous bortezomib when combined with thalidomide and dexamethasone in the treatment of multiple myeloma

Liu

Huang

2016

Experimental and Therapeutic Medicine

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Due to the safety, convenience and efficacy of subcutaneous administration of bortezomib (scBor), it is becoming increasingly common to treat multiple myeloma (MM) using this treatment method. The current retrospective study suggested a lower incidence of peripheral neuropathy (PN) outcomes and superior efficacy following treatment with scBor combined with thalidomide and dexamethasone (VTD) in MM when compared with intravenous Bor (ivBor) treatment. The data of 81 patients from the Affiliated Hospital of Nantong University between September 2011 and February 2014 were analyzed, including 37 scBor and 44 ivBor patients administered a median (range) of 5.5 (3-8) and 6 (3-10) chemotherapy cycles, respectively. Adverse events (AEs) were assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for AEs, and response and progression were assessed by the International Myeloma Working Group criteria. Evidence of histopathology using transmission electron microscopy (TEM) was obtained from an model of adult Sprague Dawley (SD) rats. Following bortezomib-based VTD chemotherapy, patients had achieved very good partial remission or demonstrated no significant difference between the scBor and ivBor treatment groups (75.6 vs. 84.1%, respectively; P=0.350). The 1-year progression-free survival (83.8 vs. 84.1%, scBor vs. ivBor; P=0.921) and 1-year overall survival (OS) (91.9 vs. 90.9%, respectively; P=0.926) were also similar. PN rates of all the NCI grades were 51.3 and 61.3% (P=0.371); grade ≥2, 35.1 and 56.8% (P=0.052); and grade ≥3, 32.7 and 20.5% (P=0.015) in the subcutaneous and intravenous treatment groups, respectively, which suggests that severe PN may be less common following scBor treatment. There were no severe injection site reactions in the scBor-treated group. The incidence of adverse events were comparable between the two groups, including thrombocytopenia, anemia, fatigue and gastrointestinal symptoms such as nausea and vomiting. Furthermore, TEM images of the SD rat sciatic nerves revealed that all rats suffered PN to varying degrees, except the control group, and that the PN of ivBor-treated rats (in the presence and the absence of thalidomide) was more severe than that of scBor-treated rats. It was concluded that a subcutaneous dose of bortezomib of 1.3 mg/m may result in a lower incidence and severity of PN, with equivalent efficacy, as a component of combination VTD chemotherapy.

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Weekly intravenous bortezomib is effective and well tolerated in relapsed/refractory myeloma

Abstract: Weekly intravenous bortezomib when used in combination with steroids ± alkylator is effective in relapsed/refractory MM, producing outcomes comparable with biweekly regimens and with lower rates of peripheral neuropathy.

Cited by 13 publications

References 25 publications

The use of single armed observational data to closing the gap in otherwise disconnected evidence networks: a network meta-analysis in multiple myeloma

The use of single armed observational data to closing the gap in otherwise disconnected evidence networks: a network meta-analysis in multiple myeloma

Acetyl-l-carnitine (ALCAR) for the prevention of chemotherapy-induced peripheral neuropathy in patients with relapsed or refractory multiple myeloma treated with bortezomib, doxorubicin and low-dose dexamethasone: a study from the Wisconsin Oncology Network

Peripheral neuropathy outcomes and efficacy of subcutaneous bortezomib when combined with thalidomide and dexamethasone in the treatment of multiple myeloma

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