Efficacy and toxicity profile of carfilzomib based regimens for treatment of multiple myeloma: A systematic review

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Abstract

Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has side effects like peripheral neuropathy (PNP) with reported incidence of grade ≥3 PNP between 2%–23% Schlafer et al., 2017. Carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PNP. CFZ is already approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone. Extensive literature search identified a total of 1839 articles. Twenty-six articles (n = 5980) met the inclusion criteria, 15 in newly diagnosed multiple myeloma (NDMM) and 11 in RRMM group. CFZ demonstrates comparable or even better efficacy to bortezomib with much favorable AE profile. Deep, rapid and sustainable response using KRd with safer toxicity profile supports extension of KRd therapy to frontline therapy for all risk categories of MM. High incidence of grade ≥3 HTN underscores the importance of serial BP monitoring. In RRMM, CFZ has documented efficacy with standard 20–27mg/m2 dose. Further large-scale trials are needed to study benefit-to-risk profile of 20–56 and 20–70 mg/m2 dose of CFZ vs standard 20–27 mg/m2 dose in NDMM and RRMM.

Introduction

Multiple Myeloma (MM) is characterized by monoclonal proliferation of plasma cells in the bone marrow. Based on cytogenetics, disease can be classified as high risk: t(14;16), t(14;20), and/or del (17p13), intermediate risk: t(4;14) and/or (1q) gain, and standard risk: trisomies, t(11;14) and/or t(6;14) (Strite et al., 2015). Consensus based treatment guidelines recommend 4 cycles of induction therapy such as bortezomib, lenalidomide and dexamethasone (VRd) followed by autologous stem cell transplantation therapy (ASCT) in transplant eligible patients with newly diagnosed multiple myeloma (NDMM) (Strite et al., 2015). Some guidelines such as mSMART recommend patients with high risk NDMM should be given carfilzomib based triple combination induction regimen. In patients with second or higher relapses, treatment depends on prior therapy, comorbidities (peripheral neuropathy, renal failure), marrow functioning as indicated by blood counts, and rapidity of relapse. Combination therapy incorporating proteasome inhibitors, immunomodulators, steroids and alkylating agents is generally recommended (Strite et al., 2015).

Over the past two decades, advancements in MM therapy have markedly improved disease outcome and overall survival (OS). According to national institute of health (NIH) cancer statistics death rates due to MM have declined on average 0.7% each year over 2005–2014 (N.C. Institute, 2018). Despite noticeable improvement in disease outcome, MM remains incurable with high rates of relapses, highlighting the unmet need for new treatment strategies. Proteasome inhibitor bortezomib was approved by the US Food and Drug Administration (FDA) for treatment of multiple myeloma in 2003 (Kane et al., 2003). Despite its notable efficacy there are serious issues of side effects such as peripheral neuropathy (PNP), which has been reported in up to 30% of patients treated with bortezomib based regimens (Mohty et al., 2010; Wang et al., 2013). Risk of PNP with bortezomib has been mitigated with subcutaneous and once weekly administration (Rosinol et al., 2012). In 2012, carfilzomib (CFZ), a novel proteasome inhibitor, was approved for treatment of relapsed and refractory multiple myeloma (RRMM) (Siegel et al., 2012a). CFZ is highly selective, irreversible epoxy-ketone molecule that targets chymotrypsin like activity of 20S proteasome leading to cellular apoptosis which is particularly beneficial in malignant cells. CFZ has minimal off target activity causing fewer side effects including lower rates of PNP (Wang et al., 2013; Moreau et al., 2015a). Further, CFZ has demonstrated activity in bortezomib resistant cell lines (Siegel et al., 2012a; Vij et al., 2012a; Jagannath et al., 2012). Since 2012, CFZ has been studied in various clinical trials. The aim of our study is to conduct comprehensive literature search for efficacy, dosing and toxicity profile of CFZ in both newly diagnosed and relapsed setting. Our secondary aim is to analyze whether CFZ treatment can be extended to the frontline setting.

Section snippets

Literature search

A comprehensive literature search was performed on 6/5/2017 in the following resources: PubMed, EMBASE, Wiley Cochrane library, Scopus, Web of Science, CINAHL, and Clinicaltrials.gov. Search results were not limited to any geographical area or language, in the case English translations were available. However, studies done only after 2007 were included. Example search strategy is provided in Appendix A. Relevant articles from following conference proceedings were also included: the European

Search results

The literature search identified a total of 1835 articles. Additional 4 articles were identified through citation analysis. After excluding 630 duplicate studies, remaining 1209 were screened for relevance based on titles and abstracts. 89 studies were found potentially useful for our study after excluding 1120 studies. After reading full texts of remaining articles, further 63 articles were excluded due to one or more of the following reasons: phase 1 study, interim analysis, not focused on

Carfilzomib, lenalidomide and dexamethasone (CRd) (5 studies, n = 268)

We summarized five studies (Roussel et al., 2016; Zimmerman et al., 2016; Korde et al., 2013; Jasielec et al., 2013; Jakubowiak et al., 2013) with total of 268 NDMM patients who were treated with CRd. Roussel et al. (2016) conducted a phase II study (n = 46) to assess efficacy of CRd regimen. All patients underwent 4 cycles of CRd induction, 43 patients received ASCT, 41 patients received further 4 cycles of consolidation therapy followed by 1 year of Len maintenance therapy in 27 patients. The

Phase III (1 study, n = 315)

Hájek et al. (2017) compared single agent carfilzomib with best supportive treatment (low dose corticosteroids and optional cyclophosphamide) in heavily pretreated RRMM patients with median 5 prior lines of therapy. A total of 315 patients were randomized into CFZ group (n = 157) and control group (n = 158). Primary end-point was OS (time form randomization to death from any cause) which was not statistically different in 2 groups (10.2 months vs 10 months in carfilzomib and control group

Toxicity profile of carfilzomib

Incidence of grade ≥3 AE was as follows: anemia(11–41%), lymphopenia (5.7–50%), thrombocytopenia (4–53%), neutropenia (11–53%), leukopenia (1.4–43%), dyspnea (3.4–11%), pyrexia (1.5–2.4%), URTI (1.8–5.7%), increased creatinine (2.6–2.9%), PN (1–1.1%), hypophosphatemia (1.7–16%), hyponatremia (7.1–11%), pneumonia (8.6-18%), renal failure (3.4–9%), febrile neutropenia (0.8–7%), hypertension (3–25%), heart failure (3.4–20%) and hypokalemia (1.7–9.4%) (Siegel et al., 2012b; Stewart et al., 2015;

Discussion

CFZ based therapies have been evaluated in RRMM setting, a population that is more difficult to treat than NDMM patients for multiple reasons. Based on literature summarized in this review, it is suggested that CFZ based treatment was very successful in the frontline setting. PN is a crippling condition that can develop as complication of disease itself or its treatment including agents like bortezomib and thalidomide (Morawska et al., 2015). Reported incidence of bortezomib induced grade ≥ 3

Conclusion

Our results suggest that CFZ demonstrates comparable efficacy to bortezomib with much favorable AE profile both in NDMM and RRMM. There are only two studies with head to head comparison of CFZ based regimens with bortezomib based regimens.(ClinicalTrials.gov, 2017a; Dimopoulos et al., 2016b) Cross-trial comparisons of studies on CFZ with studies on bortezomib can be imprecise due to significant heterogeneity in patient population, number of prior lines of therapy, dose and schedule of drug used

Authorship statement

AM (co-first author): literature search, figures, study design, data collection, data analysis, data interpretation, writing, editing

VK (co-first author): literature search, figures, study design, data collection, data analysis, data interpretation, writing, editing

AL (co-first author): literature search, figures, study design, data collection, data analysis, data interpretation, writing, editing

AI: literature search, figures, study design, data collection, data analysis, data interpretation

UZ:

Conflict of interest statement

Authors declare that there is no conflict of interest with this manuscript. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of

Financial disclosure statement

This work was supported by grant P30 CA023074 (FA) from the National Cancer Institute, National Institutes of Health, Bethesda, MD.

Acknowledgements:

We acknowledge the efforts of all investigators and their teams who worked on the original trials. We sincerely appreciate all myeloma patients and their families, who volunteered and participated in these clinical trials which are mentioned in our manuscript.

Adeela Mushtaq is a medical doctor, who graduated from Rawalpindi Medical College (RMC), Pakistan. Dr. Adeela is working as research volunteer in Hematology/Oncology at University of Arizona Cancer Center (UACC).

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  • Cited by (0)

    Adeela Mushtaq is a medical doctor, who graduated from Rawalpindi Medical College (RMC), Pakistan. Dr. Adeela is working as research volunteer in Hematology/Oncology at University of Arizona Cancer Center (UACC).

    Vikas Kapoor has his MD and is a graduate from RMC, Pakistan. He is working as a research volunteer in Hematology/Oncology at UACC.

    Azka Latif has her MD and is a graduate from RMC, Pakistan. She is currently working as a research volunteer in Hematology/Oncology at UACC.

    Ahmad Iftikhar has his MD degree from RMC, Pakistan. He is working as a research volunteer in Hematology/Oncology at UACC.

    Umar Zahid has his MD degree from Punjab medical college (PMC), Pakistan. He is a graduate student of MPH Biostatistics at the Mel & Enid Zuckerman College of Public Health, University of Arizona. He is also a research associate at the Department of Medicine, Hematology/Oncology division at UACC.

    Ali McBride has his PharmD and MS and is the Clinical Coordinator of Hematology/Oncology UACC.

    Ivo Abraham is a chief scientist at Matrix45 and professor (part-time) at University of Arizona in the Department of Pharmacy Practice. He has lectured, consulted, and conducted research throughout the America, Europe, the Asia-Pacific region, and Africa.

    Irbaz Bin Riaz had his MD from Nishtar Medical College, currently working as a Hem/Onc trainee fellow at Mayo Clinic, Department of Hematology and Oncology, Rochester, Minnesota.

    Faiz Anwer has his MD, is team leader for Multiple Myeloma program, Clinical Director of the adult Blood and Marrow Transplant Program and the Director of the Stem Cell Harvest Program in the Division of Hematology/Oncology at UACC and is an Assistant Professor of Medicine at the University of Arizona, College of Medicine.

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    Equal contribution as first co-authors.

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