Ixazomib for the treatment of multiple myeloma

ABSTRACT

Introduction: Proteasome inhibitors (PIs) are among the backbones of multiple myeloma (MM) treatment; however, their long-term use can be limited by parenteral administration and treatment-related toxicities. Ixazomib, the first oral PI to enter the clinic, is approved around the world, in combination with lenalidomide and dexamethasone, for the treatment of patients with MM who have received at least one prior therapy.

Areas covered: This review summarizes the clinical data leading to approval of ixazomib; its pharmacology, efficacy, and safety. Building on the data in relapsed/refractory MM (RRMM), it also reviews the available clinical trial data for ixazomib across the MM treatment algorithm in newly diagnosed MM, RRMM, and as maintenance therapy, and looks ahead to ongoing clinical trials and the expanding role of ixazomib in these indications.

Expert opinion: Ixazomib is an efficacious and well-tolerated addition to the treatment armamentarium for RRMM, with benefit as a long-term, continuous therapy for all patients, including ‘poor prognosis’ patients, such as those with advanced stage disease, high-risk cytogenetic abnormalities, and elderly and frail patients. Data from ongoing clinical studies are expected to expand the role of ixazomib across the MM treatment algorithm and in a broader range of combination regimens.     

Proteasome inhibitors for the treatment of multiple myeloma

Introduction: Multiple Myeloma (MM) management is rapidly evolving, with a spectrum of novel treatments that have changed our approach to the therapy. Proteasome inhibitors (PIs) have revolutionized the scenario of both relapsed/refractory and newly diagnosed patients. The efficacy of bortezomib, the first PI approved, followed by carfilzomib and, the oral ixazomib, have been tested in several trials as single agents or in combination.

Areas covered: In this review, the authors summarize mechanism of action, efficacy and safety of proteasome inhibitors in MM and focus on data derived from clinical trials, analyzing adverse events and their relative management.

Expert opinion: The authors believe that, currently, the best course of action in the treatment of MM is to use PIs in combination with immunomodulatory drugs (IMiDs) and/or with monoclonal antibodies for all patients. However, based on the patient-specific characteristics, it is important to avoid inappropriate discontinuation by knowing the single side effects of every agent in order to balance their efficacy and safety.     

首个治疗多发性骨髓瘤的口服药物——依沙佐米

依沙佐米(ixazomib)是由日本武田制药研制的新一代蛋白酶体抑制剂,2015年11月美国FDA批准其联合来那度胺以及地塞米松,用于既往已接受过至少一种治疗方案的多发性骨髓瘤(MM)的治疗。作为首个口服蛋白酶体抑制剂,依沙佐米为业界普遍看好,其突破了现有蛋白酶抑制剂无法口服的局限性,对改善患者的生活质量具有重要现实意义。笔者就依沙佐米的基本信息、作用机理、药动学、药效学、临床试验及应用等研发动态作一概述,以期为医院临床用药提供一定的指导。     

Safety of proteasome inhibitors for treatment of multiple myeloma

Introduction: Proteasome inhibitors (PIs) have revolutionized the treatment of multiple myeloma and are a backbone of therapy. Bortezomib, the first PI approved, has shown efficacy in both front-line and relapsed/refractory settings however the development of resistance and side effects such as peripheral neuropathy can limit its use. The second generation PIs carfilzomib and ixazomib, both approved in relapsed/refractory cases, may help to overcome resistance mechanisms and increase tolerability. While bortezomib is approved to be administered intravenously (IV) or subcutaneously (SC) and carfilzomib IV, ixazomib is the first and only approved PI that is orally bioavailable.

Areas covered: This review focuses on the safety data from clinical trials for the three approved PIs and how to manage adverse effects. A summary of efficacy data from select clinical trials is also included.

Expert commentary: Targeting the proteasome/ubiquitin system is a validated and important part of current anti-myeloma therapy. The availability of an oral proteasome inhibitor without significant neuropathy as a side effect offers patients an important step forward over their treatment.     

Pharmacokinetic drug evaluation of ixazomib citrate for the treatment of multiple myeloma

Introduction: multiple myeloma (MM) is a plasma cell disorder that represents the second most frequent hematologic cancer. Although MM is still an incurable disease, prognosis has improved in the last decades thanks to the introduction of novel agents such as proteasome inhibitors (PIs), immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors.

Areas covered: ixazomib is the first oral PI recently approved by Food and Drug Administration (FDA) and European Medicine Agency (EMA) in combination with lenalidomide and dexamethasone as salvage therapy in MM patients. In this paper, we focus on its pharmacokinetics features, as well as its safety and efficacy in clinical studies.

Expert opinion: ixazomib can be considered an oral analogue of bortezomib, with 9.5-day half-life, 58% of oral bioavailability, and a large distribution volume of 543L. These features make it a versatile molecule, potentially useful both in combination and as single agent. Oral route of administration and good efficacy/safety profile are its winning characteristics, providing the rationale for a future role also in the maintenance setting.     

Ixazomib: an investigational drug for the treatment of lymphoproliferative disorders

Introduction: Ixazomib is a new, orally administered, reversible proteasome inhibitor which is under investigation for the treatment of refractory/relapsed multiple myeloma (MM), systemic light chain amyloidosis (AL) and Waldenström macroglobulinemia (WM).

Areas covered: This article covers the mechanism of action, pharmacology and clinical trial results of ixazomib while under investigation for the treatment of various lymphoproliferative disorders. We examine the findings from several phase 3 clinical trials (i) the pivotal TOURMALINE-MM1 study investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone; (ii) the TOURMALINE-MM3 study investigating ixazomib versus placebo as a maintenance therapy in newly diagnosed MM following induction therapy and autologous stem cell transplantation; (iii) the TOURMALINE-MM2 study investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly diagnosed MM; and (iv) TOURMALINE-AL1 investigating ixazomib plus dexamethasone in patients with relapsed/refractory AL amyloidosis. Finally, we explore early phase clinical studies of this agent in Waldenström macroglobulinemia.

Expert opinion: A key advantage of ixazomib is that it could allow an efficacious treatment approach to MM and other lymphoproliferative disorders through a convenient oral administration route. Ixazomib could soon be used in combination treatment regimens, but more work is necessary to define the place of this agent going forward.     

Safety of ixazomib for the treatment of multiple myeloma

Introduction: Despite a major positive impact of proteasome inhibitors (PI), such as bortezomib and carfilzomib, on the survival of patients with multiple myeloma (MM) over the last few years, their use in clinical practice is limited by the development of drug resistance, significant side-effects or constraining administration schedules. Ixazomib is the first, and for now the only, oral PI, which was approved by the US Food and Drug Administration in 2015 and by the European Medicines Agency in 2016.

Areas covered: In this review, we provide an overview of the preclinical and early-phase studies of ixazomib used as single-agent and in combination. Furthermore, we discuss the results of a recently published pivotal trial, which evaluated the safety profile and clinical benefit of the combination of ixazomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in 722 patients with relapsed/refractory MM.

Expert opinion: Ixazomib combines the comfort of oral administration, substantial clinical efficacy and a good safety profile with manageable side-effects, which mainly comprise low-grade hematological, digestive or cutaneous events, and the agent will therefore play an active part in long-term treatment strategies, both as single agent and as part of combination regimens. Ongoing phase III trials are currently defining its place in first-line, maintenance and relapse settings.     

The safety of bortezomib for the treatment of multiple myeloma

Introduction: There is now 16 years’ worth of established results of various trials demonstrating the bortezomib efficiency in the treatment of multiple myeloma. Over this time, the introduction of bortezomib has been a major break through in the treatment of multiple myeloma. Bortezomib can be administered in the outpatient setting with manageable toxicities.

Areas covered: A literature search was carried out using PubMed and Google Scholar. This review gives an overview of the critical role of the bortezomib in multiple myeloma and provides a comprehensive summary of key clinical benefit and safety data with the bortezomib. Initial toxicity profile has improved dramatically with introduction of subcutaneous administration and also, implementation of guidelines for early recognition and treatment. Triplet and quadruplets of bortezomib with agents possessing similar toxicities constitute a challenge.

Expert opinion: Bortezomib is an important part of current anti-myeloma therapy with a good clinical efficacy and manageable side effects. Although gastrointestinal disturbances and fatigue are the most common adverse effects, peripheral neuropathy and thrombocytopenia are the key dose-limiting toxicities of bortezomib-based combination regimens. Since these combinations are more effective, with faster disappearance of disease related symptoms and anti-inflammatory effects of bortezomib toxicities were not found to be augmented.     

Panobinostat for the treatment of relapsed or relapsed/refractory multiple myeloma: pharmacology and clinical outcomes

Recently, outcomes for patients with multiple myeloma have improved dramatically due to improved and innovative therapies. However, most patients will either relapse or become refractory to current therapy. Thus, a significant unmet need remains for novel agents to treat this patient population. Panobinostat, a potent pan-deacetylase inhibitor with a unique mechanism of action targeting both epigenetic regulation of gene expression and protein metabolism, has preclinical synergy with a number of agents, including the proteasome inhibitor bortezomib. In a phase 3 trial of panobinostat with bortezomib and dexamethasone, addition of panobinostat significantly prolonged the median progression-free survival of patients with relapsed or relapsed and refractory multiple myeloma. This review focuses on clinical development of panobinostat, with particular emphasis on pharmacokinetics and adverse event management.     

Novel agents derived from the currently approved treatments for MM: novel proteasome inhibitors and novel IMIDs

Introduction: Several novel proteasome inhibitors (PIs) and immunomodulatory agents (IMIDs) with similar, but not exactly the same, mechanisms of action than their predecessors have been developed in the last years with three different aims: to increase the efficacy; to overcome the resistance and to exhibit a better toxicity profile.

Areas covered: This review summarizes the mechanism of action of novel PIs (carfilzomib, ONX-0912, MLN-9708, marizomib and CEP-18770) and IMIDs (pomalidomide), stressing the similarities and differences with their parental drugs. It also reviews their most updated clinical results. A search of the recent literature in published papers and abstracts from the most important oncology scientific meetings (ASCO and ASH) has been performed.

Expert opinion: Novel PIs and IMIDs show clinical activity as single agents and in combination with dexamethasone, with similar or even higher efficacy than their predecessors; moreover, they may even overcome resistance to their parental drugs, indicating that there are some differences in their mechanisms of action and resistance. The investigation of these mechanisms of resistance and ways to overcome it would allow the optimization of the sequential use of these agents, and the design of novel therapeutic strategies and more appropriate scientifically based combinations.     

An update in treatment options for multiple myeloma in nontransplant eligible patients

Introduction: Despite the fact that multiple myeloma (MM) is still an incurable disease, the outcome of patients who are eligible and ineligible for high-dose therapy has dramatically improved with the introduction of novel agents, that is proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs). However, this improvement is often not seen in elderly patients (above 75 years).

Areas covered: This review will focus on the impact of known prognostic factors in elderly MM patients, and risk factors to identify frail elderly patients. Furthermore, data on known and novel PIs and IMiDs, as well as data on other promising novel treatment strategies, chosen based on current practice and anticipated timely approval, will be discussed. Novel treatment strategies include the use of monoclonal antibodies, such as elotuzumab, daratumumab, SAR650984 and more targeted therapies, such as histone deacetylase inhibitors, kinesin spindle protein inhibitors, and selective inhibitors of nuclear export.

Expert opinion: Besides efficacy of treatment, toxicity and quality of life play an important role in treatment choice. Treatment and treatment dosing for the frail elderly as well as risk factors to identify the frail elderly require further consideration, as these patients frequently do not benefit from these novel agents due to early discontinuation of treatment due to toxicity.     

An overview of the role of carfilzomib in the treatment of multiple myeloma

Introduction: Carfilzomib is a second-generation proteasome inhibitor that binds selectively and irreversibly with the chymotrypsin-like site of the proteolytic core. Its initial approval by the Food and Drug Administration, as monotherapy for relapsed/refractory multiple myeloma (RR-MM), followed soon by a global authorization of its combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of RR-MM after 1–3 prior lines. In order to optimize its administration, carfilzomib is currently examined in different doses and regimens in relapsed/refractory as well as in newly diagnosed myeloma.

Areas covered: This review will focus on the introduction of carfilzomib as an effective anti-myeloma treatment, describing the evolution of the drug from its pre-clinical development to its established use by phase III clinical trials. Based on the latest evidence, we will present its mechanism of action, its efficacy and its toxicity profile on treated myeloma patients and we will try to reply to all raised concerns about its current use.

Expert opinion: Either alone or in combination with other agents, carfilzomib seems to be an effective and safe therapeutic option for MM management. Results of ongoing trials are expected to update its application, even at an earlier level of the disease course.     

Menogaril in the treatment of relapsed multiple myeloma

Summary Fifteen patients with relapsed multiple myeloma (MM) were treated with menogaril 160 mg/m² intravenously (IV) every 28 days. No responses were seen: 8 patients had stable disease, 4 progressed after one course of therapy, and 3 patients were removed from study after 1 course for other reasons. Four of the 8 patients with stable disease had an improved performance status, and 3 had a decrease in analgesic use. The major toxicity was myelosuppression. The median progression-free interval was 3.0 months with a range of 0.7 to 22 months and median survival was 11.3 months with a range of 0.7 to 39+ months. Menogaril displays little activity in patients with previously treated MM.     

多发性骨髓瘤治疗策略及治疗新药

多发性骨髓瘤是一种起病隐匿、治疗难度较大的浆细胞恶性增殖性疾病,如何更准确地判断治疗时机以及选择适宜的治疗策略和治疗药物一直是临床上亟待解决的重大课题。近20年来,随着造血干细胞移植术和治疗新药的应用,多发性骨髓瘤治疗已取得重大进展,治疗疗效和患者的预后都得到了明显改善。     

Melphalan hydrochloride for the treatment of multiple myeloma

Introduction: Multiple myeloma (MM) is an incurable disease characterized by clonal plasma cell proliferation and overproduction of monoclonal paraprotein, hypercalcemia, renal failure, anemia, osteolytic bone lesions, and infections.

Melphalan, a nitrogen mustard, is an alkylating agent synthesized in 1953, and it has been used in multiple myeloma therapy for fifty years. Although novel agents have been introduced in the past few decades improving prognosis of the disease, melphalan still maintains a crucial role in the treatment of MM acting both as cytotoxic agent through damage to DNA, and as immunostimulatory drug by inhibiting Interleukin-6, as well as interaction with dendritic cells, and immunogenic effects in tumor microenvironment.

Areas covered: This review focuses on available data about melphalan pharmacology and its role in clinical practice.

Expert opinion: Melphalan remains crucial in therapy of multiple myeloma because of its good manageability, safety profile, efficacy, and economic sustainability. These characteristics make it pivotal also for new regimens in combination with novel agents.     

An update on the use of lenalidomide for the treatment of multiple myeloma

Introduction: Lenalidomide, an immunomodulatory agent with unique mechanism of action, represents the cornerstone in the treatment of patients with multiple myeloma (MM) providing rapid and sustained control of the disease with a manageable safety profile.

Areas covered: This review article, synthesizing all available data coming from trials and evaluating the efficacy and safety of lenalidomide in patients with MM, tries to provide to the clinicians with an easy-to-grasp synopsis of recent and clinically meaningful advances on the field.

Expert opinion: Lenalidomide combined with dexamethasone is a safe and effective option for newly diagnosed MM patients ineligible for autologous stem cell transplantation (ASCT). Long-term administration of the agent as continuous treatment for ineligible for ASCT patients or maintenance therapy after ASCT has documented unprecedented progression-free survival improvements, whereas lenalidomide in combination with dexamethasone has shown deep and durable remissions for patients with relapsed and/or refractory disease.     

Panobinostat for the treatment of multiple myeloma

Introduction : Multiple myeloma (MM) is a B-cell malignancy characterized by proliferation of monoclonal plasma cells in the bone marrow. Although new therapeutic options have been introduced and response rates have improved in recent years, MM still remains incurable and new treatment options are urgently needed. The histone deacetylase inhibitors (HDACi) are a new class of anticancer agents in early clinical development in many malignancies including MM. HDACi target the enzyme histone deacetylase (HDAC) involved in the deacetylation of histone and non-histone cellular proteins that play important roles in epigenetic regulation of gene expression inducing death, apoptosis and cell cycle arrest in cancer cells. Panobinostat (LBH589) is a highly potent HDACi with demonstrated antitumor activities at low nanomolar concentration in several preclinical studies and its clinical efficacy is currently under investigation in several clinical trials.

Area covered : In this review the authors discuss the role of HDACs in the regulation of gene expression and the biological mechanisms mediating the anticancer effects of HDACi with particular focus on the recent development of panobinostat as anti-MM agent in preclinical and clinical studies.

Expert opinion : As a ‘multi-target' drug, panobinostat appears attractive as potential anti-MM therapeutic for its ability to modulate a variety of biological pathways essential in MM biology. This ‘multi-target' property of panobinostat may also be one its major shortcomings, and a better understanding of its mechanisms of action and targets will permit to identify the best combination therapies that will ultimately overcome and improve outcomes in MM patients.