New developments in the management and treatment of newly diagnosed and relapsed/refractory multiple myeloma patients

Introduction: The introduction of autologous stem cell transplantation as well as novel agents such as proteasome inhibitors (bortezomib) and immunomodulatory drugs (IMiDs; thalidomide and lenalidomide) have significantly improved long-term outcome of multiple myeloma patients. However, patients with high-risk disease at diagnosis had less benefit from these new strategies. In addition, myeloma patients with lenalidomide and bortezomib double-refractory disease have a very poor survival.

Areas covered: Several next generation novel agents are active in patients with double-refractory disease including carfilzomib and pomalidomide. Various monoclonal antibodies are also promising in the setting of relapsed/refractory disease, including daratumumab, elotuzumab and lorvotuzumab mertansine. This editorial will focus on the most promising next generation novel agents for the treatment of multiple myeloma.

Expert opinion: Incorporation of these new novel agents in frontline therapies will lead to more effective and less toxic combination therapies. Furthermore, new diagnostic techniques such as gene-expression profiling and next-generation sequencing will hopefully result in more personalized treatments for molecularly-defined subgroups.     

New pharmacotherapy options for multiple myeloma

Introduction: Novel agents and the availability of autologous stem-cell transplantation have revolutionized the treatment of patients with multiple myeloma. First-generation novel agents namely thalidomide, lenalidomide, and bortezomib have significantly improved response and survival of patients. Second-generation novel agents such as pomalidomide, carfilzomib, and monoclonal antibodies are being tested both in the newly diagnosed and relapse settings, and results are promising.

Areas covered: In this review article, the main results derived from Phase III trials with thalidomide, lenalidomide, and bortezomib for the treatment of myeloma patients, both at diagnosis and at relapse, are summarized. Data about second-generation novel agents such as pomalidomide and carfilzomib are also reported. Newer effective drugs currently under investigation and the promising results with monoclonal antibodies are described.

Expert opinion: The availability of new effective drugs has considerably increased the treatment options for myeloma patients. A sequential approach including induction, transplantation (when possible), consolidation, and maintenance is an optimal strategy to achieve disease control and prolong survival. Despite these improvements, the best combination, the optimal sequence, and the proper target of newer drugs need to be defined.     

Tofacitinib in kidney transplantation

Introduction: The introduction and exploration of novel agents has significantly improved patient outcome in the treatment of multiple myeloma (MM). One such compound, bortezomib, was the first proteasome inhibitor (PI) to be approved as a MM therapeutic. The efficacy and safety data provided by bortezomib usage has provided the basis for the development of a second generation of PIs.

Areas covered: This review focuses on PIs that are currently under evaluation in Phase II clinical trials for the treatment of MM. Furthermore, the article summarizes the currently understood mechanisms of action and the available clinical data for its use in MM.

Expert opinion: Second generation PIs have demonstrated promising activity in patients with advanced-stage myeloma, including those refractory to bortezomib. It should be noted, however, that their efficacy in upfront settings is currently under investigation. Future PI development should include schedule optimization and the investigation of PIs potential synergistic activity with other anti-myeloma agents.     

Estudio observacional restrospectivo para evaluar la efectividad y seguridad de esquemas de tratamiento con bortezomib para el mieloma múltiple en nuestro hospital

ObjectivesTo analyse therapeutic regimens including bortezomib used in our centre for the treatment of multiple myeloma, to evaluate its effectiveness and safety in clinical practice in our hospital, and to assess the appropriateness of the indications described in guidelines.Material and methodsRetrospective analysis of patients diagnosed with multiple myeloma in the period between January 2008 and December 2009 (24 months) that received treatment with a regimen including bortezomib. We analysed demographic variables (age, sex), disease characteristics (type of multiple myeloma, stage, and clinical cytogenetic abnormalities), concomitant drugs, response, and side effects of the regimen including bortezomib.ResultsWe included 59 patients who were diagnosed with multiple myeloma (25 males and 34 females) with an average age of 63 years (range 30-82 years). The overall response rate for patients who received first-line regimens with bortezomib ranged between 69% (vincristine, carmustine, cyclophosphamide, melphalan and prednisone / vincristine, carmustine, doxorubicin, and dexamethasone plus bortezomib) and 82% (bortezomib, melphalan and oral prednisone). When we analysed the salvage treatment regimens: Bortezomib-Dexamethasone, Bortezomib-Cyclophosphamide-Dexamethasone and bortezomib, doxorubicin, melphalan alternating with thalidomide, cyclophosphamide, and dexamethasone achieved overall response rates of 72%, 77% and 89%, respectively. Adverse reactions to bortezomib or a treatment regimen that included it occurred in 32 (54%) patients, highlighting neurotoxicity in 19 patients (32%) and gastrointestinal toxicity in 12 (20%).ConclusionsThe results of our study show the important role of bortezomib in the treatment of multiple myeloma, with response rates and side effects comparable to published data, although the conditions for using it in clinical practice are not yet recognized in the guidelines for use.     

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.     

Therapeutic drug monitoring of antiretroviral drugs in HIV-infected patients

Introduction: Therapeutic drug monitoring (TDM) may be beneficial when applied to antiretroviral (ARV). Even though TDM can be a valuable strategy in HIV management, its role remains controversial.

Areas covered: This review provides a comprehensive update on important issues relating to TDM of ARV drugs in HIV-infected patients. Articles from PubMed with keywords relevant to each topic section were reviewed. Search strategies limited to articles published in English.

Expert commentary: There is evidence supporting the use of TDM in HIV treatment. However, some limitations need to be considered. The evidence supporting the use of routine TDM for all patients is limited, as it is not clear that this strategy offers any advantages over TDM for selected indications. Selected groups of patients including patients with physiological changes, patients with drug-drug interactions or toxicity, and the elderly could potentially benefit from TDM, as optimized dosing is challenging in these populations.     

Ixazomib for the treatment of multiple myeloma

Introduction: Proteasome inhibition is a mainstay in the treatment of multiple myeloma (MM). Bortezomib, the first proteasome inhibitor (PI) approved for MM therapy, has shown efficacy in relapsed/refractory patients and in the front-line setting. Among second-generation PIs, MLN9708 (ixazomib) is the first oral compound to be evaluated in MM treatment and has shown improvement in pharmacokinetic and pharmacodynamic parameters compared with bortezomib with a similar efficacy in the control of myeloma growth and in the prevention of bone loss.

Areas covered: In this review, the authors discuss the rationale for use of PIs. They then summarize the clinical development of ixazomib in MM, from initial Phase I to Phase II studies as a monotherapy and in combination with other chemotherapeutics.

Expert opinion: Preliminary data of Phase I/II trials showed that ixazomib had a good safety profile and exerted anti-myeloma activity as a single agent in relapsed/refractory patients. Furthermore, ixazomib also had efficacy in patients who were refractory to bortezomib. Its use in combination with lenalidomide and dexamethasone was shown to be an effective and well-tolerated regimen in up-front treatment leading to minimal residual disease negativity in a significant number of patients. Results of Phase III trials, evaluating ixazomib in induction or maintenance therapy, are awaited.     

Sorafenib for the treatment of multiple myeloma

Introduction: Sorafenib is an orally available compound that acts predominantly by targeting the Ras/Raf/MEK/ERK pathway and by inhibiting the vascular endothelial growth factor (VEGF). Since the Ras/Raf/MEK/ERK pathway is implicated in the proliferation of multiple myeloma (MM) cells and VEGF in bone marrow neovascularization, sorafenib is a drug offering the potential for targeting two important pathogenetic mechanisms involved in MM. Thus, sorafenib is being proposed for use in MM.

Areas covered: In this review, the authors discuss the rationale for the use of sorafenib in MM. They then summarize the clinical development of sorafenib in MM, from initial Phase I to Phase II studies. A systematic literature review of the trials was performed using PubMed.

Expert opinion: Preliminary data from phase I/II trials showed that sorafenib had a good safety profile but minimal anti-myeloma activity as a single agent in relapsed/refractory patients. Results of phase II trials, evaluating sorafenib combined with new drugs, such as bortezomib and lenalidomide are eagerly awaited.     

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.     

Current treatments for renal failure due to multiple myeloma

Introduction: Renal impairment (RI) is a common complication of symptomatic myeloma; 20 – 40% of newly diagnosed patients present with moderate or severe RI and 10% of them may require dialysis. Immediate initiation of specific antimyeloma therapy is crucial in order to improve RI.

Areas covered: There has been a significant improvement in the outcome of patients with RI over the past 15 years. The authors review current data on the role of antimyeloma therapy on the improvement or resolution of RI and the importance of novel regimens, especially those based on bortezomib. IMiDs-based regimens, conventional chemotherapy and high-dose therapy is also reviewed. The role of extrarenal free light chain removal, by means of plasma exchange or extended hemodialysis with the use of high cutoff dialysis membranes, is also discussed.

Expert opinion: Bortezomib/dexamethasone-based regimens are the preferred regimens for most patients with multiple myeloma (MM) who present with RI, especially for newly diagnosed patients; however, other novel agents (thalidomide, lenalidomide) in combination with dexamethasone may also improve RI in several patients. Further investigation is needed for the clarification of the role of plasma exchange or extended high cutoff dialysis. Carfilzomib, which was recently approved, may also be a treatment choice for selected patients with relapsed MM and RI.     

Bortezomib in multiple myeloma

BACKGROUND: Bortezomib is a novel, first-in-class proteasome inhibitor that has improved outcomes in multiple myeloma, with manageable toxicities. OBJECTIVE: To summarise the chemistry, pharmacokinetics and metabolism of bortezomib, and review its clinical efficacy and toxicity, including use in elderly patients, use in patients with renal impairment and/or a poor prognosis, and effects on bone metabolism. METHODS: Literature search of bortezomib studies (within 10 years) and recent congress abstracts. RESULTS/CONCLUSIONS: Bortezomib has improved response rates, overall survival, and time to progression in relapsed or refractory disease, both as a single agent and as part of combination regimens. Promising results have also been reported with bortezomib combinations in frontline induction therapy. Patient subgroups where conventional approaches are inappropriate may also benefit, thereby expanding the therapeutic armamentarium against this debilitating disease.     

Aripiprazole for the treatment of bipolar disorder: a review of current evidence

Introduction: Several medications are available for the treatment of different phases of bipolar disorder, yet many of the drugs that are currently approved carry a substantial burden of side effects or do not lead all treated patients to remission.

Areas covered: This paper comprises a review and commentary regarding the use of oral and intramuscular aripiprazole in the acute and maintenance phases of bipolar disorder. Basic principles in dosing, switching, management of side effects and co-administration of aripiprazole with other medications are provided. This paper presents practical strategies to translate the data from clinical research into clinical practice.

Expert opinion: Aripiprazole has proven to be an effective medication for the acute treatment of manic and mixed episodes, as well as for the prophylactic–maintenance phase of bipolar disorder in patients recovering from a manic/mixed episode. Choosing the appropriate dosing and tapering strategy, addressing the side effects, controlling withdrawal symptoms from previous medications and using adjunctive medications when necessary are key to successful treatment with aripiprazole.     

Role of new drugs incorporated into consolidation and maintenance therapy in transplant-eligible multiple myeloma patients

Introduction: Since in multiple myeloma (MM) patients the depth of response achieved with autologous stem-cell transplantation (ASCT) seems to correlate with the time to progression, various strategies have been undertaken to control disease and improve prognosis. Novel agents thalidomide, bortezomib and lenalidomide that have allowed deeper responses to be achieved in the induction phase have been tested following the ASCT as consolidation and maintenance treatments.

Areas covered: Consolidation is generally a short-term treatment and aims to increase the depth of the response achieved with high-dose melphalan, whereas maintenance therapy consists of protracted therapy of either a fixed duration or until response and has the goal of prolonging duration of the first response. The goals of both treatments are the extension of progression-free survival and, hopefully, overall survival. This editorial will focus on the consolidation and maintenance strategies after ASCT for the treatment of MM.

Expert opinion: The incorporation of new drugs into the continuum of MM care resulted in improved outcomes and long-term disease control. However, optimal consolidation and maintenance strategies are still to be defined in the light of newer drugs to be utilized for induction strategies.     

An analysis of the safety profile of proteasome inhibitors for treating various cancers

Introduction: Emerging evidence demonstrates that the ubiquitin-proteasome pathway is a promising target for cancer therapy. Bortezomib (Velcade) exhibits great efficacy against multiple myeloma (MM) since the first clinical application. However, there are still several limitations associated with the use of bortezomib, including severe toxicities. To overcome bortezomib’s shortcomings and to improve its safety profile, several second-generation proteasome inhibitors, for example, carfilzomib, ixazomib, oprozomib and marizomib, have been developed and currently tested in various clinical trials.

Areas covered: A literature search was carried out using PubMed and Google Scholar. The activity and safety profiling of proteasome inhibitors in treatment of various cancers were reviewed.

Expert opinion: Bortezomib, as a single or in combination therapy, demonstrates efficacy against MM or other hematological malignancies in clinical settings. However, it encounters two major problems, the acquired resistance and the severe side effects. Future direction in bortezomib-based therapy should focus on how to increase or retain its efficacy but improve its safety profile through, for example, rational combination therapies. Second-generation proteasome inhibitors have shown benefits in both overcoming bortezomib resistance and reducing related side effects, although these encouraging results should be further confirmed in a larger clinic population.     

RebiSmart™ (version 1.5) device for multiple sclerosis treatment delivery and adherence

Introduction: First-line disease-modifying drugs for the treatment of multiple sclerosis (MS) are mostly administered by injection. Although these treatments can control the symptoms and progression of the disease to some extent, patients often fail to adhere to their therapy in the long term, so may not obtain the maximum clinical benefits. As injection-related problems are common barriers to adherence, autoinjectors have been developed to improve the ease and convenience of self-injection.

Areas covered: This article discusses RebiSmart^?, an electronic autoinjector for the subcutaneous administration of interferon β-1a, focusing on the device features and data from clinical trials of the device. An overview of other available autoinjectors for first-line MS therapies is provided for context.

Expert opinion: The device is the first electronic autoinjector for use in MS and offers several innovative features, including adjustable injection settings and an electronic dosing log, which may improve adherence. The dosing log can be reviewed with the patient, allowing the physician to open a dialogue to discuss possible issues with treatment adherence. The use of multidose cartridges also provides a softer impact on the environment and easier disposal. The hidden needle helps avoid needle phobia and reduces the risk of needle stick injury.     

地塞米松联合硼替佐米对老年多发性骨髓瘤的治疗效果

目的 分析地塞米松联合硼替佐米对老年多发性骨髓瘤的治疗效果。方法 选择2014年1月—2016年12月在宿州市市立医院血液科进行诊治的41例老年多发性骨髓瘤患者,随机分为两组,观察组21例,对照组20例。两组均给予沙利度胺和环磷酰胺进行治疗,分别口服沙利度胺100 mg,1次/d,并分别于第1、8、15天静滴环磷酰胺300 mg/m²。同时,对照组于第1~4天静脉滴注地塞米松20 mg。观察组在对照组基础上皮下注射硼替佐米1.3 mg/m²,1次/周,1个疗程为4周,2个疗程后进行综合评价。比较两组的临床治疗效果,检测两组治疗前后的β2微球蛋白、骨髓瘤细胞以及免疫球蛋白水平及不良反应。结果 观察组的有效率为85.71%,明显高于对照组的60.00%,差异有统计学意义（P<0.05）。两组治疗后的β2微球蛋白、骨髓瘤细胞以及免疫球蛋白水平均明显降低,同组治疗前后比较差异有统计学意义（P<0.05）;且观察组明显低于对照组,差异有统计学意义（P<0.05）。两组间各不良反应的发生率无统计学差异,且各不良反应通过停药或给予相应对症处理后均可得到缓解。结论 地塞米松联合硼替佐米治疗老年多发性骨髓瘤的临床效果明显,可作为初治、难治或复发老年多发性骨髓瘤患者的一线治疗方案。     

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.     

Lenalidomide in multiple myeloma: current role and future directions

Importance of the field: Lenalidomide and other new agents are improving survival of multiple myeloma patients. This review describes current data on lenalidomide in myeloma and how the unique properties of lenalidomide may lend its use in new settings, such as maintenance and preventive therapy.

Areas covered in this review: This review covers the activity of lenalidomide in multiple myeloma, efficacy in both newly diagnosed and relapsed/refractory patients, how to manage effectively common adverse events observed with lenalidomide, and its potential use in new settings based on clinical trials published up to 2009.

What the reader will gain: This review describes the mechanism of action of lenalidomide in myeloma which provides the basis for its clinical use in newly diagnosed, relapsed/refractory, and high-risk smoldering myeloma in combination with other agents. Strategies to reduce or effectively manage myelosuppression and thromboembolic events, the main adverse events associated with lenalidomide plus dexamethasone therapy, are also described.

Take home message: Lenalidomide is an oral immunomodulatory drug that is highly effective in treating multiple myeloma, has a favorable safety profile and is now being evaluated as maintenance therapy, preventive therapy and in combination with other new agents.     

AKT as a therapeutic target in multiple myeloma

Introduction: Multiple myeloma remains an incurable malignancy with poor survival. Novel therapeutic approaches capable of improving outcomes in patients with multiple myeloma are urgently required. AKT is a central node in the phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin signaling pathway with high expression in advanced and resistant multiple myeloma. AKT contributes to multiple oncogenic functions in multiple myeloma which may be exploited therapeutically. Promising preclinical data has lent support for pursuing further development of AKT inhibitors in multiple myeloma. Lead drugs are now entering the clinic.

Areas covered: The rationale for AKT inhibition in multiple myeloma, pharmacological subtypes of AKT inhibitors in development, available results of clinical studies of AKT inhibitors and suitable drug partners for further development in combination with AKT inhibition in multiple myeloma are discussed.

Expert opinion: AKT inhibitors are a welcome addition to the armamentarium against multiple myeloma and promising clinical activity is being reported from ongoing trials in combination with established and/or novel treatment approaches. AKT inhibitors may be set to improve patient outcomes when used in combination with synergistic drug partners.