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.     

Results of the first bortezomib-based induction therapy in the treatment of multiple myeloma

This is a comment on the IFM 2005 – 01 Phase III trial that compared, for the first time, the efficacy and the safety of a bortezomib-containing induction regimen with conventional chemotherapy before autologous stem-cell transplantation in multiple myeloma (MM) patients. Between 2005 and 2008, 482 patients were randomized to vincristin/doxorubicin/dexamethasone (VAD), VAD + dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) consolidation, bortezomib + dexamethasone and bortezomib + dexamethasone + DCEP consolidation followed by autologous stem-cell transplantation. The trial was conducted in 89 sites in France, Belgium and Switzerland. The novel agent-based induction therapy (bortezomib/dexamethasone) achieved higher complete remission (CR)/nearCR rates, as well as less treatment-related mortality, but higher rates of polyneuropathy than the conventional chemotherapy-based induction therapy (VAD/VAD + DCEP). The difference in progression-free survival (PFS) difference was not statistically significant but a trend to longer PFS was seen to favor to the bortezomib-containing regimen; bortezomib and dexamethason (BD) was, therefore, proposed to be a standard of care by the authors of the study.     

Emerging drugs in multiple myeloma

The treatment of multiple myeloma has seen significant changes from the time of the initial use of cytotoxic agents such as melphalan, to the introduction of high-dose chemotherapy and stem cell transplantation, and most recently the era of novel targeted agents. These new drugs have rapidly become the mainstay of therapy of this disease and transformed the treatment paradigm, leading to improvements in survival and quality of life. Existing therapeutic options include agents such as thalidomide, bortezomib and lenalidomide, either used alone or in combination with standard agents, including glucocorticoids, and in conjunction with high-dose chemotherapy supported with stem cell transplantation. Several other targeted agents have demonstrated exciting preclinical activity, and are presently being tested in early Phase I and II clinical trials. This review summarizes the role of novel therapeutic agents in multiple myeloma, and the promising effect of multiple new agents in development.     

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.     

New generation pharmacotherapy in elderly multiple myeloma patients

Background: Observational databases have demonstrated that the overall prognosis of multiple myeloma patients has markedly improved over the past decade, yet the greatest strides have been attained in younger rather than older patients. Objective: To review recent clinical trials that include new generation agents (thalidomide, lenalidomide and bortezomib) and autologous stem cell transplantation in older multiple myeloma patients. Results: Conventional regimens such as melphalan plus prednisone can be improved with the addition of thalidomide or bortezomib: more patients attain complete and near-complete remission, and progression-free survival rates are nearly doubled. In addition, autologous hematopoietic stem cell transplantation studies show that this treatment approach can be used successfully in selected older myeloma patients in whom the toxicity profile of autotransplant and resulting overall survival may be similar to that obtained in the younger patient group. Conclusions: In the advanced-age population, implementation of new therapies results in significant benefits in older as well as younger patients.     

多发性骨髓瘤并发静脉血栓的研究进展

多发性骨髓瘤是源于浆细胞的恶性肿瘤,易发生静脉血栓栓塞。多发性骨髓瘤患者血液的高凝状态、年龄、静脉血栓栓塞病史、肥胖、合并疾病以及中心静脉置管、免疫调节剂及化疗药物的应用均使静脉血栓栓塞的危险性增加。研究表明,多发性骨髓瘤患者治疗时采取抗凝药物等预防血栓措施可有效降低静脉血栓栓塞的发生率。     

New pharmacotherapy options for pulmonary arterial hypertension

Introduction: Epoprostenol was the first targeted therapy available for the treatment of pulmonary arterial hypertension (PAH). Since then great advances in our knowledge of the disease have been made and the spectrum of therapeutic options for PAH has expanded. After an overview of current available treatments, this article describes the new pharmacotherapy options and their place in the management of PAH.

Areas covered: This paper is based on a literature search and the review of studies published on PAH pharmacotherapy using the MEDLINE database.

Expert opinion: The last decade has been particularly important in PAH management with the emergence of six new molecules, the development of novel routes of administration and improvement of pharmacokinetics. Moreover, pediatric formulations have been developed. However, further research is required to inform clinicians regarding optimal choices of combination therapies (progressive add-on therapy or upfront combination therapy, selection of associated molecules regarding the patient’s profile...), to continue to improve the quality of life of patients with new drugs and to reach the ultimate goal of curing the disease.     

The pharmacologic management of multiple myeloma in older adults

Introduction: Multiple myeloma is a disease predominately affecting older adults. Pivotal to treating older adults is understanding their physiologic differences compared to younger subjects and how the complexity of therapies has an impact upon this patient population.

Areas covered: Herein, the authors address the efficacy of chemotherapy regimens, decision-making for older adults, chemotherapy-associated toxicity and the approach to management. This review focuses on the complex treatment of older multiple myeloma patients and management of treatment-related adverse events.

Expert opinion: Balancing efficacy and managing toxicity is a challenge for older myeloma patients. This group is more susceptible to treatment toxicities due to a higher incidence of pre-existing comorbidities and underlying diminished physiologic reserve. Intensive therapies such as autologous hematopoietic cell transplant (AHCT), however, still should be considered for all multiple myeloma patients, including older adults. The continued development of novel therapies and increased use of multi-drug regimens has changed the treatment paradigms yet understanding the complexity of the aging adult in the context of various drugs is warranted.     

社交恐惧症药物治疗新进展

药物治疗是社交恐惧症(SP)的主要治疗手段,除传统的苯二氮艹卓类(BZ)抗焦虑药外,一些新型抗抑郁药因具有抗抑郁和抗焦虑双重作用,近年来被推荐用于SP的治疗,特别是选择性5羟色胺(5HT)再摄取抑制剂与选择性5HT和去甲肾上腺素(NA)再摄取抑制剂。一些新型的非苯二氮艹卓类抗焦虑药因疗效好,不良反应少,应用日趋广泛。本文重点对BZ和非苯二氮艹卓类抗焦虑药以及新一代抗抑郁药、部分抗惊厥药治疗SP的进展情况进行综述。     

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.     

Current treatments for renal failure due to multiple myeloma

Introduction: Renal impairment (RI) is one of the most common complication of multiple myeloma (MM). RI is present in almost 20% of MM patients at diagnosis and in 40%-50% of patients during the course of their disease.

Areas covered: Biology along with tools for diagnosis and management of RI are reported in this paper. Papers published in PubMed and reported abstracts up to May 2016 were used.

Expert opinion: Moderate and severe RI increases the risk of early death; thus rapid intervention and initiation of anti-myeloma treatment is essential and improves renal outcomes in RI patients. Bortezomib and dexamethasone triplet combinations are the current standard of therapy for MM patients with acute kidney injury due to cast nephropathy; they offer high rates of both anti-myeloma response and renal recovery. Thalidomide and lenalidomide may be used in bortezomib refractory patients. In the relapsed/refractory setting additional treatment options such as carfilzomib, pomalidomide and monoclonal antibodies are available; however, there is limited data for their effects on patients with RI. High dose melphalan with autologous stem cell transplantation should be considered in otherwise eligible patients with RI. Finally, high cut-off hemodialysis membranes do not seem to offer significant additive effects on anti-myeloma therapies.     

The latest pharmacotherapy options for type 1 diabetes

Introduction: Pharmacotherapy of type 1 diabetes (T1D) is mainly restricted to insulin treatment. Insulin analogues have replaced human insulin sometimes without reason. A broader approach is needed.

Areas covered: Insulin and insulin analogues, but also other available hormone therapies and drugs, based on literature in PubMed are included in this study.

Expert opinion: At diagnosis, T1D patients should, when resources allow, participate in clinical trials aiming at preservation of beta cell function, for example, with combination therapies involving auto-antigen/s. In very young children insulin pump is recommended, when enough resources for ALL patients; in older patients pump or multiple insulin therapy is recommended. Human insulin still has a place, with insulin analogues on special indications. Patients with pronounced insulin resistance might need Metformin, and Glitazones need more studies. Incretins, for example, GLP-1 may be of interest in patients with residual C-peptide. Amylin will probably be restricted to highly motivated patients. IGF-1 also requires more studies. C-peptide may be a hormone, probably part of future treatment. Glucosoxidase inhibitors might be considered in obese patients. Whether drugs increasing glucosuria will be of clinical value in T1D remains to be shown. In summary, insulin replacement is not enough for several patients. A broader pharmacotherapy is needed, at onset, and later when metabolic control needs improvement.     

Pharmacological therapy for atrial fibrillation: current options and new agents

Atrial fibrillation is the most commonly encountered cardiac arrhythmia and is directly or indirectly responsible for considerable mortality, morbidity and health care burden. The available medical therapy is limited by marginal efficacy, end-organ toxicity, as well as the potential for undesired ventricular proarrhythmia. Elucidation of the potential mechanisms that underlie the development of atrial fibrillation may provide new targets for drugs that circumvent the problems associated with current medical options. This review focuses on the current and potential future pharmacological agents directed at rhythm control and maintenance of sinus rhythm.     

Emerging therapies for multiple myeloma

Multiple myeloma (MM) is a clonal plasma cell malignancy clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. There are an estimated 750,000 people diagnosed with MM worldwide, with a median overall survival of 3 – 5 years. Besides chromosomal aberrations, translocations, and mutations in essential growth and tumor-suppressor genes, accumulating data strongly highlight the pathophysiologic role of the bone marrow (BM) microenvironment in MM pathogenesis. Based on this knowledge, several novel agents have been identified, and treatment options in MM have fundamentally changed during the last decade. Thalidomide, bortezomib, and lenalidomide have been incorporated into conventional cytotoxic and transplantation regimens, first in relapsed and refractory and now also in newly diagnosed MM. Despite these significant advances, there remains an urgent need for more efficacious and tolerable drugs. Indeed, a plethora of preclinical agents awaits translation from the bench to the bedside. This article reviews the scientific rationale of new therapy regimens and newly identified therapeutic agents – small molecules as well as therapeutic antibodies – that hold promise to further improve outcome in MM.     

不同剂量硼替佐米治疗多发性骨髓瘤的近期疗效观察

目的观察不同剂量硼替佐米治疗多发性骨髓瘤的近期疗效和不良反应。方法 41例多发性骨髓瘤患者均给予硼替佐米为主的化疗方案治疗(硼替佐米1.0~1.3mg·m-1·d-1,第1、4、8、11天;多柔比星20mg/d,第1~4天;地塞米松20~40mg/d,第1~4天;联合或不联合沙利度胺100mg每晚睡前服用;21d为1个疗程)。根据硼替佐米应用剂量分为高剂量组(1.3mg·m-1·d-1)20例和低剂量组21例(1.0mg·m-1·d-1),患者分别接受1~6个疗程的治疗。结果 41例患者给予不同剂量硼替佐米化疗方案后,高剂量组总有效率为85.0%高于低剂量组的71.4%,差异有统计学意义(P<0.05)。高剂量组出现不良反应14例,低剂量组出现不良反应10例,2组比较差异无统计学意义(P>0.05)。结论硼替佐米应用高剂量(1.3mg·m-1·d-1)时对多发性骨髓瘤的临床疗效更好,虽有一定不良反应,但患者耐受良好。     

Current and developing synthetic pharmacotherapy for treating relapsed/refractory multiple myeloma

Introduction: The introduction of novel agents has significantly improved multiple myeloma (MM) patient outcome during the last two decades. MM received the most drug approvals for any one malignancy during this time period, both in the United States as well as in Europe.

Areas covered: Proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies are prototype drug classes, which target both specific MM cell functions, as well as the tumor supportive bone marrow microenvironment, and represent current cornerstones of MM therapy. Importantly, the unprecedented extent and frequency of durable responses, in relapsed/refractory multiple myeloma (RRMM), in particular, is predominantly based on the combinatorial use of these agents with conventional chemotherapeutics or representatives of other drug classes. This article will summarize past landmark discoveries in MM that led to the dramatic progress of today’s clinical practice. Moreover, developing strategies will be discussed that are likely to yet improve patient outcome even further.

Expert opinion: Despite significant therapeutic advancements, MM remains an incurable disease. With several novel agents in the preclinical and early clinical pipeline, among those novel CD38 and BCMA mAbs, immune checkpoint inhibitors, as well as ricolinostat, selinexor, venetoclax, CAR-T cells, and vaccines, further advances in MM patient outcome are expected in the near future.     

Current pharmacotherapy options for labor induction

Introduction: Labor induction is now reported to occur in up to 30 – 40% of obstetrical patients. There are a number of pharmacological options available to facilitate labor induction, including oxytocin and analogues of prostaglandins E1 and E2, which have particular utility when labor induction necessitates cervical ripening, as when labor induction occurs in the context of an unfavorable cervix.

Areas covered: This paper reviews acceptable pharmacological options for labor induction, especially when cervical ripening is required. These options include oxytocin and a number of prostaglandin formulations using dinoprostone and misoprostol. It also covers several analyses of published clinical trials (Phase-III) describing evidence of effectiveness.

Expert opinion: Oxytocin is best used when labor needs to be induced in the context of a favorable cervix. When the cervix is not favorable, cervical ripening using prostaglandins should precede labor induction. Either dinoprostone or misoprostol are superior to oxytocin alone for cervical ripening. However, judicious, careful considerations need to be made at the outset of labor induction so as to balance maternal and fetal risks, and these should be guided by institutional policies that reflect the evidence-base.     

Current pharmacotherapy options for labor induction

Introduction: Labor induction is now reported to occur in up to 30 - 40% of obstetrical patients. There are a number of pharmacological options available to facilitate labor induction, including oxytocin and analogues of prostaglandins E1 and E2, which have particular utility when labor induction necessitates cervical ripening, as when labor induction occurs in the context of an unfavorable cervix. Areas covered: This paper reviews acceptable pharmacological options for labor induction, especially when cervical ripening is required. These options include oxytocin and a number of prostaglandin formulations using dinoprostone and misoprostol. It also covers several analyses of published clinical trials (Phase-III) describing evidence of effectiveness. Expert opinion: Oxytocin is best used when labor needs to be induced in the context of a favorable cervix. When the cervix is not favorable, cervical ripening using prostaglandins should precede labor induction. Either dinoprostone or misoprostol are superior to oxytocin alone for cervical ripening. However, judicious, careful considerations need to be made at the outset of labor induction so as to balance maternal and fetal risks, and these should be guided by institutional policies that reflect the evidence-base.