How to treat patients with relapsed/refractory multiple myeloma: evidence-based information and opinions

INTRODUCTION: Relapsed/refractory multiple myeloma (rrMM) remains a difficult condition to treat despite the availability of new drugs. This review aims to provide evidence to guide physicians in the choice of salvage therapy in certain subgroups of patients. AREAS COVERED: The review attempts to present evidence-based information and suggest possible approaches based on data on previous therapies, previous remission duration and toxicity of previous treatments, patient's co-morbidities and disease characteristics at relapse. Unfortunately, little evidence is available; there are no large and/or randomized trials, direct comparisons of drugs or combinations for rrMM patients to draw any definite conclusion. EXPERT OPINION: Almost all the studies presented here suggest that depth of response is a key factor also for patients with rrMM. Identifying the best approach between combinations and sequential therapies remains controversial. Several studies favor the former approach in early relapse as it leads to a higher complete response rate, regardless of previous therapies. However, in both strategies, achieving maximal response should always remain a main goal. Consolidation/maintenance therapy is beneficial both in combination and sequential therapies also in rrMM. Second generation new drugs, such as pomalidomide, carfilzomib, bendamustine and HDAC inhibitors, will probably expand the rescue possibilities also in this setting.     

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.     

Targeted therapy of hepatocellular cancer

Importance of the field: Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide and third leading cause of cancer death. HCC is highly resistant to conventional systemic therapies, and prognosis for advanced HCC patients remains poor. However, identification of signaling pathways responsible for HCC growth and progression such as RAS/RAF/MEK/ERK or PI3K/AKT/mTOR has determined crucial molecular targets and led to development of novel promising targeted therapies.

Areas covered in this review: This article presents molecular mechanisms responsible for development and progression of HCC and strategies aimed to block important molecules involved in signal transduction. It also reviews the clinical studies evaluating efficacy and safety of novel targeted approaches for treatment of this malignancy.

What the reader will gain: Inhibition of molecular targets (ligands, membrane receptors and receptor-associated kinases) represents a promising strategy for treatment of HCC; in the case of sorafenib, this has already been demonstrated to significantly improve survival of advanced HCC patients. This article reviews novel therapeutic approaches that are based on combinations of different targeted agents with or without classic cytotoxic drugs.

Take home message: Despite significant progress, advanced HCC remains an incurable disease, and the overall efficacy of recently approved targeted therapy (sorafenib) remains moderate. It is to be hoped that several ongoing clinical trials evaluating novel targeted approaches for treatment of HCC will lead to further improvement in the management of advanced disease.     

Pharmacotherapy and management strategies for coeliac disease

Introduction: Coeliac disease is a common disease that affects approximately 1% of Northern European and American populations. Evidence suggests it is caused by an inappropriate immune response in genetically susceptible patients to dietary gluten found in wheat, rye, barley and, in a small minority of patients, oats. Treatment involves a lifelong gluten-free diet. This diet limits nutritional variety and is costly and difficult to maintain.

Areas covered: This review covers the current treatment options available and discusses novel emerging therapies for coeliac disease.

Expert opinion: Novel therapies are still in early stages of development and therefore, at present, a gluten-free diet remains the treatment of choice in coeliac disease due to its low side-effect profile. A replacement for a gluten-free diet would be superior to an adjunct; in this case dietary modification of gluten may well have the least side effects, be tolerated by a wider group of coeliac patients and therefore be accepted.

Search terms used: Pubmed, Medline and clinicaltrials.gov were searched with ‘celiac disease’ and ‘therapy’ as MESH terms. Patent database was searched using the term ‘celiac disease’. Conference attendance at DDW Chicago 2011 and Columbia 2010 was also used to gain further information from conference abstracts.     

Emerging drugs for neuroblastoma

Introduction: Neuroblastoma accounts for 8 – 10% of pediatric cancers and is responsible for 15% of childhood cancer deaths. Despite multimodality treatment, the overall survival (OS) and event-free survival (EFS) in high-risk patients remain suboptimal. More than half of children diagnosed with high-risk neuroblastoma either do not respond to conventional therapies or relapse after treatment.

Areas covered: This review discusses about the unmet medical needs for new therapeutic options against high-risk neuroblastoma. New drugs and therapeutic strategies that are under development in clinical trials, which are currently recruiting patients.

Expert opinion: There is a need to improve the response rate of induction chemotherapy, which is not effective in a third of patients and also the other components of the current treatment, little efficacious in avoiding the relapses. Few drugs have been introduced as upfront therapy in the last years. Topotecan, irinotecan and temozolomide are expected to improve the response in high-risk neuroblastoma, but their impact on OS and EFS is unknown. Anti-GD2 antibodies combined with other immunomodulators (IL-2, GM-CSF) are an important advance in the treatment of these children. Nevertheless, the hope is put in the new drugs directed to molecular targets of neuroblastoma. Anti-angiogenic drugs, ALK antagonist and PI3K/Akt/mTOR inhibitors are among the most promising.     

Emerging drugs and alternative possibilities in the treatment of tuberculosis

Introduction: Tuberculosis (TB) remains a global health problem. Drug resistance, treatment duration, complexity, and adverse drug reactions associated with anti-TB regimens are associated with treatment failure, prolonged infectiousness and relapse. With the current set of anti-TB drugs the goal to end TB has not been met. New drugs and new treatment regimens are needed to eradicate TB.

Areas covered: Literature was explored to select publications on drugs currently in phase II and phase III trials. These include new chemical entities, immunotherapy, established drugs in new treatment regimens and vaccines for the prophylaxis of TB.

Expert opinion: Well designed trials, with detailed pharmacokinetic/pharmacodynamic analysis, in which information on drug exposure and drug susceptibility of the entire anti-TB regimen is included, in combination with long-term follow-up will provide relevant data to optimize TB treatment.

The new multi arm multistage trial design could be used to test new combinations of compounds, immunotherapy and therapeutic vaccines. This new approach will both reduce the number of patients exposed to inferior treatment and the financial burden. Moreover, it will speed up drug evaluation.

Considering the investments involved in development of new drugs it is worthwhile to thoroughly investigate existing, non-TB drugs in new regimens.     

Inflammation and the heart – prime time for new therapeutic approaches

Introduction: Atherosclerosis remains one of the main causes of cardiovascular disease.

Areas covered: A brief overview of the work summarized by Berman et al. [Berman JP, Farkouh ME, Rosenson RS. Emerging anti-inflammatory drugs for atherosclerosis. Expert Opin Emerg Drugs 2013;18(2):193-205] on the development of anti-inflammatory drugs to tackle atherosclerosis is provided.

Expert opinion: Indeed, recent data from clinical trials on anti-inflammatory drugs in coronary artery disease highlight the potential of such therapies.     

Emerging drugs targeting human epidermal growth factor receptor 2 (HER2) in the treatment of breast cancer

Introduction: Human epidermal growth factor 2 (HER2) overexpression is present in 20% of breast cancer patients. It is associated with more aggressive disease and worse clinical outcome. New drugs are thus needed. Approved and future treatments will be discussed in this review.

Areas covered: The monoclonal antibodies trastuzumab and pertuzumab, the tyrosine kinase inhibitor lapatinib and the antibody-drug conjugate trastuzmab emtansine are approved for HER2 positive breast cancer. The combination of trastuzumab, pertuzumab and docetaxel is currently the first-line treatment in the metastatic setting. New therapies are still needed due to frequent relapse and resistance. These include mammalian target of rapamycin inhibitors, heat shock protein 90 inhibitors, pan-HER2 tyrosine kinase inhibitors, antibody-drug conjugates, immunotherapy agents (antibodies and vaccines), radioimmunotherapy and HER2 specific affinity proteins. Possible developmental issues are the complexity of the molecular biology of the HER2 positive cancer cell, the occurrence of resistance, toxicity and the high cost.

Expert opinion: The determination of the right sequence of use of old and new therapies remains a challenging issue. The selection of patients who do or don’t benefit from potentially toxic chemotherapy is also difficult. Central nervous system metastases are a common problem in HER2 positive breast cancer that needs to be addressed in future trials.     

Emerging treatments for hepatitis C

Introduction: About 2.35% of the world population can be infected with hepatitis C virus (HCV) responsible for chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Currently available interferon-based medication is successful in up to 75% of the patients infected with HCV genotypes 1, 2 or 3 and lower efficacy in other genotypes. Unfortunately sustained virologic response (SVR) rate in genotype 1 infected non-responders to previous therapy with advanced hepatic fibrosis even after retreatment with the first generation direct acting antivirals (DAA) is about 40% only.

Areas covered: The second generation DAA, which have recently been submitted for registration (Sofosbuvir and Simeprevir) still need combination with PegIFNα and RBV in patients infected with HCV genotype 1. There is a need for more effective antiviral therapy for difficult to treat patients who are interferon intolerant, developed liver cirrhosis or non-responders to previous therapies. Therefore, IFN-free regimens are step for future therapies consisting of combinations of novel investigational DAA and host targeting agents.

Expert opinion: The introduction of novel DAA with a good safety profile and high barrier to resistance can lead to SVR rates exceeding 90% in treatment naïve patients and non-responders to previous therapy infected with different genotypes.     

Safety review of combination drugs for hyperlipidemia

Introduction: Despite statin monotherapy, many high-risk patients are not at recommended low-density lipoprotein cholesterol goals. Moreover, these patients are also likely to exhibit an atherogenic dyslipidemia characterized by decreased high-density lipoprotein cholesterol and elevated triglycerides. As a consequence, combination lipid-altering drug therapies are frequently required to improve the lipid profile. The long-term safety and tolerability of these combination therapies are key determinants for good compliance and cardiovascular benefits.

Areas covered: This review summarizes the safety data published on combination drugs for the treatment of hyperlipidemia by examining the various combinations with a statin and also the other combination therapies used when statin treatment is not tolerated. The reader will gain insight into the incidence and severity of the major adverse events expected with combination therapies and the recommendations on the use of these combined treatments. A specific focus is made on muscle-related side effects.

Expert opinion: The existing data suggest that ezetimibe, bile acid sequestrants and ω-3 fatty acids appear unlikely to increase the risk of adverse events, particularly myopathy, when used in combination with a statin, even with a high-dose statin. Although the combination of niacin or fenofibrate with moderate-dose statins appears to be safe, prescribing a combination of these drugs with high-dose statins needs caution and requires giving careful information to the patient.     

Emerging drugs for Cushing’s disease

Introduction: Considering the effects of uncontrolled hypercortisolism on morbidity and mortality, there is a clear need for effective medical therapy for patients with Cushing’s disease (CD). Therefore, the search for new medical effective tools remains active, and already promising results have been obtained.

Areas covered: The importance of the design and conduct of trials to validate old drugs or to test new compounds is discussed. The results of the ongoing clinical trials, targeting the specific properties of drugs, such as ketoconazole, LCI699, mifepristone, etomidate and pasireotide, are also reported. The authors also emphasise the advantages and drawbacks of each particular drug, and the potential combined use of agents with complementary mechanisms of action.

Expert opinion: CD is an excellent example of a situation where effective therapy is essential, but where the balance of risk and benefit must be carefully judged. Metyrapone is the drug of choice when rapid control of the hypercortisolaemia is required, ketoconazole represents a good second-line drug, although in the future LCI699 may be a better alternative. Mifepristone can also be used in the rare situation when previous drugs are inappropriate. Etomidate is useful where immediate parenteral action is required. For drugs working directly on the pituitary, cabergoline is occasionally effective and pasireotide can be attempted in patients with mild CD.     

Pharmacotherapy of myelodysplastic syndromes

Importance of the field: Despite the remarkable progress in the treatment of patients with myelodysplastic syndromes (MDS) in the past decade, response to the hypomethylating agents azacitidine and decitabine in non-del(5q) MDS patients remains at ～ 50%, leaving half of patients needing treatment with essentially no options. As biologic insight into the molecular pathways that account for disease evolution and clinical heterogeneity is expanded, the arsenal of potential drugs that may elicit significant response is also increasing. One of the greatest challenges for the treating physician is to decide when to initiate therapy and which therapy (approved drug or newer agents still in clinical trial) is likely to be the most beneficial. While there is no single answer to these issues, there are several approaches that may be considered, and these are addressed in this review.

Areas covered in this review: This review examines the clinical outcomes of the FDA-approved drugs as well as of the promising new therapies that are in current clinical trials.

What the reader will gain: The clinician now has multiple treatment options for patients with MDS. It is important to consider multiple factors before initiating therapy with disease-modifying drugs. This review presents some of the decision-making approaches that are in practice at present.

Take home message: For the first time, various treatment options are available for patients with MDS. In light of the intense efforts now in progress, the next decade promises to be one of hope and excitement for both MDS patients and treating clinicians.     

Emerging therapeutic options for advanced enteropancreatic neuroendocrine tumors

Introduction: Several chemotherapy agents and combinations have proven effective in the therapy of advanced enteropancreatic neuroendocrine tumors (EP-NETs). However, their toxicity can be significant. Recent understanding of the molecular mechanisms of these tumors, especially the central role of tumor angiogenesis, has led to the identification of new therapeutic targets and agents directed at the molecular level.

Areas covered: This paper gives a comprehensive evaluation of the existing therapeutic armamentarium for EP-NETs. Narrated in a historical perspective, this review analyzes the available information on traditional chemotherapy agents, interferon-α and somatostatin analogs, as well as newer therapies and experimental agents.

Expert opinion: Despite recent advances, a curative approach for metastatic EP-NETs is yet to be discovered. To date, sunitinib and everolimus have been shown to impact progression-free survival only in pancreatic NETs, and the duration of this benefit has not yet been established. Further research is necessary to determine whether a combination of these drugs, either together or with other therapies, may yield superior outcomes. Moreover, sequential use of these agents should be explored in an attempt to improve survival. Efficacy of a variety of experimental agents is also being tested in clinical trials.     

Controversies in the pharmacological treatment of Graves’ disease in children

ABSTRACT

Introduction: Graves’ disease (GD) is a disorder, in which auto-immunity against the thyroid- stimulating hormone (TSH) receptor is the pivotal pathogenetic element. This disease may have different clinical manifestations, the most common being thyrotoxicosis. Treatment of this condition differs according to its etiology, but there is currently no evidence-based therapeutic strategy which is universally adopted in all countries.

Areas covered: a systematic review of the updates on the management of pediatric GD was performed using the Pubmed data base until March 2018. Systematic reviews with or without meta-analysis were analyzed using the following terms: Antithyroid drugs, Childhood, Hyperthyroidism, Radioactive iodine, Thyroidectomy.

Expert commentary: As the best way to manage children with GD remains a matter of debate among pediatric endocrinologists, and there is currently no evidence-based therapeutic strategy which is universally adopted, we confirm that the original and prolonged treatment with anti-thyroid drugs (ATDs) remains the mainstay of treatment for juvenile hyperthyroidism. Alternative treatments include radioiodine (RAI) therapy or surgery (total thyroidectomy). We recommend individualizing the therapeutic approach, without prejudices toward radical therapies that become necessary in case of relapse, adverse effects or poor compliance to ATDs. The optimal approach depends on patient or family preference, and specific patient clinical features.     

Pemetrexed disodium in ovarian cancer treatment

Introduction: Current therapies for recurrent ovarian cancer (OC) yield relatively modest improvements in survival. Many drugs are available but recently a renewed interest is addressed on antimetabolite drugs. Pemetrexed (PEM) is a multitargeted antifolate cytotoxic agent mainly used in lung cancer.

Areas covered: This review summarizes the available evidence on the use of PEM in the treatment of OC. This article consists of material obtained via Medline, PubMed and EMBASE literature searches, up to November 2011. Currently available published data on mechanism of action, pharmacokinetics, safety and efficacy of PEM in the treatment of recurrent OC are described.

Expert opinion: Eight trials evaluated the use of PEM in OC patients. Studies using PEM in combination with carboplatin in platinum-sensitive OC suggested that the response rate is similar to other combination therapies. However, based on the absence of randomized trials comparing this doublet with currently used combination treatments, it is difficult to draw conclusions on the efficacy of PEM regimens in these patients. In platinum-resistant OC patients, two studies suggested that PEM alone might have equivalent activity to other single-agent treatment. Further pharmacogenomic and clinical data are warranted to better define the role of PEM in the treatment of recurrent OC.     

Pharmacotherapy of neuroblastoma

Importance of the field: Neuroblastoma, a tumor of the sympathetic nervous system, is the most common extracranial solid tumor of early life. High risk disease in older children remains a therapeutic challenge, despite high-intensity therapy with correspondingly significant short- and long-term toxicities.

Areas covered in this review: We have reviewed therapy for neuroblastoma over the last three decades. This includes cytotoxic chemotherapy, immunotherapy, radionuclides, antiangiogenic compounds, and molecularly targeted agents. We provide a perspective on the incorporation of these drugs into therapy for neuroblastoma.

What the reader will gain: The reader will gain a better understanding of these novel agents and their targets in neuroblastoma. The reader will also gain insight into the need to define through sequential, carefully designed clinical trials, the roles and toxicities of these therapies, especially if the combination of targeted and conventional cytotoxic agents is used.

Take home message: Advanced-stage neuroblastoma in older infants and children remains a disease that is difficult to cure. New, targeted agents may improve both the therapeutic index and the outcome, but are, for the most part, in early development and present a challenge for clinical trial design given both the rarity of this disease and its responsiveness (albeit incomplete) to currently used cytotoxic agents.     

Novel investigational therapies for onychomycosis: an update

Introduction: Onychomycosis is an infection of the nail plate that is prevalent among the ageing population. Onychomycosis is difficult to treat with low initial cure rates, high rates of relapse, and reinfection. Present treatment options include oral and topical therapies, with oral therapies yielding better results. However, there has been a greater emphasis on the development of topical antifungal therapies as they have fewer side effects and drug interactions.

Areas Covered: This review summarizes new and reformulated drugs. Results from in vitro studies to Phase III clinical trials are discussed. Novel drugs include: the oral azole VT-1161, the topical azole efinaconazole, the benzoxaborole tavaborole, reformulations of terbinafine P-3058 and LI-P, novel inhibitor of succinate dehydrogenase ME1111, and off-label use of tazarotene. Enhanced permeation of the morpholine amorolfine through the nail plate is also discussed using ultraviolet (UV) curable gels, and a fractional CO₂ laser.

Expert opinion: Novel topical antifungals and the reformulation of current antifungals have demonstrated marked improvement in nail penetration. Current research has an emphasis on topical therapies due to their minimized risk for adverse effects and higher patient demand. Nevertheless, few topical agents have surfaced in the past few years and the investigation of efficacious combination therapies may become more important.     

Current and prospective pharmacotherapy for autoimmune hepatitis

Introduction: Corticosteroids alone or in combination with azathioprine are the mainstay therapies of autoimmune hepatitis. Suboptimal responses (treatment failure, partial response, drug toxicity), frequent relapse after drug withdrawal, and the emergence of alternative immunosuppressive medications have fueled the pursuit of new treatments. The goals of this review are to present current management strategies and evolving interventions.

Areas covered: PubMed searches from 1970 – 2014 provide the bases for this review. Corticosteroid regimens should be administered until resolution of symptoms, laboratory tests, and liver tissue abnormalities. Treatment failure warrants high doses of the original regimen, and relapse warrants re-treatment followed by long-term maintenance with azathioprine. The calcineurin inhibitors, budesonide, and mycophenolate mofetil are evolving as frontline therapies, and they may be considered as salvage therapies with the exception of budesonide. Rapamycin, rituximab, and infliximab have also rescued refractory patients but experiences are limited. Anti-oxidants, recombinant molecules, mAbs, and modulators of critical cell populations are key prospects.

Expert opinion: Autoimmune hepatitis must be managed by multiple medications that supplement or supplant current regimens depending on the clinical situation. Rescue therapies will emerge as adjunctive interventions to minimize tissue damage (prevent fibrosis and hepatocyte apoptosis) and improve immune tolerance (regulatory T cell manipulations).     

Pasireotide for the treatment of Cushing's disease

Importance of the field: It is important to treat patients with Cushing's disease as rapidly as possible to limit both the mortality and morbidity of the disease. Pituitary surgery remains the treatment of choice, but the rate of cure at long-term follow-up is suboptimal and recurrence rates are high. If surgery fails or relapse occurs, no treatment has proven to be fully satisfactory. Currently available medical therapies are considered a transient and palliative treatment. However, recently there has been renewed interest in medical therapy due to new insights in pathogenetic mechanisms of corticotroph pituitary tumors.

Areas covered in this review: We summarize the pharmacodynamics and possible mechanism of action of pasireotide (SOM230), a novel multireceptor-targeted somatostatin analogue. Pasireotide has a unique binding profile, with high affinity for four of the five somatostatin receptors, especially SSTR₅, the receptor most prevalent in corticotroph tumors.

What the reader will gain: The reader should gain an understanding of preclinical and clinical data supporting the potential use of pasireotide in patients with Cushing's disease.

Take home message: Preliminary data suggest that pasireotide shows promise as a tumor-targeted medical therapy in patients with Cushing's disease. If the efficacy of pasireotide is confirmed by larger studies, this compound may be a useful treatment option not only in patients with severe Cushing's disease, but also in patients with mild hypercortisolism where its efficacy might be more evident.     

Pharmacotherapeutic treatment of germ cell tumors: standard of care and recent developments

Introduction: Testicular germ cell tumors are the most common malignancy among men aged 40 and less. Since the introduction of cisplatin-based combination chemotherapy, germ cell tumors are among the most curable solid tumors with cure rates of 95% in all patients and > 80% in metastatic disease.

Areas covered: Current standards and future developments in GCT treatment, including adjuvant chemotherapy, first line treatment for metastatic disease, and salvage regimens in case of relapse and refractory disease.

Expert opinion: Maintaining therapeutic success while further reducing treatment-related toxicity is paramount. Cancer-specific survival in localized disease approximates 100%. Therefore, orchidectomy followed by active surveillance is the preferred approach for all seminomas and non-seminomas lacking lymphovascular invasion. Non-seminomas with lymphovascular invasion should be offered adjuvant treatment with one cycle of bleomycin, etoposide and cisplatin (BEP). The BEP regimen remains standard of care for metastatic disease, while the role of primary high-dose chemotherapy in case of inadequate tumor-marker decline or presence of high-risk features (i.e. mediastinal origin, non-pulmonary visceral metastases) remains to be elucidated. Several curative salvage chemotherapy combinations are available, i.e. TIP, VeIP, GIP or high-dose carboplatin and etoposide. GOP is the current option of choice in cisplatin-refractory patients. Novel targeted agents failed to improve treatment outcome so far.