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.     

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.     

From cell biology to therapy: ENMD-2076 in the treatment of multiple myeloma

Introduction: Multiple myeloma (MM) remains incurable, indicating the need for continued investigation of innovative strategies. Recent progress in molecular biology has advanced the discovery of novel drugs for MM. ENMD-2076 is an orally bioavailable, multi-target kinase inhibitor with multiple mechanisms of action, including anti-proliferative and pro-apoptotic activity, and anti-angiogenic effects.

Areas covered: In this review, the authors summarize the preclinical in vitro and in vivo data that have formed the rationale for clinical investigation of ENMD-2076 in MM. In addition, the authors review the early clinical results of ENMD-2076 in MM and other malignancies, and speculate on potential avenues of future clinical research in the development of this drug for MM.

Expert opinion: There is a strong preclinical rationale for investigating ENMD-2076 in MM that is confirmed by early clinical results in an ongoing Phase I trial in patients with relapsed or refractory MM. Optimal strategies for developing ENMD-2076 in MM will require better elucidation of its mechanism of action, investigation of biomarkers for response and development of rationale synergistic combinations with other active agents.     

Initial cytoreductive treatment with thalidomide plus bolus vincristine/doxorubicin and reduced dexamethasone followed by autologous stem cell transplantation for multiple myeloma

Background High-dose chemotherapy supported by autologous stem cell transplantation (ASCT) after combined chemotherapy with infusional vincristine/doxorubicin plus dexamethasone is effective in multiple myeloma (MM). Outpatient treatment with bolus vincristine/doxorubicin infusion plus dexamethasone is convenient and has acceptable efficacy and toxicity for MM. Thalidomide has recently been shown to have significant antimyeloma activity. We assessed the efficacy and toxicity of the combination of bolus vincristine/doxorubicin and reduced dose dexamethasone with thalidomide (T-bVAd), administered on an outpatient basis, in untreated MM. Patients and methods Twenty-six patients prospectively received T-bVAd, consisting of intravenous (i.v.) vincristine 0.4 mg plus doxorubicin 9 mg/m², administered as a single bolus on days 1 to 4, dexamethasone 20 mg per os daily for 4 days, and thalidomide 200 mg/day at bedtime. Response assessment was conducted after each 4-week treatment cycle. Patients who achieved response were allowed to proceed to high-dose chemotherapy with ASCT. Results On an intention-to-treat basis, 23 of the 26 patients (88%) responded to treatment, with 16 (61%) achieving complete response (CR), 2 (8%) very good partial response (VGPR) and 5 (19%) partial response. Only three patients (12%) were rated as non-responders. Grade 3 and 4 hematologic toxicities consisted of neutropenia (13%), febrile neutropenia (6%), and thrombocytopenia (4%), without significant nonhematologic events. Of the 23 patients who showed response, 7 proceeded to single ASCT and 9 to tandem ASCT. With median follow-up time of 15.3 months (range, 9–25 months), median event free survival (EFS) and overall survival (OS) have not been reached yet, and OS and EFS rates for patients who achieved complete response after T-bVAd regimen were significantly higher than patients not. Conclusions Induction therapy with T-bVAd, administered as an outpatient regimen, was efficient and relatively well tolerated in the treatment of MM.     

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.     

Medical treatment of small cell lung cancer: state of the art and new development

Introduction: Small cell lung cancer (SCLC) is a rapidly progressive disease that accounts for approximately 15% of all lung cancers. Chemotherapy remains the cornerstone of treatment of SCLC, but in the last two decades, its progress has reached a plateau. Although a significant sensitivity to chemotherapy and radiotherapy is a feature of SCLC, an early development of drug resistance unavoidable occurs during the course of the disease. Second-line treatment for relapsed patients remains a very challenging setting, with a limited clinical benefit.

Areas covered: A thorough analysis of various therapeutic strategies reported in literature for SCLC treatment was performed. This review includes novel therapeutic approaches such as maintenance or consolidation treatments, new chemotherapy agents and targeted therapy.

Expert opinion: Against this background, there is a desperate need for the development of novel active drugs. Among these, amrubicin has also shown more favourable antitumor activity, and is the most promising at present. Concerning targeted agents, these have failed to demonstrate effectiveness for SCLC and a better understanding of the molecular mechanisms is clearly needed. In the future, further investigations are required to clarify the role of novel anti-angiogenic or pro-apoptotic agents and hedgehog pathway inhibitors.     

Overcoming multidrug resistance with nanomedicines

Introduction: Cancer remains the leading cause of death worldwide. Numerous therapeutic strategies that include smart biological treatments toward specific cellular pathways are being developed. Yet, inherent and acquired multidrug resistance (MDR) to chemotherapeutic drugs remains the major obstacle in effective cancer treatments.

Areas covered: Herein, we focused on an implementation of nanoscale drug delivery strategies (nanomedicines) to treat tumors that resist MDR. Specifically, we briefly discuss the MDR phenomenon and provide structural and functional characterization of key proteins that account for MDR. We next describe the strategies to target tumors using nanoparticles and provide a mechanistic overview of how changes in the influx:efflux ratio result in overcoming MDR.

Expert opinion: Various strategies have been applied in preclinical and clinical settings to overcome cancer MDR. Among them are the use of chemosensitizers that aim to sensitize the cancer cells to chemotherapeutic treatment and the use of nanomedicines as delivery vehicles that can increase the influx of drugs into cancer cells. These strategies can enhance the therapeutic response in resistant tumors by bypassing efflux pumps or by increasing the nominal amounts of therapeutic payloads into the cancer cells at a given time point.     

RNA interference for multiple myeloma therapy: targeting signal transduction pathways

Introduction: Multiple myeloma (MM) is a hematological malignancy characterized by infiltration of malignant plasma cells in the bone marrow (BM) and end-organ damage to the bone, BM, kidney and immune system. Although current treatments have improved the treatment of MM, it still remains an incurable disease. RNA interference (RNAi) effectors such as microRNAs and small interference RNAs have shown potential to selectively downregulate genes implicated in the pathology of a range of diseases. Signaling pathways that facilitate growth, survival and migration of MM cells, provide resistance to conventional therapies, and therefore, target these signaling pathways will prove promising for MM treatment.

Areas covered: This review focuses on signaling pathways associated with the development of myeloma cells and how interaction of these cells with the tumor microenvironment impacts disease progression. Together these elements provide potential therapeutic targets for RNAi in the future.

Expert opinion: Recent advances in oncogenomic studies have revealed the molecular pathogenesis of MM, thus providing new therapeutic targets for RNAi therapy. Pre-clinical evidence suggests that non-viral delivery technology offers the potential to translate this concept into the next generation of RNAi-based therapeutics for MM.     

Therapeutic targeting of EGFR in malignant gliomas

Importance of the field: Despite the improved prognosis for many cancer patients, the survival of those with malignant gliomas (MGs) remains dismal. Even with aggressive intervention, including surgery, chemotherapy and radiotherapy, the overall 2-year survival rate is only 25% in the most optimistic series, and 5-year survival rates are consistently in the low single digits. Therefore, it is evident that novel therapeutic paradigms are necessary to overcome the inherent limitations of conventional treatments. EGFR gene overexpression can be found in 40 – 50% of patients with MGs, whereas its expression is very low in normal brain. Therapeutic targeting of EGFR has indicated clinical success in the treatment of MGs.

Areas covered in this review: The purpose of this review is to discuss the current status of several EGFR-targeted therapies in MGs patients and address the efficacy of these drugs as monotherapy or in combination with other drugs and/or treatments. We also emphasize the lessons learned and the future perspectives in the development of EGFR-targeted therapies for MGs.

What the reader will gain: A more comprehensive understanding of the molecular, structural and biological characteristics of EGFR and the mechanisms of action of EGFR-targeted antagonists will most likely contribute to the successful use of strategies of EGFR-targeted therapy in the clinic.

Take home message: Therapeutic targeting of EGFR include anti-EGFR mAbs, small-molecule EGFR tyrosine kinase inhibitors, peptide vaccination therapy and other therapeutic strategies. Each EGFR antagonist has its own advantages and limitations in terms of BBB crossing, ease of delivery, combination therapies and potential toxicity. Therefore, a multiple approach combining different agents that target EGFR signaling at multiple levels seems to have potential as future therapeutics for MGs, once the technical and safety issues unique to each of the approaches are overcome.     

Preclinical models for pediatric solid tumor drug discovery: current trends,challenges and the scopes for improvement

Introduction: The enhancement in pediatric cancer survival achieved in the past few decades has been confined to low- and moderate-risk cancers, whereas no notable improvement in survival was observed in high-risk and advanced-stage childhood cancers. High attrition rate of candidate drugs in clinical trials is a major hurdle in the development of effective therapies for pediatric solid tumors. In order to reduce the failure rate of candidate drugs in clinical trials, more effective strategies are needed to enhance the predictability of preclinical testing.

Areas covered: The authors have described the current trends in preclinical drug development for treating pediatric solid tumors. Furthermore, the authors review their limitations and the available remedies, with regards to choice of models, pharmacokinetic considerations and the criteria for assessing the long-term efficacy of a candidate drug.

Expert opinion: In many solid tumors, common differences between pediatric and adult cancers have been observed, and therefore, clinical trials for pediatric solid tumors must be conducted on the basis of preclinical observations in pediatric solid tumor models. There is a need to invest in extensive preclinical testing on pediatric solid tumor models. None of the preclinical models can fully recapitulate the human cancers. Therefore, these limitations must be considered while conducting a preclinical trial. The dose and schedule of drugs used for preclinical testing must be clinically relevant. While testing the efficacy of drugs, the markers of apoptosis, drug resistance, hypoxia and tumor-initiating cells can inform us about the long-term therapeutic response of a cancer.     

Current immunosuppressive treatment after kidney transplantation

Introduction: Since 1995, several immunosuppressive drugs have entered the field of organ transplantation: tacrolimus, mycophenolate and the mTOR-inhibitors. Now treating physicians have a choice.

Areas covered: The authors review the important studies on immunosuppressive drugs used at present after kidney transplantation, published in the last three decades. This review also discusses the available evidence for selecting one of the calcineurin inhibitors, antiproliferative agents and induction therapy. Interesting new drugs are discussed briefly.

Expert opinion: Calcineurin inhibitors (CNIs) are considered, especially in de novo transplantation, to be the most effective maintenance drugs to prevent acute rejection. Combining CNI with mycophenolate or an mTOR-inhibitor has made it possible to reduce CNI dose and diminish nephrotoxicity. Uniform treatment regimes according to guidelines are useful but should leave room for adjustment to the needs of individual patients. Longer follow-up studies are needed to decide on the optimal maintenance treatment.     

Long-term survival of high-risk melanoma patients immunized with a Hyper-IL-6-modified allogeneic whole-cell vaccine after complete resection

Objective: Two single arm, Phase II trials (3 and 5) were undertaken to determine the efficacy and toxicity of an adjuvant treatment using Hyper-IL-6 gene-modified whole-cell allogeneic melanoma vaccine in patients with stage IIIB–IV resected disease.

Research design and methods: Ninety-seven and 99 patients were enrolled into Trials 3 and 5, respectively. The primary endpoint was disease-free survival (DFS), and the secondary was overall survival (OS). Vaccine was administered eight times every 2 weeks (induction), every month (maintenance) until patient's death. At progression, maintenance was continued or induction was repeated followed by maintenance.

Results: Median follow-up was 10.5 and 6.2 years for Trials 3 and 5, respectively. No grade 3 or 4 toxicities were observed. An extension of DFS and OS was observed, when compared with historical non-treated controls. DFS probability at 5 years for Trials 3 and 5 was, respectively, 54.8% and 40.6% for stage IIIB, 25.0% and 24.0% for IIIC, and 8.5% and 17.7% for IV. OS probability at 5 years was, respectively, 66.7% and 56.3% for IIIB, 43.8% and 39.8% for IIIC, and 26.1% and 41.2% for IV.

Conclusions: Continuous vaccination, regardless of the disease progression, re-induction, and immunization of patients until death resulted in patients a long-term survival.     

Emerging protein kinase inhibitors for the treatment of multiple myeloma

ABSTRACT

Introduction: Significant advances have been made during the last two decades in terms of new therapeutic options but also of innovative approaches to diagnosis and management of multiple myeloma (MM). While patient survival has been significantly prolonged, most patients relapse. Including the milestone approval of the first kinase inhibitor imatinib mesylate for CML in 2001, 48 small molecule protein kinase (PK) inhibitors have entered clinical practice until now. However, no PK inhibitor has been approved for MM therapy yet.

Areas covered: This review article summarizes up-to-date knowledge on the pathophysiologic role of PKs in MM. Derived small molecules targeting receptor tyrosine kinases (RTKs), the Ras/Raf/MEK/MAPK- pathway, the PI3K/Akt/mTOR- pathway as well as Bruton tyrosine kinase (BTK), Aurora kinases (AURK), and cyclin-dependent kinases (CDKs) are most promising. Preclinical as well as early clinical data focusing on these molecules will be presented and critically reviewed.

Expert opinion: Current MM therapy is directed against general vulnerabilities. Novel therapeutic strategies, inhibition of PKs in particular, are directed to target tumor-specific driver aberrations such as genetic abnormalities and microenvironment-driven deregulations. Results of ongoing Precision Medicine trials with PK inhibitors alone or in combination with other agents are eagerly awaited and hold the promise of once more improving MM patient outcome.     

Update on immunomodulatory drugs (IMiDs) in hematologic and solid malignancies

Introduction: Thalidomide and its analogs [small molecule immunomodulatory drugs (IMiDs®)] are among the most successful new therapeutic agents of recent years. Thalidomide is now an integral part of multiple myeloma (MM) therapy. Lenalidomide has been approved for the treatment of patients with relapsed MM and 5q-myelodysplastic syndromes (MDS). Currently, more than 400 clinical trials are evaluating the activity of lenalidomide, alone or in combination with other conventional or novel therapies, in newly diagnosed MM and 5q-MDS. Based on their broad range of actions within the tumor microenvironment, IMiDs are currently also evaluated in a wide variety of additional hematologic and solid malignancies.

Areas covered: This paper reviews the historic development of thalidomide and its derivatives and presents novel insights into their mode of action. Moreover, it discusses up-to-date clinical trials investigating IMiDs and potential future research and therapeutic perspectives in MM and other malignancies.

Expert opinion: Although IMiDs have emerged as powerful agents for the treatment of hematologic and solid tumors, more preclinical and clinical studies are urgently needed both to increase our knowledge of their mechanisms of action, and to optimize their clinical use, in order to further improve the patient's quality of life and survival.     

Present and future therapeutic options for locally advanced and metastatic renal cell carcinoma

Introduction: Locally advanced or metastatic renal cell carcinoma (RCC) is notoriously chemo- and radioresistant, leaving immunotherapy as the only treatment option. In recent years, targeted therapies have offered significant increases in progression-free survival (PFS). Despite this, the majority of patients soon develops resistant disease and finally succumbs. The need to implement treatment strategies that improve overall survival while having an acceptable safety profile is imperative.

Areas covered: This review provides information on the efficacy of recently studied treatment strategies for advanced RCC. These include sequential and combination therapy of established drugs as well as data on agents in early clinical development. The Medline and ASCO database were searched for clinical trials on medical therapy of advanced RCC from 2004 until May 2010. Data on targeted therapies, including tyrosine kinase inhibitors, vascular endothelial growth factor inhibitors, mammalian target of rapamycin inhibitors, and antiepidermal growth factor receptor agents are summarized.

Expert opinion: Improvements in response rates and PFS in patients with advanced RCC have been observed with new treatment strategies. The benefit in overall survival is less clear and needs further evaluation. Toxicity represents a concern especially in combination regiments.     

Emerging drugs for perennial allergic rhinitis

Introduction: Allergic rhinitis (AR) is a high-prevalence disease, sustained by an IgE-triggered reaction with histamine release, followed by an inflammatory response which involves cells, mediators, cytokines and adhesion molecules. According to its duration, AR can be either intermittent or persistent. In the persistent form, the inflammatory component usually predominates.

Areas covered: The current therapeutic strategy is based on antihistamines, antileukotrienes and on corticosteroids (which broadly act on inflammation). Allergen-specific immunotherapy is a biological response modifier that affects the immune response to allergens in a broad sense. The available pharmacotherapy is overall effective in controlling symptoms and inflammation, but safety concerns may be present (especially for prolonged treatments), and a proportion of patients remain uncontrolled. The available therapeutic innovations, as derived from the most recent literature are reviewed herein.

Expert opinion: In the last years there have been very few innovative approaches to optimize the management of AR. These include new histamine receptor antagonists, combination therapy and strategies to selectively block relevant signaling pathways of the allergic reaction. Some more promising advances have been shown for allergen immunotherapy, where a number of new strategies are currently under development.     

An overview of investigational new drugs for treating ankylosing spondylitis

Introduction: Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic condition. Pharmacological treatment relies on nonsteroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs (in case of peripheral involvement) and anti-TNF agents in case of inadequate response. To date, there are no alternate options, and about 30% of the patients do not adequately respond to anti-TNF therapy.

Areas covered: This overview is based on recent publications and programmed studies. The author provides the reader with an overview of AS, its current management and provide details of novel insights into the disorder. From there, the authors highlight novel treatments under investigation before providing their expert opinion on the field.

Expert opinion: The first results with biodrugs targeting the IL-23/Th17 pathway are encouraging, and secukinumab will likely be available in the forthcoming years to treat AS. Other targets may be evaluated in this axis. The author believes that additional head-to-head studies are needed find the place of these new drugs in AS treatment strategies. Further studies are also needed to better evaluate their long-term outcome and safety.     

Impact of United States Food and Drug Administration's boxed warnings on adverse drug reactions reporting rates and risk mitigation for multiple myeloma drugs

Purpose: To determine the relationship between boxed warnings issuance by the US Food and Drug Administration (FDA) and the proportional reporting rates of the associated adverse drug reactions (ADRs) to the FDA's Adverse Event Reporting System (FAERS) for multiple myeloma (MM) drugs.

Methods: We compiled a list of all FDA approved MM drugs and identified their associated ADR boxed warnings, through FDA's website and physician desk reference. Drugs that were issued boxed warnings after their market launch were included in the analysis, i.e., melphalan, thalidomide, vincristine, carmustine and doxorubicin. For each drug/ADR boxed warning combination, we retrieved all reported cases from the FAERS and calculated their Empiric Bayes Geometric Means (EBGMs), in pre- and post-boxed warning periods. Chi-square tests were performed to compare serious adverse drug events before and after boxed warnings for all drug/ADR combinations.

Results: A total of 10 drug/ADR boxed warning combinations were identified, of which EBGM signals increased for six combinations after a boxed warning was issued. Reports of serious adverse drug events also increased significantly (p < 0.05).

Conclusion: Boxed warnings were associated with increased FAERS reporting, indicating increased awareness of ADRs for MM drugs. Proactive pharmacovigilance programs, such as the FDA's Mini-Sentinel Project, may improve timeliness of detection of rare ADRs.     

First-line bevacizumab,cisplatin and vinorelbine plus maintenance bevacizumab in advanced non-squamous non-small cell lung cancer chemo-naïve patients

Objective: The aim of this study was to evaluate efficacy and safety of first-line treatment with bevacizumab, cisplatin and vinorelbine and bevacizumab maintenance in non-squamous, non-small cell lung cancer (NSCLC).

Research design and methods: Forty-nine patients with stage IIIB plus pleural effusion or stage IV NSCLC were included in a Phase II clinical trial. Treatment consisted of 3-week cycles of bevacizumab (15 mg/kg on day 1), cisplatin (80 mg/m² on day 1) and vinorelbine (25 mg/m² on days 1 and 8). After 6 cycles, non-progressing patients received bevacizumab maintenance therapy. The primary end point was progression-free survival (PFS), calculated using the Kaplan–Meier method.

Results: Thirteen (29%) of 45 evaluable patients presented a partial response. PFS and overall survival were 6.0 months (95% confidence interval (CI) 4.5 – 7.5) and 14.7 months (95% CI 8.4 – 21), respectively. Fourteen patients (28%) experienced grade 3 – 4 neutropenia and 7 (14%) experienced febrile neutropenia during the combination treatment. During the maintenance phase, the most frequent grade 3 – 4 adverse event was hypertension. Neither grade 3 – 4 thrombocytopenia nor toxic death was observed.

Conclusions: The studied regimen achieved a similar efficacy to other regimens containing platinum doublets. The data provide further evidence that bevacizumab may be used in combination with multiple standard platinum-based doublets in this setting.