The multiple myeloma treatment landscape: international guideline recommendations and clinical practice in Europe.

INTRODUCTION: Guidelines provide recommendations on the management of multiple myeloma (MM), but there are no standard algorithms for the choice and sequencing of treatments. As a result, there is widespread variation in the interpretation and implementation of these guidelines. Areas covered: This review will cover: the real-world data on MM treatment patterns; the approved agents available for the treatment of MM; a comparative summary of the national and international clinical guidelines; a discussion on the impact reimbursement decisions have on treatment availability. Expert commentary: In the future, treatment choices may become even more complex as clonal heterogeneity is better understood in the context of response to treatment, and next-generation agents become available. Although information on real-world practice patterns can provide further guidance, to date, few studies have generated data on patients treated with the newer agents in real-world settings. Furthermore, the translation of guideline recommendations into clinical practice across Europe is inconsistent. Additional real-world data are therefore vital to understanding current clinical practice patterns, so that new agents can be effectively incorporated into existing treatment strategies. Such information may aid the development of better guidance, which will ultimately help to ensure that patients receive the best possible care.

New Agents in Multiple Myeloma: An Examination of Safety Profiles.

Numerous treatments are available for relapsed and/or refractory multiple myeloma (MM), with safety profiles varying across drug classes and across agents within the same class. Thus, it is important to understand the toxicities of each antimyeloma agent when making treatment decisions. Neutropenia is commonly associated with lenalidomide and pomalidomide, and may be common with histone deacetylase (HDAC) inhibitors, but is relatively unusual with thalidomide, bortezomib, and carfilzomib. Infection was common in trials of lenalidomide and pomalidomide, and upper respiratory tract infection and pneumonia have been seen with carfilzomib. Cardiac toxicity was observed with thalidomide and may occur with proteasome inhibition. Thromboembolic complications occur with thalidomide and its derivatives, but are less common with bortezomib. Peripheral neuropathy (PN), an important complication of MM, may be exacerbated by bortezomib and thalidomide, and was also observed with lenalidomide. In contrast, PN is rarely observed with carfilzomib and pomalidomide. Renal impairment reduces the clearance of lenalidomide but does not seem to affect substantially the pharmacokinetics of pomalidomide, carfilzomib, or bortezomib. Several therapies have recently been approved, such as the oral proteasome inhibitor ixazomib, the HDAC inhibitor panobinostat, and the monoclonal antibodies elotuzumab and daratumumab. Others are still in clinical development, including the HDAC inhibitors romidepsin and vorinostat, with safety data continuing to emerge. Therapy decisions should consider safety profiles in association with pre-existing comorbidities and toxicities from previous therapeutic regimens. Optimal treatment selection and the management of toxicities will result in fewer patients requiring dose reductions and treatment discontinuations, ultimately leading to improved outcomes.

Recent progress in relapsed multiple myeloma therapy: implications for treatment decisions.

The availability of novel therapies for the treatment of multiple myeloma has had a dramatic impact on the depth of response that can be expected on initial treatment. Despite these advances, disease relapse remains inevitable in most patients and brings with it a different set of priorities for therapy. The most recent wave of novel agents may have a particular impact in the relapsed setting. In this review, we examine the evidence currently available from clinical trials for the use of novel agents, particularly in the formation of triplet therapy. We consider data supporting the addition of the proteasome inhibitors carfilzomib and ixazomib, or the monoclonal antibodies elotuzumab or daratumumab, to a treatment backbone of lenalidomide and dexamethasone. The clinical data set is less well developed for the addition of a third agent to the combination of bortezomib and dexamethasone; nonetheless, data are presented supporting the addition of the histone deacetylase inhibitor panobinostat, or elotuzumab or daratumumab. While acknowledging the lack of head-to-head data on which to base comparisons between the numerous regimens, we collate the latest data in order to provide a basis on which to make clinical decisions in this rapidly advancing field.

How have evolutions in strategies for the treatment of relapsed/refractory multiple myeloma translated into improved outcomes for patients?

Although multiple myeloma (MM) remains incurable, the introduction of novel agents has improved clinical outcomes dramatically over the past 15 years. Response rates have risen from ∼30% with single agents to up to 90% with combination therapies. The immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, and the proteasome inhibitor bortezomib, form the foundations for treatment of relapsed and/or refractory MM (RRMM). Newer agents, such as the IMiD pomalidomide, the histone deacetylase inhibitor panobinostat and the proteasome inhibitors carfilzomib and ixazomib, as well as the monoclonal antibodies daratumumab and elotuzumab, have further improved overall response rates in these patients. Importantly, increased response rates have been observed in heavily pretreated patients. The availability of highly effective and tolerable drugs may offer alternative treatment strategies to those who are unsuitable for treatment with thalidomide, lenalidomide or bortezomib. Improving tolerability of treatment regimens and lengthening progression-free intervals has been shown to significantly improve health-related quality of life for patients living with RRMM.

Vinflunine in platinum-pretreated patients with locally advanced or metastatic urothelial carcinoma: results of a large phase 2 study.

BACKGROUND: The activity and safety of vinflunine was evaluated in patients with locally advanced or metastatic urothelial carcinoma (UC) who developed disease progression within 12 months of platinum-containing chemotherapy. METHODS: Patients with UC were eligible if they received a prior platinum-based regimen in the neoadjuvant/adjuvant setting or as first-line treatment for advanced/metastatic disease and had developed disease progression within 12 months. Vinflunine was administered intravenously every 3 weeks. Patients with Karnofsky performance status of 80 or 90, impaired renal function, prior pelvic irradiation, or age>or=75 years received an initial dose of 280 mg/m2, which was escalated to 320 mg/m2 in Cycle 2 if well tolerated. All other patients received an initial dose of 320 mg/m2. The primary endpoint was response rate defined by an independent response review committee (IRRC). RESULTS: Per the IRRC, 22 patients achieved a partial response, with a response rate of 15% (95% confidence interval, 9%-21%) with a median duration of response of 6.0 months. Sixty-four (42%) patients had stable disease. The median progression-free survival was 2.8 months, and the median overall survival was 8.2 months. Myelosuppression was the most frequent adverse event, with grade 3 of 4 (adverse events were evaluated according to the National Cancer Institute Common Toxicity Criteria [version 2.0] guidelines) neutropenia reported in 58% of the patients. Grade 3 of 4 febrile neutropenia occurred in 10 (7%) patients. Nonhematologic treatment-related events (grade 3 of 4) were generally manageable and included constipation (17%), asthenia/fatigue (13%), ileus (5%), and abdominal pain (5%). No cumulative toxicity was observed. CONCLUSIONS: Vinflunine demonstrates moderate activity in patients with platinum-pretreated UC. Toxicity is manageable and noncumulative.