Enhanced cross‐priming of naive CD8+ T cells by dendritic cells treated by the IMiDs® immunomodulatory compounds lenalidomide and pomalidomide

The IMiDs^® immunomodulatory compounds lenalidomide and pomalidomide are agents with anti‐inflammatory, immunomodulatory and anti‐cancer activity. An excellent success rate has been shown for multiple myeloma in phase I/II clinical trials leading to Food and Drug Administration approval of lenalidomide. One mechanism by which these drugs could enhance anti‐tumour immunity may be through enhanced dendritic cell (DC) function. Thalidomide, a compound structurally related to lenalidomide and pomalidomide, is known to enhance DC function, and we have investigated whether its analogues, pomalidomide and lenalidomide, also have functional effects on DCs. We used mouse bone marrow‐derived DCs treated with 5 or 10 μm pomalidomide, or lenalidomide from day 1 of culture. Treatment with IMiD^® immunomodulatory compounds increased expression of Class I (H2‐Kb), CD86, and pomalidomide also increased Class II (I‐Ab) expression in bone marrow‐derived DCs, as measured by flow cytometry. Fluorescent bead uptake was increased by up to 45% when DCs were treated with 5 or 10 μm pomalidomide or lenalidomide compared with non‐treated DCs. Antigen presentation assays using DCs primed with ovalbumin, and syngeneic T cells from transgenic OTI and OTII mice (containing MHC restricted, ovalbumin‐specific, T cells) showed that both pomalidomide and lenalidomide effectively increased CD8⁺ T‐cell cross‐priming (by up to 47%) and that pomalidomide alone was effective in increasing CD4⁺ T‐cell priming (by 30%). Our observations suggest that pomalidomide and lenalidomide enhance tumour antigen uptake by DCs with an increased efficacy of antigen presentation, indicating a possible use of these drugs in DC vaccine therapies.     

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.     

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.     

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.     

Emerging drugs for Waldenström's macroglobulinemia

Introduction: Waldenström's macroglobulinemia (WM) is a rare but distinct B-cell lymphoproliferative disorder characterized by lymphoplasmacytic bone marrow infiltration and IgM monoclonal paraproteinemia. Alkylators or nucleosides analogs, often in combination with rituximab, are the most commonly used drugs, but WM will relapse and even salvage treatments may fail.

Areas covered: We present recent advances on the treatment of WM, focusing on drugs that are under clinical investigation and for which data indicate promising activity and positive future prospects. Bortezomib is a proteasome inhibitor that eventually becomes a major treatment option for WM. Everolimus and perifosine which target mTOR (mammalian target of rapamycin) and Akt, respectively, of the PI3K/AKT/mTOR pathway showed some activity. Bendamustine, a novel alkylating agent is active, especially in combination with rituximab. Immunomodulatory drugs can act synergistically with rituximab but are toxic. Targeting surface antigens of the lymphoplasmatic cells have shown promising results.

Expert opinion: Combinations of novel drugs with established agents are feasible and increase response rates but whether there will be an increase in the survival of patients with WM needs further investigation. The toxicity profile is an important determinant for the feasibility of these drugs in patients with WM.     

Pharmacotherapy of large B-cell lymphoma

Background: Constituting approximately 30% of lymphoid malignancies, diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma in adults worldwide. The clinical and biologic heterogeneity that exists in DLBCL suggests that this entity might actually be comprised of several distinct neoplasms that could require different therapeutic approaches. DLBCL was considered incurable until combination chemotherapy became available. Objective: Current treatment strategies for the treatment of untreated and relapsed advanced-stage DLBCL are reviewed; novel treatments for DLBCL are discussed. Methods: Relevant literature was identified using the PubMed search engine and by reviewing abstracts from major conference proceedings. Results/conclusion: Recently, novel therapeutic strategies, including the incorporation of immunotherapy to combination chemotherapy, have improved outcome for patients with DLBCL with cure rates exceeding 50%, especially in younger patients.     

Novel immunomodulatory compounds in multiple myeloma

Introduction: The treatment options for patients with multiple myeloma (MM) remain limited. Immunomodulatory agents (IMiDs), such as thalidomide and lenalidomide, have changed the landscape in the treatment of patients with MM while newer IMiDs such as pomalidomide are showing promise in early clinical trials.

Areas covered: This review focuses on the biologic rationales of IMiDs and the clinical results supporting their use in MM. It includes data on the new IMiD, pomalidomide and also explores the possible utility of combining IMiDs with other agents. A PubMed search and abstracts from oncology scientific meetings (ASCO and ASH) of articles related to IMiDs and MM was conducted.

Expert opinion: IMiDs have shown clinical activity as single agents and in combination. Thalidomide was the first in class drug. Lenalidomide has a better toxicity profile than thalidomide. Pomalidomide may overcome resistance to lenalidomide indicating differences in their mechanisms of action and resistance. Molecular biomarkers may allow us to identify patients who will respond to IMiDs.     

Dexamethasone plus lenalidomide in treatment of multiple myeloma

Combination of lenalidomide with dexamethasone(LD) is of high effectiveness for treatment of multiple myeloma(MM),resulting in an improved overall survival,response rate,and time to progression in relapsed or refractory MM.Adverse events,especially venous thromboembolism,were generally well tolerated.In addition, lenalidomide plus dexamethasone is a potential therapy in maintenance of myeloma.     

Lenalidomide and its role in the management of multiple myeloma

Treatment of multiple myeloma has changed in recent years. Advances in the understanding of the pathogenesis of the disease and the mechanism of drug resistance have led to the development of novel effective biological treatment agents such as thalidomide and bortezomib. Lenalidomide is an oral analogue of thalidomide that lacks the neurotoxic side effects associated with the parent drug, and has shown significant antimyeloma activity. Lenalidomide has now been approved by the US FDA and the European Medicines Agency for use in combination with dexamethasone in patients with at least one prior therapy. Several trials are testing lenalidomide-based regimens in both newly diagnosed and relapsed patients. This review summarizes the profile of lenalidomide and its current role in the treatment of multiple myeloma.