Immunomodulatory drugs in multiple myeloma: from molecular mechanisms of action to clinical practice

Multiple myeloma (MM) is a clonal disorder of plasma cells that is considered incurable using the currently available treatments. Cytogenetic, molecular and proteonomic techniques have contributed toward a better understanding of the pathophysiology and prognostic factors of this heterogeneous malignancy, whose management has rapidly evolved over the years. The introduction of thalidomide, and the development of safer and more effective thalidomide analogues, represents the major therapeutic advances. Thalidomide, initially used in the treatment of MM because of its angiogenic properties, has considerable therapeutic activity (alone or in combination with other drugs) at all stages of the disease. However, a number of new analogues, such as lenalidomide and pomalidomide, have been developed and are known as "immunomodulatory drugs" (IMIDs). Although they are analogues of thalidomide, they have direct anti-tumor properties, a better tolerability profile and specific activity in both relapsing refractory MM and newly diagnosed disease. The mechanisms of action of IMIDs are still being investigated, but recent studies suggest that, in addition to their anti-angiogenic activity, they have anti-inflammatory and immunomodulatory properties, and directly and indirectly target tumor activity by interfering with various components of the bone marrow (BM) micro-environment. In this paper, we review the pharmacology, mechanisms of action, pre-clinical and clinical efficacy, and the current status of IMIDs in the treatment of MM.     

Immunological effects of thalidomide and its chemical and functional analogs

Thalidomide has recently shown considerable promise in the treatment of a number of conditions, such as leprosy and cancer. Its effectiveness in the clinic has been ascribed to wide-ranging properties, including anti-TNF-alpha, T-cell costimulatory and antiangiogenic activity. Novel compounds with improved immunomodulatory activity and side effect profiles are also being evaluated. These include selective cytokine inhibitory drugs (SelCIDs), with greatly improved TNF-alpha inhibitory activity, and immunomodulatory drugs (IMiDs) that are structural analogs of thalidomide, with improved properties. A third group recently identified within the SelCID group, with phosphodiesterase type 4-independent activity, is in the process of being characterized in laboratory studies. This review describes the emerging immunological properties of thalidomide, from a historical context to present-day clinical applications, most notably in multiple myeloma but also in other cancers, inflammatory disease, and HIV. We also describe the laboratory studies that have led to the characterization and development of SelCIDs and IMiDs into potentially clinically relevant drugs. Early trial data suggest that these novel immunomodulatory compounds may supercede thalidomide to become established therapies, particularly in certain cancers. Further evidence is required, however, to correlate the clinical efficacy of these compounds with their known immunomodulatory, antiangiogenic, and antitumor properties.     

Hairy cell leukemia and multiple myeloma: Two distinct entities or a single two-phase disease

Hairy cell leukemia (HCL) and multiple myeloma (MM) originate from mature B-cell and they are characterized by different clinical symptoms and treatment. Their clinical outcome is also different. The introduction of 2-CdA makes HCL a potentially curable disease, but MM still remains incurable despite a therapeutic progress made in the recent years. We report a male patient who simultaneously developed HCL and MM. He was treated with combined therapy including 2-CdA and thalidomide and this approach resulted in complete remission (CR) of HCL and partial response (PR) of his MM. This patient continued MM treatment with CTD regimen (cyclophosphamide, dexamethasone, thalidomide) and he achieved >90% reduction of serum monoclonal protein. The attempt of stem cell collection failed and autologous transplantation has not been performed. Currently, one year off therapy he is remaining in very good PR of his MM and in CR of HCL. The possible explanations for the development of these two disorders have been discussed.     

Gene therapy for multiple myeloma

Prognosis of multiple myeloma (MM) remains insufficient despite the intervention of high dose chemotherapy with auto- or allo- hematopoietic stem cell transplantation and the advent of molecular target drugs such as thalidomide, lenalidomide, and bortezomib. Further development or new concepts of therapeutic approaches are still required for MM treatment. Current standard protocol for MM treatment does not include gene delivery method or oncolytic virus approaches. Since MM is a disorder originated from B cell lineage, it involves immunological aspects in both pathogenesis and clinical manifestations. Therefore, the comprehension of immunology as well as oncology is essential to exploit new therapeutic approaches. Recently, novel therapeutic concepts for MM have been emerging. In this review, we present current progress of gene therapy related to MM treatments as well as the overview of MM treatment history.     

TNFalpha blockade in human diseases: mechanisms and future directions

Tumor necrosis factor-alpha (TNFalpha) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFalpha antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFalpha antibodies are effective in other IMIDs. Early efforts at understanding how TNFalpha antagonists act in IMIDs centered on their ability to neutralize soluble TNFalpha or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFalpha blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFalpha antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFalpha antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFalpha antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.     

Novel therapeutic approaches for multiple myeloma

Summary: Multiple myeloma (MM) affects 15 000 new patients annually in the US, with 50 000 total patients, and remains incurable. Our preliminary in vitro and animal studies suggest a role for MM–host interactions in regulating MM cell growth, drug resistance, and migration in the bone marrow. Importantly, treatment strategies which target mechanisms whereby MM cells grow and survive in the bone marrow, including thalidomide and its potent immunomodulatory derivatives and proteasome inhibitor PS‐341, can overcome classical drug resistance in preclinical and early clinical studies.     

Thalidomide analogue CC-3052 reduces HIV+ neutrophil apoptosis in vitro

Thalidomide has significant immunomodulatory properties and has been used successfully in the treatment of oral ulcers and wasting in HIV patients. However, its use is limited by its poor bioavailability due to low solubility and short half life in solution, and teratogenic and neurotoxic side-effects. Recently, water-soluble analogues of thalidomide with significantly greater immunomodulatory activity and reduced side-effects have become available. We examined the effect of thalidomide and one analogue, CC-3052, on neutrophil apoptosis following culture for 20 h in vitro. Apoptosis was assessed by reduced CD16 expression and Annexin V binding using flow cytometry. Thalidomide or CC-3052 alone had no effect on neutrophil apoptosis when used at physiological levels. However, when used together with prostaglandin E2 (10-7 M), a potent adenylate cyclase activator, CC-3052 but not thalidomide (both 10-5 M) reduced apoptosis in neutrophils from normal and HIV+ donors. The reduced apoptosis could not be attributed to the ability of CC-3052 to reduce tumour necrosis factor-alpha (TNF-alpha) production, but may be due to its PDE4 inhibitor properties, as it increased [cAMP]i, and mimicked the effect of increasing [cAMP]i using dibutryl cAMP, a membrane-permeable analogue of cAMP. The results suggest a role for thalidomide analogue CC-3052 in reducing persistent activation of the TNF-alpha system in HIV without markedly impairing neutrophil viability.     

Leczenie podtrzymujące w szpiczaku plazmocytowym

Multiple myeloma (MM) remains the incurable disease despite considerable progress in chemotherapy. Optimal way of maintenance treatment is still searching, which it would be maximally effective near acceptable toxicity. The hypothesis about possible successful maintenance therapy, which may improve survival of MM patients became more actual in the face of the incorporate to the studies with maintenance of a new drugs as: thalidomide, lenalidomide and bortesomib. The expectations on the essential progress to establish the optimal bortesomib-based regimen of the maintenance treatment in MM cause the results of the studies with its subcutaneous administration, which proved comparable efficacy with advantage in toxicity profile, especially neurological in comparison to classic intravenous way. The standard of the maintenance treatment for multiple myeloma patients is not established. Individual therapeutic approach after induction-consolidation phase using the most effective drugs is recommended in every case.     

Theoretical basis for the activity of thalidomide

The revival of thalidomide began shortly after the drug was withdrawn from the market because of its teratogenic properties. Therapeutic effects of thalidomide were found accidentally in leprosy patients with erythema nodosum leprosum (ENL). Subsequent research widened the understanding of the activity of thalidomide, and with improved methodology and the augmented background knowledge of immunology it was possible to interpret the properties of thalidomide more coherently. Effects on tumour necrosis factor-α (TNFα) release play an important role in the ability of thalidomide to affect the immune system. Alteration of synthesis and release of cytokines such as interleukin (IL)-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 and interferon-γ is involved in the complex mechanisms of thalidomide. Thalidomide targets leucocytes, endothelial cells and keratinocytes, affecting them in a different manner and at different cellular levels. Changes in the density of adhesion molecules alter leucocyte extravasation and the inflammatory response in the tissue involved. Several mechanisms for the teratogenic action of thalidomide are currently under review, but this mode of action of the drug still remains unclear and we review evidence-based hypotheses for the teratogenicity of thalidomide. Thalidomide shows significant clinical impact in several diseases such as ENL in lepromatous leprosy, chronic graft-versus-host disease, systemic lupus erythematosus, sarcoidosis, aphthous lesions in HIV infection, wasting syndrome in chronic illness, inflammatory bowel disease, multiple myeloma and some solid tumours. In 1998 the US Food and Drug Administration approved thalidomide exclusively for the treatment of ENL, and strict conditions were stipulated for its use in order to prevent teratogenic adverse effects. However, despite the promising findings of thalidomide at the molecular level, namely its anti-TNFα properties and its intercalation with DNA, and activity in clinical trials, there is still a great need for more intensive research.     

POMALIDOMID – nowy immunomodulujący lek w terapii szpiczaka plazmocytowego

Multiple myeloma (MM) is a haematological disease characterized by plasma cells proliferation in bone marrow associated with damage of organs – mainly kidneys and bones. Previous therapies significantly extended the survival of patients, but still relapse is 100%. In February 2013, in USA, the Food and Drug Administration (FDA) introduced to therapy a new immunomodulatory drug – pomalidomide. In European Union this drug under the name IMNOVID was registered in August 2013. The authors review the mechanisms of action, pharmacokinetic and clinical properties of pomalidomide. The data discussed in this article come from publications on clinical trials I, II and III phase. It seems this drug may be a breakthrough in the treatment of MM.     

The intelligent use of systemic glucocorticoids in rheumatoid arthritis

Glucocorticoids (GC) have potent anti-inflammatory and immunomodulatory effects and are widely used in the management of rheumatoid arthritis in combination with other disease-modifying anti-rheumatoid drugs. Concern about the risk of adverse effects may be to some extent misplaced as low to moderate doses of GC have different mechanisms of action and risk profiles compared with high doses. This review discusses the current understanding about the different modes of action of GC, their strong disease-modifying properties and the efforts at improving the therapeutic ratio of GC through the development of new drugs which promise greater safety such as selective GC receptor agonists, liposomal GC and modified-release (MR) prednisone.     

CD38-targeting antibodies in multiple myeloma: mechanisms of action and clinical experience

Introduction: Multiple myeloma (MM) is generally an incurable hematological malignancy with heterogeneous overall survival rates ranging from a few months to more than 10 years. Survival is especially poor for patients who developed disease that is refractory to immunomodulatory drugs and proteasome inhibitors.

Areas covered: This review will discuss the importance of CD38-targeting antibodies for the treatment of MM patients to improve their outcome.

Expert commentary: Intense immuno-oncological laboratory research has resulted in the development of functionally active monoclonal antibodies against cell surface markers present on MM cells. In this respect, CD38-targeting antibodies such as daratumumab, MOR202, and isatuximab, have high single agent activity in heavily pretreated MM patients by virtue of their pleiotropic mechanisms of action including Fc-dependent effector mechanisms and immunomodulatory activities. Importantly, CD38-targeting antibodies are well tolerated, with infusion reactions as most frequent adverse event. Altogether, this makes them attractive combination partners with other anti-MM agents. Daratumumab is already approved as monotherapy and in combination with lenalidomide-dexamethasone as well as bortezomib-dexamethasone in pretreated MM patients. Furthermore, results from studies evaluating CD38-targeting antibodies in newly diagnosed MM patients are also promising, indicating that CD38-targeting antibodies will be broadly used in MM, resulting in further improvements in survival.     

Statins and the vascular endothelial inflammatory response

Statins reduce cholesterol synthesis and are widely used for the treatment of hyperlipidaemia and ischaemic heart disease. Besides their cholesterol-lowering effects, statins also possess broad immunomodulatory and anti-inflammatory properties. Vascular endothelial cells have a crucial role in the pathogenesis of inflammatory disease, and, alongside leukocytes and antigen-presenting cells, represent a key cellular target for statin therapy. Recent studies investigating how these drugs modify endothelial cell function demonstrate that the therapeutic effect of statins can be attributed, in part, to their action on the endothelium. Accordingly, statins attenuate endothelial MHC class II expression, increase endothelial nitric oxide synthase and fibrinolytic activity, decrease leukocyte adhesion and transmigration, and enhance resistance to local injurious stimuli. Many of these effects are brought about by the modulation of small GTPase function and the downregulation of proinflammatory gene expression.     

The role of SLAMF7 in multiple myeloma: impact on therapy

Introduction: Multiple myeloma (MM), a mature B-cell neoplasm, is the second most common hematologic malignancy worldwide. Despite significant improvements in outcome with new therapies, the majority of responding patients will eventually develop resistance to treatment. Furthermore, patients swith disease refractory to both proteasome inhibitors and immunomodulatory drugs (IMiDs) have a poor prognosis.

Areas covered: Several new therapeutic approaches are emerging and immunotherapeutic strategies present an important advance for the treatment of patients with relapsed or refractory MM. Among the monoclonal antibodies under development in MM, those targeting SLAMF7 and CD38 have shown the most consistent benefit in trials to date. In this review, we will specifically focus on elotuzumab (anti-SLAMF7 antibody), and provide a summary of the mechanism of action, the clinical results and the safety profile of this new drug.

Expert commentary: Although elotuzumab has no single agent activity in MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when the agent is added to bortezomib-dexamethasone or lenalidomide-dexamethasone. Furthermore, this agent with its novel mechanism of action can be combined with standard therapies without a significant increase in toxicity. Elotuzumab is a highly effective therapy and future data are necessary to identify the best place for this therapy in the setting of MM.     

Novel immunotherapies for psoriasis.

New insights into the pathophysiology of psoriasis have suggested possibilities for targeted therapeutic intervention. Several novel, systemic immunomodulatory therapies are currently in clinical development and results of recent clinical trials are remarkable. These include approaches targeting antigen presentation and costimulation, T-cell activation and leukocyte adhesion, the action of proinflammatory mediators and the administration of anti-inflammatory cytokines. These trials contribute to our further understanding of the disease, indicating which mechanisms play a greater or lesser part in its development. Moreover, they will lead to new therapeutic options. If psoriasis is considered as a visible model disease for T-cell-mediated disorders characterized by a type-1 cytokine pattern these recent findings might have a more general impact on the treatment of autoimmune disorders.     

Monoclonal antibodies targeting CD38 in hematological malignancies and beyond

CD38 is a multifunctional cell surface protein that has receptor as well as enzyme functions. The protein is generally expressed at low levels on various hematological and solid tissues, while plasma cells express particularly high levels of CD38. The protein is also expressed in a subset of hematological tumors, and shows especially broad and high expression levels in plasma cell tumors such as multiple myeloma (MM). Together, this triggered the development of various therapeutic CD38 antibodies, including daratumumab, isatuximab, and MOR202. Daratumumab binds a unique CD38 epitope and showed strong anti-tumor activity in preclinical models. The antibody engages diverse mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, programmed cell death, modulation of enzymatic activity, and immunomodulatory activity. CD38-targeting antibodies have a favorable toxicity profile in patients, and early clinical data show a marked activity in MM, while studies in other hematological malignancies are ongoing. Daratumumab has single agent activity and a limited toxicity profile, allowing favorable combination therapies with existing as well as emerging therapies, which are currently evaluated in the clinic. Finally, CD38 antibodies may have a role in the treatment of diseases beyond hematological malignancies, including solid tumors and antibody-mediated autoimmune diseases.     

Thalidomide: Mechanisms of Action

The classification of thalidomide as an orphan drug with anti-inflammatory actions has led to its off-label use in conditions refractory to other medications. Although the observed clinical effects of thalidomide suggest it to have immunomodulatory capabilities, the mechanism of action is unclear. Here we review both the positive and negative studies of thalidomide at the bench in order to improve our understanding of the possible mechanisms of this drug in treating a variety of diseases at the bedside. Studies on the effects of thalidomide on the innate and adaptive immune system as well as tumorigenesis and angiogenesis are discussed.     

New therapies in multiple myeloma

The melphalan-prednisone regimen has been considered as standard therapy for patients with multiple myeloma (MM) for many years. Recently, high-dose chemotherapy with stem-cell support has extended progression-free survival and increased overall survival, and it is now considered conventional therapy in younger patients. However, most patients relapse and the salvage treatment is not very effective. New active drugs, including immunomodulatory agents, thalidomide (Thal) and lenalidomide, and the proteasome inhibitor bortezomib, have shown promising anti-myeloma activity. These novel treatments are aimed at overcoming resistance of tumour cells to conventional chemotherapy, acting both directly on myeloma cells and indirectly by blocking the interactions of myeloma cells with their local microenvironment and suppressing growth and survival signals induced by autocrine and paracrine loops in the bone marrow. Thal has been widely studied, mostly in combination regimens in patients with relapsed MM and, more recently, in front-line therapy, showing efficacy in terms of response rate and event-free survival. Bortezomib has been found to possess remarkable activity, especially in combination with other chemotherapeutic agents, in relapsed/refractory and newly diagnosed MM, as well as in patients presenting adverse prognostic factors. Lenalidomide, in combination with dexamethasone, is showing high overall response rates in relapsed and refractory MM and promising results also in first-line therapy. In this paper, the results of the most significant trials with Thal, bortezomib and lenalidomide are reported. Several ongoing clinical studies will hopefully allow the identification of the most active combinations capable of improving survival in patients with MM.     

Thalidomide: mechanisms of action

The classification of thalidomide as an orphan drug with anti-inflammatory actions has led to its off-label use in conditions refractory to other medications. Although the observed clinical effects of thalidomide suggest it to have immunomodulatory capabilities, the mechanism of action is unclear. Here we review both the positive and negative studies of thalidomide at the bench in order to improve our understanding of the possible mechanisms of this drug in treating a variety of diseases at the bedside. Studies on the effects of thalidomide on the innate and adaptive immune system as well as tumorigenesis and angiogenesis are discussed.