Multiple Myeloma - A New Era of Treatment Strategies

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Although multiple myeloma has probably been present for centuries, the first welldocumented case was published less than 160 years ago. The famous patient, Thomas Alexander McBean excreted large amounts of a peculiar protein that was studied by Henry Bence Jones. Jones was a well-recognized physician as well as chemist. Less than a half-century ago, Bence Jones protein was found to consist of monoclonal light chains. Otto Kahler described a patient with autopsy-proven multiple myeloma; this patient survived eight years after the onset of symptoms despite the absence of effective therapy. The discovery of Roentgen’s rays facilitated the diagnosis of multiple myeloma. Serum electrophoresis followed by immunofixation allowed physicians to readily make the diagnosis. Melphalan was introduced for therapy half a century ago but little progress was made until autologous stem cell transplantation became available almost 20 years ago. This was followed by the introduction of the “novel” agents thalidomide, bortezomib and lenalidomide in the last decade.

Multiple myeloma (MM) is a yet incurable malignancy of mature B lymphocytes that account for approximately 1% of all cancers in Whites and 2% of all cancers in Blacks in the United States (US). Demographic patterns of MM incidence and mortality are well described, but more precise characterization of individuals at the greatest risk for MM to have proven elusive. A vast body of literature on the etiology of MM identifies a few likely risk factors—including family history of MM or MGUS and the potentially modifiable risk factor, obesity-but also illustrates the inconsistencies that arise in the epidemiologic study of rare and lethal malignancies due to inherent methodologic and practical challenges. The study of risk factors for the benign precursor condition called monoclonal gammopathy of undetermined significance (MGUS) lags behind that of MM. However, recent studies on MGUS have provided intriguing new insights on the natural history of monoclonal gammopathy, including demonstration of the occurrence of MGUS prior to essentially all diagnoses of MM and the suggestion that MGUS and MM share several etiologic factors. Improved characterization of risk factors for MM, MGUS, and MGUS progression is necessary to inform the development of MM prevention strategies. In the following review, we offer a summary of the current understanding of the descriptive epidemiology and etiology of MM and MGUS and suggest areas of focus for future research.

Multiple myeloma (MM) is a malignant disorder due to clonal proliferation of plasma cells in the bone marrow in association with elevated serum or urine monoclonal paraprotein levels. MM is associated, particularly in the most advanced stages of the disease, with severe complication, like lytic bone lesion, anemia, immunodeficiency and renal failure. Despite advances in the understanding of the disease and the use of high-dose chemotherapy, MM remains an incurable disease.

From a genetic standpoint, MM development is a multistep process characterized by the presence of a series of chromosomal abnormalities and complex translocations, involving known oncogenes and tumor-suppressor genes. Genomic aberrations are present with increasing frequency as disease progresses. There is an increasing evidence that, in addition to genomic abnormalities, epigenetic dysregulation plays a pivotal role in MM development, making the picture even more complex.

Multiple Myeloma (MM) is a clonal plasma cell malignancy with a highly heterogeneous genetic background, characterized by bone marrow (BM) plasmacytosis, production of monoclonal proteins, osteolytic bone lesions, renal disease, anemia, hypercalcemia, and immunodeficiency. The inclusion of thalidomide, bortezomib, and lenalidomide into conventional cytotoxic and transplantation regimens, first in relapsed and refractory and now also in newly diagnosed MM, has fundamentally changed treatment in MM during the last decade and steadily improved MM patient outcome.

High-dose therapy plus autologous stem-cell transplantation (ASCT) is currently the standard of care for patients with multiple myeloma up to the age of 65 without severe comorbidities. The introduction of novel agents (thalidomide, bortezomib, lenalidomide) has already dramatically improved the ASCT results. Two or three-drug bortezomib-based induction treatments are superior to the classical VAD. Post-ASCT treatment with thalidomide and probably in the near future with lenalidomide further improves the response rate and the progression-free survival. The use of novel agents both before and after ASCT yields unprecedented complete plus very good partial response rates and progression-free survival. These new strategies partially overcome poor prognosis related to t(4;14) and/or del(17p).

At the same time, novel agents without ASCT have also improved the outcome in patients who are not candidates for ASCT and yield complete plus very partial response rates that are comparable to those achieved with high-dose therapy. Therefore the place of ASCT in the treatment of MM (upfront or after progression) should be addressed in future randomized trials

In this context, the role of allogeneic stem-cell transplantation remains limited since it still induces a high incidence of treatment-related morbidity and mortality despite the use of reduced conditioning regimens.

More than 80% of multiple myeloma (MM) patients present with bone involvement frequently develop serious complications that negatively affect both quality of life and overall survival. Bone disease in MM is a consequence of unbalanced remodeling resulting in the development of osteolytic lesions. Generalized osteoclast (OC) activation is the underlying mechanism coupled with osteoblast (OB) inhibition. The molecular events leading to this imbalance of the OC/OB axis is a result of the interaction of MM cells with bone cells within the bone marrow milieu and consequent cytokine deregulation. Here we will discuss the pathogenesis, clinical sequelae and therapeutic strategies for the treatment of MM bone disease. We will focus on novel therapeutic strategies under investigation to restore bone homeostasis. Such approaches are being studied not only with the goal of alleviating morbidity from bone disease but also for their resultant anti-MM activity.

Patients with multiple myeloma have a high rate of complications related to their underlying disease. This includes anemia, renal failure, complications related to bone disease such as hypercalcemia, bone pain and fractures, infection and renal insufficiency. Adequate supportive care is therefore an essential part of each anti-myeloma treatment and can significantly improve overall survival and the quality of life of multiple myeloma patients. This review focuses on the management of specific complications associated with advanced multiple myeloma.

Treatment of multiple myeloma has undergone a significant change in the past decade due to a combination of better understanding of the disease biology, improved risk stratification models and several very effective therapies. As a result, the survival of patients with myeloma nearly doubled during this time period. However, patients eventually become refractory to current therapies and the disease remains incurable even with aggressive treatment approaches. As a result it is important to continue to develop new therapies for the disease, ideally based on better understanding of the basic disease pathophysiology. In fact several promising drugs are currently undergoing clinical evaluation for myeloma, and these drugs are at various stages of development. In this chapter, we summarize the ongoing clinical trials in the treatment of symptomatic myeloma, many of which likely will lead to effective treatments in the near future. Broadly these trials can be classified into three groups; (i) new drugs from drug classes shown to have efficacy in myeloma, (ii) new classes of drugs and (iii) combinations of new and old drugs. Other trials in myeloma are also examining different aspects of disease, including use of many of these drugs in the setting of smoldering myeloma to reduce risk of progression, use of new and current drugs in maintenance and consolidation therapy setting, as well as new drugs that are being examined as part of supportive care for myeloma.

Multiple myeloma (MM) is a plasma cell malignancy that characteristically involves extensive infiltration of bone marrow (BM), with the formation of plasmacytomas, as clusters of malignant plasma cells inside or outside the BM milieu. Despite limits to our understanding of the molecular events of neoplastic transformation in MM, substantial advances have been made in understanding the biology of the disease through the study of the BM microenvironment, which appears to be fundamental for the proliferation, survival, and resistance of myeloma; providing the preclinical evidences for targeting MM cells and BMSCs as an anti-tumor strategy in this disease.

Angiogenesis is a constant hallmark of multiple myeloma (MM) progression and has prognostic potential. It is induced by plasma cells via angiogenic factors with the transition from monoclonal gammopathy of undetermined significance (MGUS) to MM, and probably with loss of angiostatic activity on the part of MGUS. Soluble angiogenic factors are elevated in the bone marrow and peripheral blood samples form MM patients. The pathophysiology of MM-induced angiogenesis involves both direct production of angiogenic cytokines by plasma cells and their induction within the bone marrow microenvironment cells. The latter are secreted by stromal cells and promote plasma cell growth, survival and migration, as well as paracrine cytokine secretion and angiogenesis in the bone marrow milieu. More recently, a direct involvement of bone marrow macrophages and mast cells in vasculogenic mimicry has been demonstrated, thus contributing together with circulating endothelial cells and endothelial precursor cells (EPCs) to the MM neovascularization. Finally, controversial data are available concerning the correlation between angiogenesis and disease stage and prognosis.

Multiple myeloma (MM) is a complex disease which strongly relies on a network of humoral and cellular interactions within the human bone marrow milieu. Although outcomes of anti-MM treatments have improved over the past decade, the disease is still incurable. Translational research for the development of novel therapeutic approaches against MM requires experimental preclinical models able to recapitulate the disease microenvironment. Over the last few years, a variety of murine MM models have been developed. These models have significantly improved our understanding of the disease and led to the development of new therapeutics. We here review the most known models of MM and discuss both advantages and pitfalls.

The development of multiple myeloma (MM) is a complex multi-step process involving both early and late genetic changes in the tumor cell as well as selective supportive conditions by the bone marrow (BM) microenvironment. Based predominantly on our understanding of the functional importance of the MM BM microenvironment and its interrelation with the MM cell, which triggers tumor cell homing, seeding, proliferation, and survival, a multitude of new molecular targets have been identified. The clinical approval of four derived agents, thalidomide, its immunomodulatory derivative Len, the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin have fundamentally changed treatment regimens in MM during the last decade. Moreover, based on a pathophysiologic rationale a multitude of additional agents, most prominently carfilzomib, pomalidomide, vorinostat, and perifosine have demonstrated promising preclinical and early/ advanced clinical activity indicating the evolvement of further treatment advancements in near future.

The unmet need for improved multiple myeloma (MM) therapy has stimulated clinical development of monoclonal antibodies (mAbs) targeting either MM cells or cells of the bone marrow (BM) microenvironment. In contrast to small-molecule inhibitors, therapeutic mAbs present the potential to specifically target tumor cells and directly induce an immune response to lyse tumor cells. Unique immuneeffector mechanisms are only triggered by therapeutic mAbs but not by small molecule targeting agents. Although therapeutic murine mAbs or chimeric mAbs can cause immunogenicity, the advancement of genetic recombination for humanizing rodent mAbs has allowed large-scale production and designation of mAbs with better affinities, efficient selection, decreasing immunogenicity, and improved effector functions. These advancements of antibody engineering technologies has largely overcome the critical obstacle of antibody immunogenicity and enabled the development and subsequent Food and Drug Administration (FDA) approval of therapeutic Abs for cancer and other diseases.

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