Novel agents and new therapeutic approaches for treatment of multiple myeloma

This review summarizes the therapeutic strategies and the drugs actually in development for the management of myeloma patients. Multiple myeloma is caused by the expansion of monoclonal plasma cells and secretion of M-protein(immunoglobulins, Bence Jones protein and free light chains). Multiple myeloma still remains an incurable disease with a high incidence rate in the elderly, despite the introduction of several new therapeutic agents(bortezomib, lenalidomide and thalidomide) which have changed its natural history. The high heterogeneity of this disease leads to large differences in clinical responses to treatments. Thus, the choice of the best treatment is a difficult issue. However, the introduction of new drugs has made it possible to achieve high response rates and good quality respons-es with long-term disease control. Interactions between tumor cells and their bone marrow microenvironment play a pivotal role in the development, maintenance, and progression of myeloma, inducing also drug resistance. These knowledges have improved treatment options, leading to the approval of new drugs which not only target the malignant cell itself, but also its microenvironment. These agents are in preclinical/early clinical evaluation and they appear to further improve disease control, but their use is still not approved outside of clinical trials.

Identify multiple myeloma stem cells: Utopia?

Multiple myeloma(MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells(CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activate stemness signaling(Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs.

The bone marrow niche landscape:a journey through aging,extrinsic and intrinsic stressors in the haemopoietic milieu

Inflammation and its effects in the bone marrow microenvironment represent a paradigmatic condition in which the hematopoietic niche and the immune systems,thought to properly sustain blood cell production and distinguish between friend and foe,can actively sustain a corrupted neighborhood within a chronic aberrant inflamed state.The bone marrow niche hijacks the physiologic hematopoiesis.The interactions between the hematopoietic stem cells and the niche in the bone marrow are critical determinants of quiescence.We examined several approaches to confront the available evidence;three key points emerged,pointing to the chronic inflammation process,especially the chronic infection and systemic inflammatory states,as leading causes of hematopoietic stem cell depletion.Clonal hematopoiesis,defined as a relative expansion of individual clones,is caused by somatic alterations in essential hematopoietic genes,which increase stem cell fitness.Moreover,terminal differentiation plays a significant role in progenitor loss and inflammatory signaling,promoting clonal selection and clonal hematopoiesis conditions.Specific myeloid malignancies as paradigmatic examples are discussed as a condition associated with inflammation,including the 5q-syndrome,Philadelphia negative myeloproliferative neoplasms,and chronic myeloid leukemia.Aging with increased fitness and hematopoietic stem cell attrition,extrinsic stress,enhanced stressor-specific fitness,and intrinsic defect across the hematopoietic process represent the route for novel insights in defective hematopoiesis.The discussion in this review also points out that the hematopoietic niches’inflammatory stimulation may affect differentiation patterns and the function of downstream cells.