A Comprehensive Biological and Clinical Perspective Can Drive a Patient-Tailored Approach to Multiple Myeloma: Bridging the Gaps between the Plasma Cell and the Neoplastic Niche

Abstract

There is a broad spectrum of diseases labeled as multiple myeloma (MM). This is due not only to the composite prognostic risk factors leading to different clinical outcomes and responses to treatments but also to the composite tumor microenvironment that is involved in a vicious cycle with the MM plasma cells. New therapeutic strategies have improved MM patients’ chances of survival. Nevertheless, certain patients’ subgroups have a particularly unfavorable prognosis. Biological stratification can be subdivided into patient, disease, or therapy-related factors. Alternatively, the biological signature of aggressive disease and dismal therapeutic response can promote a dynamic, comprehensive strategic approach, better tailoring the clinical management of high-risk profiles and refractoriness to therapy and taking into account the role played by the MM milieu. By means of an extensive literature search, we have reviewed the state-of-the-art pathophysiological insights obtained from translational investigations of the MM-bone marrow microenvironment. A good knowledge of the MM niche pathophysiological dissection is crucial to tailor personalized approaches in a bench-bedside fashion. The discussion in this review pinpoints two main aspects that appear fundamental in order to gain novel and definitive results from the biology of MM. A systematic knowledge of the plasma cell disorder, along with greater efforts to face the unmet needs present in MM evolution, promises to open a new therapeutic window looking out onto the plethora of scientific evidence about the myeloma and the bystander cells.

New Insights into Diffuse Large B-Cell Lymphoma Pathobiology

“…Monocytic myeloid-derived suppressor cells and tumor-associated macrophages (TAMs) play a crucial role in the “stromal 2” signature [ 19 , 20 ]. Overall, as in other hematological niche addicted malignancies [ 21 , 22 , 23 , 24 ], the current evidence pinpoints that DLBCL disease progression is a multistep transformation process characterized by a complex vicious cycle between lymphoma cells and the tumor milieu.…”

The Anti-VEGF(R) Drug Discovery Legacy: Improving Attrition Rates by Breaking the Vicious Cycle of Angiogenesis in Cancer

“…Circulating EPCs move to hypoxic sites and contribute to the generation of new blood vessels, and the inhibition of VEGF prevents the mobilization of EPCs to the tumor site [ 22 , 23 ]. Hypoxia triggers the differentiation of tumor-infiltrating myeloid cells to M2-pro-angiogenic tumor-associated macrophages (TAMs), the recruitment of EPCs, genetic instability in tumor endothelial cells, and the selection of more invasive metastatic tumor cell clones, resistant to anti-angiogenic agents [ 24 , 25 , 26 ].…”

Cancer-Associated Angiogenesis: The Endothelial Cell as a Checkpoint for Immunological Patrolling

“…Multiple myeloma (MM) is a clonal proliferation of malignant plasma cells (PCs) accumulating and disseminating in the bone marrow (BM) with ensuing induction of focal skeletal lesions and osteoporosis driving myeloma bone disease, anemia, renal insufficiency, hypercalcemia [ 72 ], higher infection rates [ 73 , 74 , 75 ], and secondary life-threatening complications [ 76 , 77 , 78 ]. MM represents an ideal model of colonization and interaction of tumor cells in the bone microenvironment [ 79 , 80 , 81 ], where the immune-milieu [ 82 , 83 ] and aberrant angiogenesis shape a permissive ecosystem, supporting disease progression via a plethora of autocrine [ 84 , 85 ] and paracrine loops [ 86 , 87 ].…”