The Route of the Malignant Plasma Cell in Its Survival Niche: Exploring “Multiple Myelomas”

Abstract

Growing evidence points to multiple myeloma (MM) and its stromal microenvironment using several mechanisms to subvert effective immune and anti-tumor responses. Recent advances have uncovered the tumor-stromal cell influence in regulating the immune-microenvironment and have envisioned targeting these suppressive pathways to improve therapeutic outcomes. Nevertheless, some subgroups of patients include those with particularly unfavorable prognoses. Biological stratification can be used to categorize patient-, disease- or therapy-related factors, or alternatively, these biological determinants can be included in a dynamic model that customizes a given treatment to a specific patient. Genetic heterogeneity and current knowledge enforce a systematic and comprehensive bench-to-bedside approach. Given the increasing role of cancer stem cells (CSCs) in better characterizing the pathogenesis of solid and hematological malignancies, disease relapse, and drug resistance, identifying and describing CSCs is of paramount importance in the management of MM. Even though the function of CSCs is well-known in other cancer types, their role in MM remains elusive. With this review, we aim to provide an update on MM homing and resilience in the bone marrow micro milieu. These data are particularly interesting for clinicians facing unmet medical needs while designing novel treatment approaches for MM.

Drug resistance in multiple myeloma: Soldiers and weapons in the bone marrow niche

“…Indeed, bortezomib resistance is also developed through spliced X-box binding protein 1 (Xbp1) suppression, which reduces immunoglobulin production and consequently endoplasmic reticulum (ER) stress and susceptibility to PI ( 166 ). These findings emphasize the tumor progenitor makeup in MM and its contribution to disease progression and drug resistance ( 167 ).…”

Lactate trafficking inhibition restores sensitivity to proteasome inhibitors and orchestrates immuno‐microenvironment in multiple myeloma

“…The progression from the early stages of the disease as monoclonal gammopathy of undetermined significance (MGUS) and smouldering MM (SMM) to MM is drastically affected by the tumour microenvironment (TME) 3 . Indeed, it is well established that TME acts as a determinant player in tumour cell growth, adaptation and resistance to anti‐cancer therapy 4–7 . In this context, malignant PCs rapidly reprogram their metabolism to adapt to cellular stress, prevent apoptosis and escape immune system 8 .…”

“… 3 Indeed, it is well established that TME acts as a determinant player in tumour cell growth, adaptation and resistance to anti‐cancer therapy. 4 , 5 , 6 , 7 In this context, malignant PCs rapidly reprogram their metabolism to adapt to cellular stress, prevent apoptosis and escape immune system. 8 Concomitantly, cancer metabolic reprogramming reshapes TME towards a hypoxic, acid (due to high lactate concentration) and nutrient depleted niche, thereby supporting tumour proliferation and immune evasion.…”

Editorial: ‘Engineering the Tumor Immune Microenvironment’ Special Issue

“…Additional review topics include an investigation of the barriers faced by adoptive T-cell therapies in solid tumors, which is presented by Fuchsl and Krackhardt [ 10 ], as well as considerations of the role of perhaps lesser-known components of the TIME, such as tertiary lymphoid structures discussed by Vaghjiani and Skitzki [ 11 ], the role of the stromal microenvironment in multiple myeloma explored by Solimando et al [ 12 ], and the role of microglia and immunosuppression in glioblastoma (GBM), discussed by Mormino and Garofalo [ 13 ]. We are hopeful that these reviews will help to point the way forward, contributing to the development of new therapies or approaches for these highly refractory tumor types.…”