Preclinical models of multiple myeloma: a critical appraisal

Abstract

All models discussed here have their defined strengths, but also limitations with respect to their predictive features. Understanding the preclinical models in a more profound way should lead to optimized clinical trials, thereby expanding the therapeutic arsenal and improving patient outcome further.

European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

“…Moreover, since several groups have demonstrated substantial genetic heterogeneity between MM patients, [82][83][84][85] subclones, linear disease evolution, genetic instability and dynamics of clonal evolution, as well as profound changes in the BM microenvironment, are currently being evaluated by several groups. [86][87][88][89] Intratumor genetic heterogeneity occurs in addition to intertumor heterogeneity and contributes to the emergence of drug resistance in HR MM. Given this, in conjunction with the MM cellular hierarchy and the BM EMN recommendations on the treatment of newly diagnosed MM haematologica | 2014; 99 (2) 239 © F e r r a t a S t o r t i F o u n d a t i o n microenvironment being altered during tumor progression, this makes targeting of both an attractive approach, and fuels the ongoing pursuit of in vitro assays and murine models as crucial steps forward.…”

“…Given this, in conjunction with the MM cellular hierarchy and the BM EMN recommendations on the treatment of newly diagnosed MM haematologica | 2014; 99 (2) 239 © F e r r a t a S t o r t i F o u n d a t i o n microenvironment being altered during tumor progression, this makes targeting of both an attractive approach, and fuels the ongoing pursuit of in vitro assays and murine models as crucial steps forward. [89][90][91][92] That clinical drug resistance is linked to interconvertible phenotypic and functional states of tumor-propagating cells has been described for MM subpopulations, where post-germinal pre-PCs are more quiescent, enriched in epigenetic regulators and 300-fold more drug-resistant than mature PCs, suggesting that these might be responsible for MRD, drug-resistant relapse and require development of alternative therapeutic strategies. 93 Understanding genetic events in MM also involves clarification of the genetic predisposition of MGUS and MM.…”

Microenvironment-dependent growth of preneoplastic and malignant plasma cells in humanized mice

“…In nearly all cases, MM is preceded by clinically asymptomatic precursor states, termed monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic MM (AMM). Although several transgenic mouse models of plasma cell tumors have been described, these lack the known genetic drivers that characterize human MM/MGUS 2 . Hence, there is an unmet need for in vivo mouse models that would allow the growth and investigation of patient-specific primary human tumors (and particularly precursor states) 2 [?].…”

“…Although several transgenic mouse models of plasma cell tumors have been described, these lack the known genetic drivers that characterize human MM/MGUS 2 . Hence, there is an unmet need for in vivo mouse models that would allow the growth and investigation of patient-specific primary human tumors (and particularly precursor states) 2 [?]. Immune-deficient mice implanted with fetal human bone (SCID-hu) or synthetic bone scaffolds (SCID-synth-hu) have been utilized to study the growth of MM cells (though not MGUS), but have several limitations, including the limited availability of human fetal tissues in large parts of the world 2–4 .…”

Establishment of a Human Multiple Myeloma Xenograft Model in the Chicken to Study Tumor Growth, Invasion and Angiogenesis

“…MM cells strongly depend on their respective microenvironment, i.e. the presence of stroma-derived growth factors, cytokines and ECM components to survive and proliferate [31][32][33] . In addition, drugs might be inefficient or display altered activity when myeloma cells are protected by their local microenvironment 31,34 .…”