Table 1.
Mechanisms of action and drug resistance of the most used classes of drugs in Multiple Myeloma.
| Agents | Mechanism of Action | Type of Resistance | Mechanism of Resistance |
|---|---|---|---|
| Proteasome Inhibitors (bortezomib, carfilzomib and ixazomib) | Inhibition of proteasome activity; inhibition of NF-κB; induction of apoptosis by activating caspase-8 and caspase-9; upregulation NOXA; down-regulation of adhesion molecules [52,53,55,61]. | Genetics and Genomics | Mutations of gene TP53; mutation of gene MAF, t14;16) and t(14;20); point mutations of the gene PSMB5 with overexpression of B5 subunit; upregulation of the proteasomal system; overexpression of the gene MYC; 1q21 gain; modification or loss of 8p21 [122,123,124,125]. |
| Epigenetics | downregulation of miR-15a; downregulation of mir-33b [126,127]. | ||
| Abnormal Drug Transport | Upregulation of P-gp (mainly for carfilzomib) [128,129]. | ||
| Escape from apoptosis, autophagy and dysregulated intracellular signaling pathways | Upregulation of pro-survival proteins (Mcl-1, Bcl-2, Bcl-XL); constitutive activation of the NF-κB pathway; Activation of the aggresome and autophagy pathway; Low levels of the UPR transcription factor XBP1 and autophagy-inducer activating transcription factor 4; increase in heat shock proteins (Grp78, Hsp90, Hsp70, Hsp8) [130,131,132,133,134,135,136,137,138,139,140,141,142]. | ||
| Persistence of Cancer Stem Cells | Stem cell-like phenotype with increased levels of multidrug transporters (ABCG2/BCRP) and ALDH1A1 enzymatic activity; Activation of Hedgehog, Wnt and Notch pathways; upregulation of BTK receptors and RARa2 [118,143,144]. | ||
| Microenvironment | Proliferation and cell survival signaling such as IL6/JAK/STAT3, MAPK, PI3/AKT, IGF-1; Increase production of VEGF leading to angiogenesis, cell proliferation and migration; Increase of pro-inflammatory TNF-α; Increase of cell adhesion molecules (LFA1, VLA4, ICAM1, VCAM1); Activation of SDF1/CXCR4 axis; Increase expression of MARCKS in adhesion and metastatic spread; EVs cargo and cell communication [126,145,146,147,148]. | ||
| Immunomodulatory agents (thalidomide, lenalidomide, pomalidomide) | Interaction with BM microenvironment with down-regulation of adhesion molecules; targeting the cereblon and downstream targets; regulation of pro and anti-inflammatory cytokines; regulation of T cell and NK cells activity; anti-angiogenesis; induction of apoptosis by activating caspase 8 and 9 [64,65,66,67,68,69,70,71]. | Reduced target expression | Mutations in cereblon and genes in the cereblon-pathway (IFKF1 and KPNA2); Mutations in Ras/Raf pathway (KRAS G12D and BRAF V600E) [70,149,150,151]. |
| Genetics and Genomics | Mutations in cereblon and genes in the cereblon-pathway (IFKF1 and KPNA2) [151]. | ||
| Persistence of Cancer Stem Cells | Stem cell-like phenotype with increased levels of multidrug transporters (ABCG2/BCRP) and ALDH1A1 enzymatic activity; Activation of Hedgehog, Wnt and Notch pathways; upregulation of BTK receptors and RARa2 [118,143,144]. | ||
| Microenvironment | Increase of cell adhesion molecules (CD44 thought the Wnt/B-catenin signaling) [152]. | ||
| Monoclonal antibodies (daratumumab, elotuzumab, isatuximab) | Antibody-dependent cellular cytotoxicity; complement-dependent cytotoxicity; macrophage-mediated phagocytosis; FCyR-mediated crosslinking; modulation of target antigen enzymatic activity; regulation of Tregs and stimulation of T cell and NK activity [79,81,85,91,92,96]. | Reduced target expression | Reduced expression of CD38 and SLAM7 [153]. |
| Complement resistance | Increased expression of CD46, CD56 and CD59 blocking anti-body-induced CDC [153,154]. | ||
| Microenvironment | Competition by the extracellular soluble forms of CD38 and SLAM7 [78]. | ||
| Neutralization | Anti-idiotype antibodies neutralizing the activity of the therapeutic monoclonal antibodies [99]. | ||
| Histone deacetylase inhibitors (panobinostat, vorinostat) | Activation of tumour suppressor genes; synergetic activity with proteasomal and aggresomal protein degradation; upregulation p21 [101,102]. | Escape from apoptosis, autophagy activation and dysregulated intracellular signaling pathways | Abnormal regulation of actin cytoskeleton and abnormal protein processing in endoplasmic reticulum (activation of PI3/AKT, MEK/ERK and FAK signaling pathway) [137,138,139,140] |
| Exportin 1 inhibitors (selinexor) | Nuclear retention and activation of tumour suppressor genes, inhibition of NF-κB; reduction of oncoprotein mRNAs translation [109,110]. | - | - |
| Alkylating agents (melphalan, cyclophosphamide) and Anthracyclines (doxorubicin) | DNA damage; topoisomerase II inhibition | Genetics, Genomics and Epigenetics | Overexpression of the gene MYC; upregulation of miR-21; downregulation of miR-15a [126,155,156,157]. |
| Abnormal Drug Transport | Upregulation of P-gp; increased ABCG2 expression [117,158]. | ||
| Persistence of Cancer Stem Cells | Stem cell-like phenotype with increased levels of multidrug transporters (ABCG2/BCRP) and ALDH1A1 enzymatic activity; Activation of Hedgehog, Wnt and Notch pathways; upregulation of BTK receptors and RARa2 [117,118,144,152,158]. | ||
| Microenvironment | Increase of cell adhesion molecules (VLA4) [159]. | ||
| Corticosteroids (dexamethasone, prednisolone, methylprednisolone) | Induction of apoptosis | Reduced target expression | Functional defect of the glucocorticoid receptor [114,115,116,117]. |
| Genetics, Genomics and Epigenetics | Overexpression of the gene MYC and FGFR3; epigenetic inactivation of RASD1 [114,115,116,117]. | ||
| Microenvironment | Increase secretion of pro-survival cytokines [114,115,116,117] |