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Simple Summary: Monoclonal gammopathies comprise a spectrum of disorders defined by the clonal proliferation of plasma cells and include monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM) and multiple myeloma (MM), which can also evolve from MGUS and SMM. We aimed to analyze the impact of mitochondrial DNA copy number (mtDNACN) and also SNVs and INDELs in frequently mutated mitochondrial-related genes on the disease course of monoclonal gammopathies and MM. We confirmed the increased levels of mtDNA in SMM and MM, their gain as the gammopathy progresses and the similarities in the mitochondrial hallmarks between rapidly-progressing SMM and MM. Our data suggest that mitochondria participate in the malignant transformation of monoclonal gammopathies and contribute to disease progression. Our findings support the clinical importance of mtDNACN evaluation and monitoring to guide clinical decision making in patients with SMM. Many studies over the last 20 years have investigated the role of mitochondrial DNA (mtDNA) alterations in carcinogenesis. However, the status of the mtDNACN in MM and its implication in the pathogenesis of the disease remains unclear. We examined changes in plasma cell mtDNACN across different stages of MM by applying RT-PCR and high-throughput sequencing analysis. We observed a significant increase in the average mtDNACN in myeloma cells compared with healthy plasma cells (157 vs. 40 copies; p = 0.02). We also found an increase in mtDNACN in SMM and newly diagnosed MM (NDMM) paired samples and in consecutive relapses in the same patient. Survival analysis revealed the negative impact of a high mtDNACN in progression-free survival in NDMM (p = 0.005). Additionally, we confirmed the higher expression of mitochondrial biogenesis regulator genes in myeloma cells than in healthy plasma cells and we detected single nucleotide variants in several genes involved in mtDNA replication. Finally, we found that there was molecular similarity between "rapidly-progressing SMM" and MM regarding mtDNACN. Our data provide evidence that malignant transformation of myeloma cells involves the activation of mitochondrial biogenesis, resulting in increased mtDNA levels, and highlights vulnerabilities and potential therapeutic targets in the treatment of MM. Accordingly, mtDNACN tracking might guide clinical decision-making and management of complex entities such as high-risk SMM. [ABSTRACT FROM AUTHOR]