Multiple myeloma (MM) is a hematological neoplasm characterized by the uncontrolled aberrant clonal proliferation of plasma cells (PCs) in the bone marrow [1]. This disease is the second most common hematological malignancy, after non-Hodgkin lymphoma [2,3], affecting elderly patients with a median age of 65 years [4]. Despite the latest advances in treatment strategies, which have significantly increased patient survival, MM is still considered an incurable disease, with a median overall survival of 7 years.

MM is a very heterogeneous disease, which is reflected in the inter-individual differential diagnosis and survival of patients. Different studies have associated this variability with a wide range of genetic and epigenetic alterations present in MM patients [5,6], including distinct molecularly defined subtypes with different features [7]. Regarding the genetic variability, MM is divided into hyperdiploid (HRD) and non-HRD subtypes [7]. HRD MM is characterized by the trisomy of chromosomes 3, 5, 7, 9, 11, 15, 19 and 21 [6], whereas non-HRD MM is characterized by translocations of the immunoglobulin (Ig) alleles. The majority of these translocations affect chromosome 14, where the Ig H-chain is located [6,7]. However, Ig translocations can also affect the kappa and lambda light chains, the co-occurrence of which is common with HRD MM. Besides, some of these light-chain translocations are associated with a poor outcome for MM patients, as is the case for IgL-MYC translocations [8]. Some of the common heavy-chain translocations are also considered as high-risk prognostic factors, such as t(4;14) and t(14;16), which affect MMSET and MAF genes, respectively [6,7,9]. Epigenetic aberrations of the DNA methylation and histone modifications are also thought to play an important role in MM pathogenesis. The study of global DNA methylation of MM has led to the identification of a highly heterogeneous DNA methylation pattern, which results in extensive DNA hypomethylation of intergenic regions and DNA hypermethylation associated with intronic and enhancer regions [2,5]. In addition, the study of histone modifications in MM has revealed a de novo gain of active chromatin marks preferentially located in regulatory elements, such as enhancer and promoter regions, which arise from heterochromatic regions in normal B cells [10,11,12]. These results suggest the possibility that these epigenetically regulated non-coding genomic regions could lead to the transcription of non-coding RNA genes (ncRNAs) and, in particular, to the expression of long non-coding RNAs (lncRNAs), which may play a relevant role in the pathobiology and clinical outcome of MM [13]. Nowadays, studies about the role of certain lncRNAs in MM are emerging. However, more comprehensive analyses are required to better understand their function in this disease. In this review, we summarize the current knowledge regarding the role of lncRNAs in the development and outcome of MM and discuss the possibility of lncRNAs as targets for the development of novel RNA-based therapeutic strategies for MM patients.

Traditionally, cellular functions of DNA and proteins have overshadowed the roles of RNAs. In recent years, the development of high-throughput techniques, such as RNA sequencing (RNA-seq), has brought great advances in the understanding of the cell transcriptome. So far, it is known that, although only 1–2% of the human genome is translated into proteins, around 70–90% of it is transcribed into RNA, resulting in a huge amount of ncRNAs [14]. Among these ncRNA genes, lncRNAs are defined as those non-coding transcripts longer than 200 nt that do not encode proteins, with open reading frames (ORFs) smaller than 100 amino acids, and with a lack of or low coding potential. However, the latest RNA-seq studies have shown that some lncRNAs contain cryptic ORFs, which could encode for small ORFs or non-conserved peptides [15,16,17].

The characteristics of lncRNAs may differ from each other and they can be capped at the 5′end, spliced and/or polyadenylated (poly(A)+). Remarkably, transcripts with the poly(A)+ tail have higher stability than those with poor or no polyadenylation. On the other hand, there are lncRNAs that can present both polyadenylated and non-polyadenylated isoforms, such as MALAT1 (metastasis associated lung adenocarcinoma transcript 1) or NEAT1 (nuclear paraspeckle assembly transcript 1) [18,19]. Although the size of lncRNAs varies between 200 nt and more than 1 MB (known as macro lncRNAs), 42% of lncRNAs only present two exons [19,20]. In contrast to mRNAs, which are located at the cytosol, lncRNAs can be located either in the nucleus or in the cytoplasm, where they can exert various functions. Thus, regarding the location where lncRNAs act and their transcription site, they are capable of acting as cis and/or trans transcripts [15,21]. Cis lncRNAs are known to influence the expression and/or chromatin states of their neighboring genes, while trans lncRNAs act over distal genes [22,23,24]. Interestingly, lncRNAs are cell- and tissue-specific, and they may affect different biological processes, such as chromosome conformation, imprinting of genomic loci, or gene and protein regulation [15,25]. lncRNAs have the ability to regulate at DNA, RNA and protein levels, and their functions can be divided into four different groups depending on their molecular mechanisms [18,26]: (1) signal lncRNAs are regulatory molecules that can trigger the transcription of other genes by their presence. They can infer chromatin states, affect gene imprinting or mark certain spaces, times or stages for gene regulation, such as Air or PANDA (p21-associated ncRNA DNA damage activated) [26,27]. (2) Decoy lncRNAs are transcripts that bind to targets and prevent them from binding to their own targets, thus leading to the alteration of post-transcriptional control. This type of lncRNA can act as an miRNA sponge, binding to miRNAs thanks to their complementary sequence (Figure 1) [26]; PTENP1 (phosphatase and tensin homolog pseudogene 1), for example, leads to tumor suppressor activity due to the decoy of different miRNAs [28,29,30]. (3) Guide lncRNAs can regulate gene expression through the recruitment and re-localization of ribonucleoprotein complexes at specific chromatin loci, such as MEG3 (maternally expressed 3), which guides the EZH2 subunit to TGFβ-regulated genes (Table 1) [18,31,32]. (4) Scaffold lncRNAs can act as central platforms upon the assembly of different ribonucleoprotein complexes, affecting their molecular components (Figure 1) [32]; for instance, HOTAIR (HOX transcript antisense intergenic RNA) adopts a four-module secondary structure for the interaction with polycomb repressive complex 2 (PRC2) (Table 1), promoting gene repression [18,26].