Multiple myeloma: clinical characteristics, current therapies and emerging innovative treatments targeting ribosome biogenesis dynamics.

Introduction

Multiple myeloma (MM) is a pathological condition indicated by abnormal proliferation of plasma cells inside the bone marrow (BM) microenvironment. This syndrome is characterized by the presence of clonal proliferation of malignant plasma cells, the identification of monoclonal protein in the bloodstream or urine, and the onset of organ dysfunction. It comprises around 2% of the total neoplastic diseases and constitutes 13% of all hematologic malignancies [ 1 , 2 ]. Globally, the frequency of MM has increased significantly, with a particular focus on its occurrence among men, those aged 50 and older, and populations living in high-income countries. The regions with the greatest incidence rates of MM include North America, Australia, New Zealand, and Europe, whereas the lowest rates are seen in Asia, excluding Western Asia. Around 37% of patients with first diagnosis of MM are below the age of 65, while 26% are within the age range of 65 to 74. The remaining 37% of patients are age 75 and above. Among individuals who are less than 30 years old, the prevalence of MM ranges from 0.02% to 0.3% [ 3 , 4 ].

Stages of multiple myeloma

Multiple myeloma (MM) is distinguished by substantial genetic abnormalities, resulting in a highly heterogeneous syndrome. This disorder progresses from a premalignant state known as monoclonal gammopathy of undetermined significance (MGUS) to a later stage known as smoldering multiple myeloma (SMM), which has the potential to proceed to symptomatic myeloma [ 5 ]. Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant syndrome with absence of characteristic symptoms, which serves as a precursor for the development of MM. This disorder affects around 3% of individuals who are 50 years of age or older. Black individuals face a higher level of vulnerability compared to Whites [ 6 ]. MGUS has the potential to advance to MM or other associated myeloproliferative disorders and malignancies such as Waldenstrom macroglobulinemia, light chain amyloidosis and lymphoma at an annual rate of about 1%.

Smoldering multiple myeloma (SMM) is a pathological condition that manifests as an intermediary stage between MGUS, and MM. It is characterized by the absence of clinical manifestations such as hyper c alcemia, r enal impairment, a nemia and b one lytic lesions (CRAB), despite the existence of monoclonal protein levels below 3 g/dL and/or aberrant plasma cells comprising 10–59% of the bone marrow [ 7 ]. It is considered as premalignant disease and exhibits a yearly risk of 10% for progressing into MM during the first 5 years after diagnosis. Over the subsequent 5 years the condition presents a 3% annual risk, and a 1.5% annual risk thereafter [ 8 ]. The unregulated proliferation of plasma cells is a defining feature of both active and asymptomatic MM that leads to CRAB. (Fig. 1 A).

Multiple risk factors have been identified for the development of MM, including male gender, overweight status, occupational exposure to certain industries, and exposure to dioxin or Agent Orange. However, the precise etiology of MM remains elusive. Common findings in newly diagnosed individuals with MM include anemia, presence of one or more lytic lesions on conventional radiograph (79% of cases), elevated creatinine levels (19% of cases), lymphadenopathy (1% of cases), hypercalcemia (13% of cases), and thrombocytopenia (5% of cases) [ 9 ]. About 3% of newly diagnosed patients have extramedullary illness detected as extraosseous plasmacytomas on imaging, with central nervous system involvement, and plasma cell leukemia.

Diagnosis of multiple myeloma

Diagnosis of MM is established by one or more myeloma defining events (MDE), as well as the presence of 10% or more clonal plasma cells in bone marrow or biopsy confirming plasmacytoma. It is characterized by a group of clinical symptoms (CRAB), with the presence of three biomarkers (Table 1 ). When there is a clinical suspicion of MM, a battery of tests to determine the presence of M proteins is advised. Serum protein electrophoresis (SPEP), serum immunofixation (SIFE), and the serum free light chain ratio (FLCR) testing should all be performed. It is advised that bone marrow exams be performed using fluorescent in situ hybridization (FISH) methods during the initial diagnosis procedure. The use of conventional karyotyping for the detection of hypodiploidy and deletion 13 is critical for risk stratification. If available, gene expression profiling (GEP) has the potential to give additional prognostic relevance. Low-dose whole-body computed tomography (WB-CT) or positron emission tomography/computed tomography (PET/CT) imaging methods are the most effective for determining the severity of bone disease. MRI scans have proven to be useful diagnostic tools in patients with suspected SMM [ 10 ].

Multiple myeloma pathogenesis and chromosomal abnormalities

A sequence of genetic and microenvironmental changes promote the transformation of normal plasma cells into malignant MM. Plasma cells from MM and MGUS show early chromosomal abnormalities such as immunoglobulin heavy chain translocations or trisomies. Secondary translocations involving the MYC gene at 8q24, the MAF BZIP Transcription Factor B (MAFB) gene at 20q12, and the IRF4 gene at 6p25 are common in instances of MM, although they are uncommon in people with MGUS [ 11 ]. Mutations in RAS or FGFR3, dysregulation of MYC, deletion of p18, or loss of expression or mutation in TP53 are unique to MM and play an important role in tumor growth and the development of treatment resistance. In addition to molecular changes in plasma cells, the existence of abnormal connections between plasma cells and bone marrow, as well as the emergence of abnormal angiogenesis, are considered as key indications of disease progression [ 1 ].

Multiple myeloma has four main subtypes, with most people suffering falling into one of these categories. Trisomic MM, MM with the t (11; 14) translocation, MM with the t (4; 14) translocation, and MM with translocations including t (14; 16) or t (14; 20), often known as MAF MM, these are the most prevalent kinds of MM observed in clinical settings [ 12 ]. Certain chromosomal abnormalities, such as translocations involving chromosomes 4 and 14, 14 and 16, and 14 and 20, as well as deletion of the 17p area, gain of the 1q region, or mutation of the p53 gene, identify high-risk MM.

Current therapy for multiple myeloma

Multiple myeloma care is constantly evolving, since a variety of pharmacological medicines have shown success in treating MM and are now available for clinical usage especially in 2015 after FDA approval of many antimyeloma drugs. As a result, there are several therapeutic regimens available for the management of MM in various clinical scenarios that include two or more of these pharmacologically active medications to control the sluggish proliferation or resilient MM cells by several ways [ 17 ].

There are two key criteria that determine the treatment approach to newly diagnosed patients with MM: their potential for autologous stem cell transplantation (ASCT) and the risk categorization procedure. Typically, characteristics such as age, performance status, and the presence of comorbidities determine appropriateness for ASCT. Contemporary therapy methods have shown the capacity to elicit dramatic responses, resulting in some patients achieving a minimum residual disease (MRD) negative status. While reaching a negative MRD status has been associated to improved progression-free survival (PFS) and overall survival (OS), it should be stressed that this is not the main goal of therapy [ 18 ].

A plethora of medication combinations have been developed to treat MM with each treatment demonstrating effectiveness via different mechanisms. To reduce possible toxicity, patients are often given a low-dose dexamethasone regimen (40 mg once weekly) throughout all treatment regimens [ 19 ]. Patients generally get three or four rounds of induction treatment before stem cell harvest. Following this, patients have the choice of undergoing frontline ASCT or continuing with induction therapy and postponing ASCT until the first relapse occurs. Bortezomib, lenalidomide, and dexamethasone (VRD) and daratumumab, lenalidomide, and dexamethasone (DRD) are the up-to-date standard of care for newly diagnosed MM [ 10 ] (Table 1 ).

In the context of individuals recently diagnosed with MM who are deemed ineligible for ASCT owing to factors such as advanced age or concurrent medical conditions, the treatment choices for first therapy are VRD (bortezomib, lenalidomide, and dexamethasone) and DRD (daratumumab, lenalidomide, and dexamethasone) [ 20 ].

Relapsed–refractory multiple myeloma (RRMM)

The International Myeloma Work Group (IMWG) defines relapsed MM as the development of the disease after a favorable response to earlier therapy. Relapse might emerge as biochemical, radiological, or clinical event [ 21 ]. Progressive Disease may also be defined as the appearance of new soft tissue plasmacytomas or bone lesions or the expansion of any pre-existing one by at least 50%. Relapsed and refractory illness occurs when salvage therapy fails, or a patient deteriorates within 60 days of therapy [ 22 ].

Patients initially respond to therapy; nevertheless, as time passes, they acquire resistance. This is the fundamental challenge in the treatment of MM. Of the total number of patients starting first-line systemic treatment, 57% are on a proteasome inhibitor (PI), 23% are on an immunomodulatory agent (IMiD), and the remaining 20% on other regimens. The percentage of patients exposed to both PI and IMiD following the second, third, and fourth lines are 40.1%, 65.1%, and 86.0%, respectively. In any given year, over 10.0% of patients relapse and display resistance to both PIs and IMiDs [ 23 ].

Treatment in a relapse situation is aimed at managing the symptoms, stopping the development of organ damage, and returning the patient to a state of prolonged disease remission. When individuals with RRMM show treatment resistance, a different kind of regimen is started. While there is no wide agreement on prescription for the most effective therapy of RRMM, realistic treatment algorithms are devised based on available up-to-date data. Well-structured, long-term observational studies are required to verify the favorable effect of novel drugs and to find ways to prolong the quality of life of patients with MM [ 24 ].

Challenges of multiple myeloma

Despite triplet and quadruplet induction regimens, ASCT, and maintenance treatment, myeloma remains incurable. Relapses occur at various phases of the progression of the disease [ 25 ]. It is critical to bear in mind that MM continues to be among the most financially burdensome forms of cancer [ 26 , 27 ].

Extramedullary multiple myeloma (EMM) involvement or extramedullary disease (EMD) is defined as a metastatic stage of MM since it arises in the bone marrow. It can potentially manifest at any location in the body and might even appear before the primary diagnosis of multiple myeloma (MM). Current research indicates that 7% to 17% of MM cases present with EMD at the time of diagnosis. Moreover, as the disease progresses, an additional 6% to 20% of MM patients develop EMD, with the prevalence varying across different studies [ 14 ]. EMD is described as a clone's or subclone's ability to multiply independent of the bone marrow microenvironment [ 28 ]. Several genetic factors have been linked to EMD. These variables include 17p deletion, p53 nuclear expression, an elevated frequency of t (4; 14), and p53 deletion. Additionally the lack of CD56 expression, excessive MAFB expression, and excessive MYC expression are potential risk factors [ 28 ]. When presented at the time of diagnosis or recurrence, EMD boosts the complexity of existing MM and is associated with a poor clinical outcome, with an overall survival of fewer than 6 months. The clinical disorders linked with EMD vary significantly, and their management presents a major challenge [ 29 ].

Resistance to treatment is one of the main challenges of MM. Resistance may result from both MM cell internal and external causes. The internal causes include genetic and epigenetic changes that increase activity of drug efflux pumps, mutations or other changes in drug targets, and disruption of intracellular signaling networks that regulate processes such as apoptosis, autophagy, and DNA repair [ 30 ]. The external causes include communications with the bone marrow (BM) microenvironment, cell adherence to the extracellular matrix (ECM) etc. Bone marrow stromal cells (BMSCs) secrete soluble substances such as interleukin (IL)-6 and insulin-like growth factor (IGF)-1, these extrinsic factors trigger signal in MM cells, which eventually contributes to resistance to treatment [ 31 ]. A key strategy for the treatment of MM relapse involves using the proteasome inhibitor (PI) and thus resistance to PI represents a considerable therapeutic challenge. Although extensive research has been undertaken, these pathways have not been thoroughly verified in RRMM patient derived specimens, and hence their clinical importance remains uncertain [ 32 ].

Interesting recent research with single cell analysis revealed that gene signatures related to ribosome and translation are associated with a poor response of MM patients to bortezomib suggesting that ribosome dysregulation and alterations in mRNA translation activity contribute to PI resistance [ 33 ]. This prompted us to investigate relevance and potential of ribosomal pathways to this disease.

Introduction to ribosome biogenesis

Human ribosome biogenesis involves a methodical assembly of 4 ribosomal RNAs and 80 ribosomal proteins. It begins inside the nucleolus with the formation of ribosomal RNA (rRNA). RNA polymerase I (Pol I) transcribes ribosomal DNA (rDNA) to generates 47S pre-rRNA, which undergoes intricately regulated splicing to produce 18S, 5.8S, and 28S rRNA molecules [ 34 ]. These rRNAs are secondarily modified by small nucleolar RNAs (snoRNAs). Ribosomal proteins (RPs) are imported from the cytosol into the nucleus, where they assemble with 5.8S and 28S rRNA molecules in addition to the 5S rRNA (transcribed from separate gene on chromosome one), to produce the 60S ribosomal subunit. The 18S rRNA molecule, following similar secondary modifications assembles with RPs to form the 40S ribosomal subunit [ 35 ]. Historically, the ribosomes were thought to be housekeeping entities for the purpose of protein synthesis rather than actively influencing the translational portfolio of the cells. Recent research has shown that the ribosome biogenesis is carefully regulated to support critical translation programs, independent of the cancer's genetic features [ 5 ]. Thus the progression of cancer is strongly dependent on changes in ribosome biogenesis [ 36 ]. Hyperactive ribosome biogenesis promotes uncontrolled cell proliferation and metastatic progression however mechanistic details are still emerging [ 37 , 38 ].

Transcription factors such as MYC and OCA-B/BOB-1, that influence translation of cell fate determinants, are responsible for a considerable number of the strong and specific dependencies in MM, especially those that play an important role in defining plasma cell identity. The POU2AF1 gene, which encodes the OCA-B/BOB-1 protein, a coactivator protein involved in B cell transcription program and is expressed at all stages of B-cell maturation. Compared to normal plasma cells, it is more highly expressed in CD138+ plasma cells from patients with precursor illnesses (MGUS and SMM), as well as in symptomatic MM. BOB1 overexpression positively fosters de novo protein synthesis in MM cells through RNA Pol I-dependent transcription [ 39 ]. Oncogenic MYC plays a critical role in the progression of MM. MYC-induced genes are involved in a variety of biological functions, including cell growth, cell cycle control, energy production, anabolic metabolism, and DNA replication. The MYC protein has a direct beneficial effect on the transcription of genes encoding ribosomal proteins, ribosomal RNA, and translation initiation complex proteins [ 40 ]. MYC activation is seen in around 66% of newly diagnosed MM patients, and it is linked to poor clinical outcomes. Approximately 20 to 40% of patients may have MYC gene translocations [ 41 , 42 ]. A key consequence of MYC activation is increased ribosome biogenesis, leading to an increased protein translation and increased biomass, which are characteristic of malignant cells [ 43 , 44 ]. Manier and colleagues found that CMLD010509 inhibits the translation of a group of oncoproteins required for MM oncogenesis [ 5 ]. These oncoproteins comprise an oncogenic translation program. Furthermore, when examined in vivo, this medication had encouraging outcomes in a variety of mouse models, showing that targeting MYC in MM might be a feasible therapeutic approach that may help treat MM and other hematological malignancies [ 5 ]. These emerging findings in the context of our analysis of the MM patient data presented below highlight the importance of ribosome biogenesis in MM. Thus, understanding and exploiting ribosome biogenesis for MM targeted treatment approaches is important.

Ribosome biogenesis, a novel therapeutic target

We queried three publicly available MM related datasets from the Gene Expression Omnibus (GEO) for ribosome biogenesis signatures (Fig. 2 A). Our thought process was guided by well-established characteristic of the MM cells. That is, MM cells are highly secretory, and thus are highly dependent on protein translation. And that ribosome biogenesis is foundational to protein translation.

The data sets GSE13591 and GSE6477 were collected in 2009 and 2006 (last updated in 2018 and 2020 respectively). Both datasets contain the gene expression profiles of purified plasma cells (PCs) obtained from normal donors (N), monoclonal gammopathy of undetermined significance, 133 MM and 9 plasma cell leukemia (PCL) at diagnosis. The third MM dataset; GSE136337 (collected in 2019 and updated in 2020), contains gene expression data of 436 newly diagnosed multiple myeloma patients which were categorized into two groups based on the response status and the R-ISS (Revised International Staging System). Based on the response status, patients were classified into four groups complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Likewise, based on R-ISS they are classified as R-ISS I, R-ISS II and R-ISS III depending on the disease progression [ 45 , 46 ].

We observed that all three data sets showed enrichment of ribosome biogenesis gene set [ 47 ]. In GSE136337 (N = 160 patients, P = 0.0099) and GSE6477 (N = 436 patients, P = 0.0034) ribosome biogenesis signature was significantly enriched. In GSE13591 (N = 158 patients, P = 0.079) we observed a noticeable trend (Fig. 2 A). We then established 217 commonly enriched ribosome biogenesis genes across these three datasets as depicted in the Venn diagram (Fig. 2 B). We then subjected the common set of 217 genes to gene ontology analysis using g:profiler™ and identified that genes associated with rRNA metabolism and rRNA processing were the main constituents of the 217 genes (Fig. 2 C). This comparative analysis aided the identification of key constituents of ribosome biogenesis that change in multiple myeloma patients (Supplemental Table 1 ). We also observed that ribosome biogenesis is enhanced throughout the progression of MM from MGUS, SMM, and MM becoming an obvious feature in PCL. This is recognized not only within the clinical spectrum of MM, but it is also seen when patients are categorized into relapsed, progressing, and stable stages (Fig. 1 B).

We then queried if ribosome biogenesis contributes to the progression of MM or resistance to treatment. Upon perusing through existing literature, we came across several notions that establish connections between ribosome biogenesis and MM advancement [ 5 , 32 , 48 , 49 ]. Interesting recent research has revealed that polysome derived gene expression patterns, as well as translation initiation, were associated with a less-than-optimal response to the PI bortezomib in samples from MM patients. This shows that alterations in ribosome breakdown and in mRNA translation activity contribute to PI resistance [ 32 , 33 ]. Thus, ribosome biogenesis may not influence MM progression but may also influence the drug resistance of MM.

Progress on therapeutically targeting ribosome biogenesis

Ribosome formation may be restricted by a variety of anti-tumor medications as a by-product of their activity; however, there are few if any specialized drugs. Among all ribosome biosynthesis influencers, mammalian target of rapamycin (mTOR) has emerged as therapeutic candidates for multiple myeloma [ 32 , 50 ]. mTOR, a cell's main nutritional sensor, promotes growth and proliferation. It regulates cellular energy sources for cell growth via several protein complexes. These complexes control protein translation to preserve the amino acid pool. Protein translation anomalies induced by mTOR pathway dysregulation are observed in different kinds of cancer. This pathway regulates protein translation via S6K1 and 4E-BP1. Crosstalk between mTOR, AKT, and PI3 kinase exacerbates dysfunction of this pathway [ 51 – 53 ]. According to recent studies pharmacological treatments that inhibit mTOR signaling and ribosome synthesis have the potential to slow the progression of cancer [ 50 , 54 , 55 ].

Ribosome biogenesis is regulated through nucleoli. The nucleoli are organized around the tandem repeats of rDNA on acrocentric chromosomes [ 56 ]. It is intuitive that chromatin dynamics plays an important role in ribosome biogenesis. SWI/SNF complex, is a prominent controller of chromatin dynamics. Bromodomain-containing protein 9 (BRD9), is a member of the bromodomain and extra-terminal (BET) protein family and a component of the SWI/SNF complex. BRD9 has bromodomain, which recognizes and binds to acetylated lysine residues on histone tails. This interaction influences chromatin structure and governs gene activation or repression [ 57 ]. The regulatory functions of BRD9 may be impaired by cancer, such as MM. Dysregulation may lead to uncontrolled growth of cancer cells since they often exploit the gene regulation function of BRD9. Ribosome biogenesis stimulation and BRD9 overexpression play critical roles in the development of multiple myeloma malignancy. Kenneth and his colleagues observed that decreasing BRD9 affected the formation of a transcription initiation complex and reduced ribosome biogenesis. This disruption influenced cell survival, indicating that BRD9 may be a viable therapeutic target for MM [ 58 , 59 ]. In their recent investigation Kurata et al. showed that in Multiple Myeloma, targeting BRD9 disrupts ribosome biogenesis [ 58 ]. Thus, BRD9 inhibitors have the potential to become an important addition to the therapies for MM [ 48 , 58 ].

The dysregulation of ribosome biogenesis in MM emphasizes its potential as a therapeutic target, creating a promising opportunity for the development of novel therapeutics. Thus, in MM targeting ribosome biogenesis has high value. While mTOR and BRD9 targeted approaches may allow ribosome biogenesis manipulation for MM, there are several other ways to target ribosome biogenesis [ 60 ]. Consequently, there is a significant opportunity to develop anti-tumor medications that specifically target genes implicated in the production of ribosomes [ 60 ]. For example, the major function of RNA polymerase (Pol I) is to transcribe ribosomal RNA (rRNA), which is an important step in the synthesis of ribosomes. This has prompted researchers to investigate specifically suppressing Pol I as a therapeutic approach [ 50 , 61 ]. G-quadruplex structures are involved in rDNA transcription [ 62 ]. Various small-molecule ligands, such as cationic porphyrins and quindolines, can stabilize these structures. CX-5461, a highly selective inhibitor of RNA polymerase I that acts by attaching to the RNA polymerase I pre-initiation complex's selectivity factor 1 (SL1) and has demonstrated efficacy for in vivo applications is also a G-quadruplex stabilizer [ 63 ]. CX-5461 has shown remarkable effectiveness in various myeloma preclinical models, both in vitro and in vivo. CX-5461's therapeutic efficacy improves when MYC expression is increased, most likely owing to an increase in ribosome biosynthesis, which prepares cells that overexpress MYC for the repercussions of the nucleolar stress response [ 61 ]. CX-5461's powerful activity against human MM cells and PI-resistant mouse MM cells is possibly due to its dual mechanism of action, which includes suppressing ribosome synthesis and activating DDR (replication-dependent DNA damage response). It was evaluated in a Phase I clinical study for advanced hematologic malignancies and shown excellent tolerability. Most of the patients in the research had myeloma, and in 50% of cases, the best response was stable disease [ 64 – 66 ]. A derivate, CX-3543 (Quarfloxin) was introduced into clinical trials. Interestingly, Quarfloxin reduces MYC transcription and has successfully completed Phase I and II clinical trials in patients with advanced solid tumors and lymphomas ( NCT00955786 ) and neuroendocrine/carcinoid tumors ( NCT00780663 ), respectively [ 67 ]. Suppression of RNA pol I activity causes p53 pathway activation, cellular senescence, and autophagy, all of which increase cell death [ 68 ]. A phase I clinical study of CX-5461 as a monotherapy in 17 advanced patients of MM who had not responded to earlier regimens, showed that those with RRMM at the start of the trial had the best results, with three out of six patients obtaining stable condition after four to six treatment cycles [ 32 ]. CX-5461 clinical studies are now being conducted on subjects with advanced solid tumors ( NCT02719977 ) and hematological cancer (ACTRN12613001061729) [ 68 ].

Another emerging lead is BMH-21 which possesses wide and potent antitumorigenic properties that effectively limit tumor growth. BMH-21 binds to DNA sequences rich in guanine and cytosine (GC-rich sequences), which are often found in genes associated to ribosomal DNA. It efficiently and swiftly inhibits the activity of RNA polymerase I (Pol I), the enzyme that transcribes ribosomal DNA [ 69 ]. It also causes the primary catalytic component of the Pol I complex to be degraded via the proteasome [ 70 ]. BMH-21 has been shown in hematological malignancies to effectively suppress rDNA transcription [ 70 ].

Ribosome biogenesis inhibition as an emerging treatment approach is not unique to MM but could extend to other solid malignancies. The combination of BMH21's ribosomal inhibition with the fibroblast growth factor receptor (FGFR) inhibitor Erdafitinib will be a potential therapy approach for glioma in the future [ 71 ]. Previous findings from our group demonstrate that Vismodegib and BMH-21 precisely target the dependence of radiation-exposed breast cancer cells, successfully preventing their dissemination to the lungs. Inhibiting RNA Pol I and Hedgehog activity in radiation therapy patients might deliver an important therapeutic benefit over existing breast cancer therapies [ 47 ].

Conclusions

Multiple myeloma (MM) is a heterogeneous and genetically complex neoplasm with an approximate 5-year survival rate of 60% with recurring episodes of remission, treatment resistance and metastatic relapse. Considering their excessively high protein synthesis and processing rates, MM cells may be affected by an imbalance in protein homeostasis, in addition to a reduction in protein degradation which is generally achieved by polyubiquitination and proteasome transport. PIs are essential for frontline and RRMM patients and many patients face eventual resistance, which is a clinical obstacle. Recent research attributes suboptimal response of MM patients to PI (bortezomib), to disrupted ribosomal function and altered mRNA translation [ 32 ]. Tomasson et al. illustrated how ACA11 overexpression boosts MM cell line proliferation and changes nucleoli in both MM cell lines and patient MM tissues. Overexpression of ACA11 causes enhanced ROS-dependent ribosome biogenesis and protein synthesis, ultimately influencing MM chemotherapeutic response [ 49 ]. Overall focusing on ribosome biogenesis through RNA polymerase I inhibition seems to be promising based on the first-in-human study by Kylee et al. that used CX-5461 [ 32 ]. In conclusion ribosome biogenesis inhibition possibly through small inhibitors of RNA polymerase I, is a promising option to MM patients suffering from relapse or refractory state. The rapidly expanding area of MM and ribosome biogenesis certainly deserves quite a bit of curiosity from researchers.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 24 KB)

Abbreviations

ATP-Binding Cassette

Autoinhibited Ca 2+ -ATPase 11

Allogenic Stem Cell Transplant

Autologous Stem Cell Transplantation

B-Cell Maturation Antigen

Bi-Specific T-Cell Engagers

B Cell Transcriptional Coactivator POU2AF1

Bone Marrow

Bone Marrow Stromal Cells

Bone Marrow Plasma Cells

Bromodomain-containing protein 9

Chimeric Antigen Receptor T-Cell

Cluster of Differentiation

Complete Response

Calcium Renal Anemia Bone

Daratumumab, Melphalan, Prednisolone, Bortezomib

Daratumumab Bortezomib, Lenalidomide, Dexamethasone

Daratumumab Bortezomib, Thalidomide, Dexamethasone

Dexamethasone, Cyclophosphamide, Etoposide, Cisplatin

DNA Damage Response

Deoxyribonucleic Acid

Daratumumab, Pomalidomide, Dexamethasone

Daratumumab, Lenalidomide, Dexamethasone

Extracellular Matrix

Extramedullary Disease

Food and Drug Administration

Fibroblast Growth Factor Receptor 3

Fluorescent In Situ Hybridization

Free Light Chain Ratio

Gene Expression Omnibus

Gene Expression Profiling

Gene Set Enrichment

Gene Set Enrichment Analysis

Immunoglobulin A

Immunoglobulin G

Immunomodulatory Agent

International Myeloma Work Group

Interferon Regulatory Factor 4

Isatuximab, Carfilzomib, Dexamethasone

Isatuximab, Pomalidomide, Dexamethasone

Carfilzomib, Cyclophosphamide Dexamethasone

Carfilzomib, Daratumumab, Dexamethasone

Carfilzomib, Pomalidomide, Dexamethasone

Carfilzomib, Lenalidomide, Dexamethasone

Carfilzomib, Lenalidomide, Dexamethasone. Cisplatin, Doxorubicin, Cyclophosphamide, and Etoposide

MAF BZIP Transcription Factor B

Monoclonal Protein

Myeloma Defining Events

Monoclonal Gammopathy of Undetermined Significance

Multiple Myeloma

Minimum Residual Disease

Magnetic Resonance Imaging

Messenger Ribonucleic Acid

Mammalian Target of Rapamycin

Myelocytomatosis Oncogene

Overall Survival

Bortezomib, Doxorubicin, Dexamethasone

Plasma Cell Leukemia

Progressive Disease

Positron Emission Tomography/Computed Tomography

Progression-Free Survival

Proteasome Inhibitor

Partial Response

Rat Sarcoma

Ribosomal Deoxyribonucleic Acid

Revised International Staging System

Ribonucleic Acid Polymerase I

RNA Sequencing

Ribosomal Proteins

Relapsed–Refractory Multiple Myeloma

Ribosomal Ribonucleic Acid

Stable Disease

Serum Immunofixation

Smoldering Multiple Myeloma

Small Nucleolar Ribonucleic Acid

Serum Protein Electrophoresis

SWItch/Sucrose Non-Fermentable, an ATP-Dependent Chromatin Remodeling Complexes

Translocation

Tumor Suppressor Gene:

Bortezomib (Carfilzomib), Lenalidomide, Dexamethasone, Cisplatin, Doxorubicin, Cyclophosphamide and Etoposide

Bortezomib, Cyclophosphamide Dexamethasone

Bortezomib, Dexamethasone, Thalidomide, Cisplatin, Doxorubicin, Cyclophosphamide and Etoposide

Bortezomib, Melphalan, Prednisolone

Bortezomib, Lenalidomide, Dexamethasone

Bortezomib, Thalidomide, Dexamethasone

Whole-Body Computed Tomography

Author contributions

Conceptualization Rajeev S. Samant. Formal analysis Mohamed H. Elbahoty, Bhavyasree Papineni. Funding acquisition Rajeev S. Samant. Investigation Mohamed H. Elbahoty, Bhavyasree Papineni. Methodology Mohamed H. Elbahoty, Bhavyasree Papineni, and Rajeev S. Samant. Resources Rajeev S. Samant. Supervision Rajeev S. Samant. Writing—review and editing Mohamed H. Elbahoty, Bhavyasree Papineni and Rajeev S. Samant.

Funding

RSS is a recipient of O’Neal Invests Award.

Data availability

Details of all data generated or analyzed during this study are included in this article and its Supplementary Files.

Consent for publication

All authors have seen and approved the manuscript and consent publication.

Declarations

Conflict of interest

The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Data Availability Statement

Details of all data generated or analyzed during this study are included in this article and its Supplementary Files.

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