A Review on Genetic Predispositions and Clinical Advancements of Multiple Myeloma Cancer

Abstract

Multiple myeloma cancer, a hematologic malignancy characterized by clonal plasma cell proliferation, remains a therapeutic challenge despite significant advancements in precision medicine. This comprehensive review synthesizes contemporary insights into its pathophysiology, diagnostic modalities (with emphasis on radiographic techniques), hereditary predispositions, and evolving treatment paradigms.

Conventional X-ray imaging, though limited by sensitivity, remains integral to initial diagnostics, detecting osteolytic lesions in 80% of cases via skeletal surveys. However, advanced modalities like whole-body CT, MRI, and PET/CT now dominate staging and response assessment due to superior resolution in identifying early marrow infiltration and metabolically active lesions. The persistence of X-ray in guidelines underscores its cost-effectiveness in resource-limited settings, while emerging techniques like DEXA enhance fracture risk stratification.

The hereditary basis of multiple myeloma cancer, though modest (2–4-fold increased risk in first-degree relatives), is substantiated by GWAS-identified loci (e.g., FAM46A, CCND1) and rare familial clusters linked to precursor states like MGUS. While hereditary syndromes (e.g., Lynch, Li-Fraumeni) contribute minimally, polygenic risk models highlight interactions between germline polymorphisms (e.g., DNA repair genes) and environmental triggers. Current evidence does not support routine genetic screening but advocates vigilance in familial cases for early detection of plasma cell dyscrasias.

Clinically, the CRAB criteria (hypercalcemia, Renal impairment, Anemia, Bone lesions) and myeloma-defining events guide diagnosis, supported by bone marrow biopsy and cytogenetic profiling (e.g., FISH for del[17p], t[4;14]). The molecular landscape, driven by IgH translocations, RAS mutations, and microenvironmental cytokines (IL-6, RANK ligand), informs risk-adapted therapies. Treatment has evolved from alkylators to triplet regimens combining proteasome inhibitors (bortezomib), immunomodulatory drugs (lenalidomide), and anti-CD38 monoclonal antibodies (daratumumab). Autologous stem cell transplantation prolongs remission in eligible patients, while BCMA-targeted CAR T-cells (idecabtagene vicleucel) and bispecific antibodies (teclistamab) show unprecedented efficacy in refractory disease.

Prognostic stratification via the R-ISS system and MRD assessment redefines survivorship, with 5-year survival rates varying from 40% to 82% based on cytogenetic risk. Survivorship challenges include managing therapy-related complications (neuropathy, secondary cancers) and maintaining bone health with bisphosphonates or denosumab.

Future directions emphasize precision medicine: exploiting synthetic lethality (e.g., PARP inhibitors in BRCA-mutated cases), liquid biopsies for clonal monitoring, and immunoprevention in high-risk MGUS. While multiple myeloma remains incurable, integration of novel agents, advanced imaging, and genetic insights is transforming its trajectory from acute lethality to chronic management.

Introduction 

Multiple myeloma cancer, a malignant proliferation of plasma cells within the bone marrow, represents approximately 10% of all hematologic malignancies. Characterized by the clonal production of monoclonal immunoglobulins or free light chains, this disease manifests through a spectrum of clinical complications, including osteolytic bone lesions, hypercalcemia, renal impairment, anemia, and immunodeficiency. The annual incidence of multiple myeloma cancer is estimated at 6-7 cases per 100,000 individuals, with a median age at diagnosis of 69 years. Despite advancements in therapeutic strategies, including proteasome inhibitors and immunomodulatory agents, the disease remains incurable for most patients, emphasizing the need for early diagnosis, risk stratification, and personalized management. This review critically examines the role of radiographic imaging, particularly X-ray diagnostics, explores the hereditary underpinnings of multiple myeloma, and synthesizes contemporary insights into its pathophysiology and treatment.

Pathophysiology and Molecular Landscape of Multiple Myeloma Cancer 

Multiple myeloma cancer arises from post-germinal center plasma cells that accumulate genetic aberrations, including translocations involving the immunoglobulin heavy chain (IgH) locus on chromosome 14q32, hyperdiploidy, and mutations in oncogenes (e.g., KRAS, NRAS) and tumor suppressors (e.g., TP53). The bone marrow microenvironment facilitates myeloma cell survival through cytokine-mediated interactions, notably involving IL-6, VEGF, and RANK ligand, which promote angiogenesis, osteoclast activation, and immune evasion. The resultant osteolytic lesions, a hallmark of advanced disease, are driven by an imbalance between osteoblastic suppression and osteoclastic hyperactivity, leading to pathologic fractures and debilitating bone pain.

Radiographic Diagnostics in Multiple Myeloma: The Role of X-ray Imaging

Conventional X-ray imaging remains a cornerstone in the initial evaluation of multiple myeloma cancer, particularly in identifying osteolytic lesions. The skeletal survey, a series of plain radiographs covering the skull, spine, pelvis, and long bones, detects lytic lesions in 80% of newly diagnosed patients. Classic radiographic findings include "punched-out" lesions without sclerotic borders, diffuse osteoporosis, and vertebral compression fractures. However, the sensitivity of X-ray is limited, as it requires 30–50% bone mineral loss for lesion detection, underscoring its inadequacy in early disease or smoldering myeloma.

Advanced imaging modalities, such as whole-body low-dose computed tomography (WB-CT), magnetic resonance imaging (MRI), and positron emission tomography (PET/CT), have supplanted X-rays in staging and response assessment. MRI excels in visualizing marrow infiltration and spinal cord compression, while PET/CT identifies metabolically active lesions with high specificity. Despite these advancements, the International Myeloma Working Group (IMWG) still recommends the skeletal survey for resource-limited settings, emphasizing its cost-effectiveness and accessibility. Emerging techniques, including dual-energy X-ray absorptiometry (DEXA) for fracture risk assessment, further complement traditional radiography.

Is Multiple Myeloma Hereditary? Unraveling Genetic Predispositions 

The question "Is multiple myeloma hereditary?" has garnered significant attention, with epidemiologic studies suggesting a 2-4-fold increased risk among first-degree relatives of affected individuals. Genome-wide association studies (GWAS) have identified susceptibility loci, including FAM46A, CCND1, and DNA repair genes (e.g., BRCA1, ATM), which implicate dysregulated cell cycle progression and genomic instability in pathogenesis. Familial clusters of multiple myeloma cancer are rare but well-documented, often co-occurring with monoclonal gammopathy of undetermined significance (MGUS), a precursor state.

Notably, hereditary syndromes such as Lynch syndrome and Li-Fraumeni syndrome have been associated with increased myeloma risk, though these cases represent a minority. The interplay between inherited polymorphisms and environmental factors (e.g., obesity, chemical exposure) further complicates risk stratification. Current guidelines do not endorse routine genetic testing for asymptomatic relatives, but familial cases warrant heightened surveillance for MGUS or related plasma cell disorders.

Clinical Presentation and Diagnostic Criteria 

The clinical manifestations of multiple myeloma cancer are encapsulated by the CRAB criteria: hypercalcemia, Renal insufficiency, Anemia, and Bone lesions. Patients often present with fatigue secondary to anemia, bone pain localized to the spine or ribs, and recurrent infections due to hypogammaglobulinemia. Laboratory findings include elevated serum creatinine, monoclonal (M) protein on serum protein electrophoresis, and increased free light chain ratio. The 2014 IMWG diagnostic criteria mandate clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma plus CRAB features or myeloma-defining events (e.g., clonal bone marrow plasma cells ≥60%, serum free light chain ratio ≥100).

Bone marrow aspiration remains indispensable for assessing clonality via flow cytometry and cytogenetic analysis. Fluorescence in situ hybridization (FISH) detects high-risk abnormalities, such as del(17p), t(4;14), and gain(1q), which inform prognosis and therapeutic decisions.

Therapeutic Strategies and Emerging Modalities 

The treatment paradigm for multiple myeloma cancer has evolved from alkylating agents and corticosteroids to triplet and quadruplet regimens incorporating proteasome inhibitors (e.g., bortezomib, carfilzomib), immunomodulatory drugs (e.g., lenalidomide, pomalidomide), and monoclonal antibodies (e.g., daratumumab, elotuzumab). Autologous stem cell transplantation (ASCT) remains a mainstay for eligible patients under 70 years, offering prolonged progression-free survival.

Recent breakthroughs include B-cell maturation antigen (BCMA)-directed therapies, such as chimeric antigen receptor (CAR) T-cells (idecabtagene vicleucel) and bispecific T-cell engagers (teclistamab), which demonstrate remarkable efficacy in refractory disease. Additionally, the oral proteasome inhibitor ixazomib and XPO1 inhibitor selinexor expand options for elderly or transplant-ineligible patients.

Prognostic Stratification and Survivorship 

The Revised International Staging System (R-ISS) integrates albumin, beta-2-microglobulin, LDH, and cytogenetics to categorize patients into three risk groups, with 5-year survival rates ranging from 82% (Stage I) to 40% (Stage III). Minimal residual disease (MRD) assessment via next-generation flow cytometry or sequencing is increasingly recognized as a surrogate for long-term outcomes, with MRD negativity correlating with improved overall survival.

Survivorship challenges include managing treatment-related complications (e.g., peripheral neuropathy, secondary malignancies) and psychosocial support. Bisphosphonates (e.g., zoledronic acid) and denosumab are standard for bone health, reducing skeletal-related events by 50%.

Future Directions: Precision Medicine and Beyond 

Ongoing research focuses on exploiting synthetic lethality (e.g., PARP inhibitors in BRCA-mutated myeloma), targeting aberrant signaling pathways (e.g., RAS-MAPK), and immunoprevention strategies for high-risk MGUS. Liquid biopsy techniques, such as circulating tumor DNA analysis, promise non-invasive monitoring of clonal evolution and resistance mechanisms.

Conclusion 

Multiple myeloma cancer exemplifies the intersection of genetic vulnerability, microenvironmental dysregulation, and therapeutic innovation. While radiographic tools like X-ray remain foundational, advanced imaging and genetic profiling are redefining diagnostic precision. The hereditary component, though modest, underscores the importance of familial risk assessment in precision oncology. As the armamentarium against myeloma expands, integrating novel therapies with robust biomarkers will be pivotal in transforming this once-fatal malignancy into a chronic condition.