Multiple Myeloma (MM) is a malignant hematological disease originating from plasma cells, characterized by the uncontrolled proliferation of plasma cells within the bone marrow, leading to immune dysfunction and multisystem damage. MM is the second most common hematological malignancy globally and predominantly affects the elderly [1], remaining incurable to date. Annually, over 580,000 people worldwide are diagnosed with MM [2]. Despite significant therapeutic advances in recent years, the pathogenesis of MM are not fully elucidated, and issues related to relapse and resistance continue to severely impact patient prognosis and quality of life [3].

Existing research has demonstrated a close relationship between the immune system and the development and progression of MM. Immune cells play a crucial role in the MM microenvironment, influencing not only the proliferation and survival of tumor cells but also regulating tumor immune evasion and treatment responses. For instance, regulatory T cells (Tregs) have been found to be significantly increased in MM, and their high levels are associated with poor patient outcomes. These cells promote the immune evasion of MM cells by suppressing anti-tumor immune responses [4]. Moreover, natural killer (NK) cells are found to be functionally impaired in MM patients, affecting their ability to recognize and kill tumor cells. The role of cytokines in immune regulation is also significant [5]. IL-6 produced by marrow stromal cells induces B7-H1 expression on myeloma cells through STAT3, MEK1/2 and JAK2 signaling, this B7-H1 up-regulation increases myeloma-cell proliferation, suppresses apoptosis and confers resistance to dexamethasone and melphalan [6].

However, to date, the specific roles and potential causal relationships of different immune cell subtypes in MM remain poorly understood. This study aims to systematically assess the causal relationships between 731 immune cell subtypes and MM using the Mendelian Randomization (MR) approach. Given the key role of cytokines in immune regulation, this study will also explore the functions of 91 cytokines as potential mediating variables, investigating their roles and potential therapeutic targets in MM.

To further research potential therapeutic targets for MM, this study utilized Summary-data-based MR (SMR) analysis focusing on sunitinib, a marketed targeted therapy primarily used for renal cell carcinoma and other solid tumors. Sunitinib, a multi-target tyrosine kinase inhibitor, inhibits several targets, including the receptor tyrosine kinase (KIT), vascular endothelial growth factor receptor, and platelet-derived growth factor receptor, thereby suppressing tumor angiogenesis and proliferation [7]. Although sunitinib is widely used in solid tumors like renal cell carcinoma and gastrointestinal stromal tumors, its application in MM treatment is limited, with existing studies primarily focusing on its in vitro inhibitory effects on MM cells [8]. The KIT signaling pathway plays a crucial role in the development and progression of various tumors, including MM [9]. The KIT, which has tyrosine kinase activity, can activate a series of downstream signaling pathways by binding to its ligand stem cell factor (SCF), promoting cell proliferation and survival [10]. Whether targeting and inhibiting KIT can effectively alter its mediated therapeutic targets and thus inhibit the growth of MM cells is another focus of this study.

Mendelian Randomization (MR) is a method that uses genetic variations as instrumental variables to assess the causal relationship between exposure factors and outcomes. This approach leverages the random allocation of genes at conception, akin to a randomized controlled trial (RCT), thus avoiding confounders and reverse causality to some extent [11]. This study systematically analyzes a large number of immune cell subtypes and cytokines to unveil key immune mechanisms in the occurrence and progression of MM, providing new insights into the pathophysiology of MM. Additionally, this study identifies potential therapeutic targets, offering theoretical justifications and experimental support for developing new immune-targeted treatment strategies. These findings aim to enhance the treatment outcomes and prognosis of MM patients.

Unlike prior MR screens that examined either immune cells or cytokines in isolation, we combine both layers in a single mediation-aware framework: two-step MR quantifies how cytokines relay immune-cell signals to myeloma risk, while bayesian weighted MR (BWMR) and SMR screen out pleiotropy and link hits to druggable gene expression, yielding ready-to-test targets within one integrated workflow.