Multiple Myeloma and Anemia: The Biological Connection

Multiple myeloma, a cancer of plasma cells in the bone marrow, frequently leads to anemia, a condition marked by a reduced number of red blood cells (RBCs). This can worsen fatigue, weakness, and overall quality of life for those affected. Understanding the biological mechanisms behind this connection is essential for improving patient management and treatment strategies.

Several factors contribute to anemia in multiple myeloma, including disruptions in blood cell production, inflammatory responses, and hormonal imbalances. Examining these mechanisms provides insight into why anemia develops and how it can be identified.

Bone Marrow Infiltration And Reduced Erythropoiesis

Anemia in multiple myeloma is closely tied to the infiltration of malignant plasma cells in the bone marrow. Normally, the bone marrow produces red blood cells, but as myeloma progresses, the proliferation of plasma cells disrupts this process by displacing erythroid precursors and altering the bone marrow environment. This reduces available space and resources for red blood cell production, leading to a decline in circulating erythrocytes.

Beyond crowding, myeloma cells disrupt regulatory signals governing erythropoiesis. Bone marrow stromal cells, which support blood cell production, become dysregulated, affecting the secretion of growth factors such as stem cell factor (SCF) and interleukin-3 (IL-3), both necessary for erythroid progenitor development. Additionally, myeloma cells interfere with erythropoietin (EPO), a kidney-produced hormone that stimulates red blood cell production. Despite normal or elevated EPO levels in some patients, the bone marrow remains unresponsive due to impaired receptor signaling on erythroid progenitors.

The bone marrow environment also undergoes remodeling, further suppressing erythropoiesis. Increased deposition of extracellular matrix components, such as fibronectin and collagen, creates fibrosis, which hinders hematopoietic stem cell mobility and proliferation. This fibrosis, often found in advanced disease stages, contributes to ineffective erythropoiesis. Additionally, altered oxygen levels in the bone marrow, driven by the metabolic activity of myeloma cells, can disrupt hypoxia-inducible factor (HIF) signaling, a pathway essential for erythropoietin-mediated red blood cell production.

Impact Of Increased Cytokine Activity On RBC Survival

In multiple myeloma, excessive pro-inflammatory cytokines reduce red blood cell lifespan. Elevated levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interferon-gamma (IFN-γ) accelerate erythrocyte destruction and impair function by promoting oxidative stress, altering membrane integrity, and increasing clearance by macrophages.

Cytokines contribute to RBC destruction through oxidative damage. Elevated TNF-α and IL-6 levels increase reactive oxygen species (ROS), leading to lipid peroxidation and protein oxidation in erythrocyte membranes. This weakens membrane stability, making RBCs more prone to hemolysis. Studies show that multiple myeloma patients exhibit increased markers of oxidative stress, such as malondialdehyde (MDA) and reduced glutathione (GSH), correlating with lower hemoglobin levels and impaired RBC function.

Additionally, cytokine-induced changes in RBC membrane composition accelerate their removal. IFN-γ and TNF-α alter phosphatidylserine (PS) expression on RBC membranes, marking them for clearance by splenic macrophages. Normally, PS is confined to the inner membrane layer, but cytokine-driven dysregulation causes its externalization, leading to premature RBC destruction.

Cytokine activity also affects RBC deformability, essential for their passage through microvasculature. IL-6 and TNF-α interact with cytoskeletal proteins such as spectrin and ankyrin, reducing membrane fluidity. This rigidity increases mechanical stress as RBCs navigate capillaries, further predisposing them to fragmentation and clearance. Research links elevated inflammatory mediators with reduced RBC deformability in anemic individuals, reinforcing the connection between cytokine activity and shortened erythrocyte lifespan.

Hormonal Pathways Affecting RBC Levels

Erythropoiesis is regulated by hormonal signals, and disruptions in these pathways contribute to anemia in multiple myeloma. Erythropoietin (EPO), primarily produced by the kidneys, stimulates erythroid progenitors in the bone marrow. However, in multiple myeloma, bone marrow cells often fail to respond adequately to EPO, despite normal or elevated circulating levels. This resistance is linked to altered receptor expression on erythroid precursors, reducing their capacity to mature into functional RBCs.

Other hormonal systems also influence RBC levels, including the renin-angiotensin-aldosterone system (RAAS). Angiotensin II enhances erythropoiesis by stimulating erythroid progenitor proliferation, but kidney dysfunction—a common complication in myeloma—can disrupt RAAS, further suppressing RBC production.

Corticosteroids, often used in myeloma treatment, can have mixed effects on erythropoiesis. While they may temporarily boost RBC production by reducing inflammation, long-term use can suppress endogenous hormone release, disrupting erythroid homeostasis.

Thyroid hormones also play a role in RBC regulation by promoting erythroid progenitor proliferation and enhancing erythropoietin sensitivity. Hypothyroidism, which can develop in some myeloma patients due to disease-related metabolic changes, is associated with reduced erythropoiesis and lower hemoglobin levels. Similarly, testosterone enhances erythropoietin synthesis and directly stimulates erythroid progenitors. Low androgen levels, whether due to disease progression or treatment effects, may worsen anemia.

Identifying Anemia In Myeloma Through Lab Tests

Diagnosing anemia in multiple myeloma requires laboratory evaluations of RBC quantity, quality, and underlying causes. A complete blood count (CBC) is the primary diagnostic tool, revealing reductions in hemoglobin concentration, hematocrit, and RBC count. In myeloma-related anemia, hemoglobin levels often fall below 10 g/dL, with more pronounced declines in advanced stages. The mean corpuscular volume (MCV) typically remains within the normocytic range, though variations may occur due to renal impairment or nutritional deficiencies.

Reticulocyte count provides insight into bone marrow activity. In myeloma, reticulocyte production is often low despite anemia, reflecting impaired erythropoiesis rather than increased RBC destruction. This distinguishes myeloma-related anemia from hemolytic conditions, where reticulocyte levels are elevated as compensation for RBC loss. Serum ferritin and transferrin saturation help rule out iron deficiency, particularly in patients undergoing frequent phlebotomy or experiencing chronic inflammation.

Additional biochemical markers refine the diagnosis. Serum erythropoietin levels, though sometimes elevated, often fail to reach compensatory levels expected for the degree of anemia, indicating an inadequate marrow response. Lactate dehydrogenase (LDH) and haptoglobin measurements help exclude hemolysis, while renal function tests assess whether kidney involvement exacerbates anemia. Bone marrow aspiration and biopsy, though not routinely performed for anemia alone, can confirm myeloma infiltration and evaluate overall hematopoietic activity.

Common Symptoms Linked To Diminished RBC Count

A reduced red blood cell count in multiple myeloma leads to a range of symptoms that worsen as anemia progresses. The most common is persistent fatigue, caused by decreased oxygen delivery to tissues. With fewer RBCs transporting oxygen, cellular metabolism slows, leading to exhaustion that does not improve with rest. Patients often describe a deep, unrelenting tiredness that affects daily activities.

Shortness of breath, particularly during physical exertion, arises as the body compensates for lower oxygen levels by increasing respiratory effort. Even mild activities, such as climbing stairs, can provoke breathlessness. Dizziness and lightheadedness, especially when transitioning from sitting to standing, occur due to reduced oxygenation of the brain.

In more severe cases, anemia can cause palpitations and an increased heart rate as the cardiovascular system works harder to circulate oxygen-depleted blood. Patients may also notice pallor, particularly in the skin and mucous membranes, as lower hemoglobin levels reduce the characteristic red coloration of well-oxygenated tissues. These symptoms collectively diminish quality of life, compounding the challenges of multiple myeloma.