What is the significance of a decreased albumin (protein in blood) to globulin (protein in blood) ratio in an older adult patient with multiple myeloma (cancer of plasma cells)?

Albumin-Globulin Ratio in Multiple Myeloma

Clinical Significance

A decreased albumin-to-globulin ratio in an older adult with multiple myeloma reflects both increased tumor burden (elevated globulins from monoclonal protein production) and disease severity (decreased albumin from systemic inflammation and malnutrition), serving as an independent prognostic marker for worse overall survival and progression-free survival. 1

Understanding the Protein Pattern

The pathophysiology involves two simultaneous processes:

• Elevated globulins: Multiple myeloma causes excessive production of monoclonal immunoglobulin (M-protein) by malignant plasma cells, which accumulates in the serum and appears as an abnormal spike in the globulin fraction on serum protein electrophoresis, leading to elevated total globulin levels in approximately 80% of cases 2

• Decreased albumin: Lower serum albumin levels in multiple myeloma patients are associated with clinical factors reflecting disease severity, including older age, lower hemoglobin, poorer performance status, higher beta-2-microglobulin, higher serum M-protein levels, and increased bone marrow plasma cell infiltration 3

• Combined effect: The albumin-to-globulin ratio (AGR) integrates both components, with an optimal cutoff of 1.16 distinguishing prognostic groups—patients with AGR <1.16 have significantly worse overall survival (hazard ratio 1.82) and progression-free survival (hazard ratio 1.53) compared to those with AGR ≥1.16 1

Prognostic Implications

Low AGR (<1.16) functions as an independent adverse prognostic factor even after adjusting for other established markers:

• Multivariate analysis confirms that low AGR independently predicts worse overall survival (HR = 1.82,95% CI = 1.15-2.94) and progression-free survival (HR = 1.53,95% CI = 1.09-2.17) in patients with multiple myeloma 1

• Serum albumin level <3.5 g/dL is itself a significant pretreatment prognostic factor, reflecting disease severity through associations with higher beta-2-microglobulin, higher serum M-protein, and greater bone marrow plasma cell burden 3

• The albumin-to-monoclonal protein (A/M) ratio, a related metric, shows that A/M <1 at diagnosis indicates significantly poorer prognosis at both 2-year (p = 0.01) and 5-year (p = 0.07) survival endpoints, even in patients treated with novel agents like proteasome inhibitors and antiangiogenic therapy 4

Diagnostic Workup When AGR is Decreased

When encountering a decreased AGR in a patient with multiple myeloma, the following evaluation is essential:

• Quantify the M-protein: Order serum protein electrophoresis to identify and quantify the M-spike, which typically appears as a discrete band in the gamma region 2

• Characterize the monoclonal protein: Perform immunofixation electrophoresis to determine the specific heavy chain type (IgG, IgA, IgM) and light chain type (kappa or lambda), as IgA and IgM types carry higher risk of progression compared to IgG 5

• Assess free light chains: Measure serum free light chain assay with kappa/lambda ratio, as an abnormal ratio (either <0.125 or >8) is an independent risk factor for progression with a hazard ratio of 3.5 5

• Evaluate tumor burden: Measure beta-2 microglobulin and lactate dehydrogenase, as these reflect tumor cell burden and are independent prognostic factors 6, 7, 8

• Check for end-organ damage: Obtain complete blood count (assess for anemia), comprehensive metabolic panel (evaluate for hypercalcemia and renal insufficiency), and skeletal imaging to detect lytic bone lesions—the presence of these CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions) distinguishes symptomatic myeloma requiring treatment from asymptomatic disease 6, 7

Important Clinical Caveats

Critical exceptions exist where AGR may not reflect disease burden:

• Light chain-only myeloma (approximately 20% of cases) produces only free light chains that are rapidly cleared by the kidneys, resulting in minimal or no elevation of serum globulin despite active disease—these patients require serum free light chain assay for diagnosis and monitoring rather than relying on AGR 2

• Non-secretory myeloma (approximately 3% of cases) produces no detectable monoclonal protein in serum or urine, resulting in normal or even low globulin levels despite active disease—diagnosis requires bone marrow examination showing ≥10% clonal plasma cells and evidence of end-organ damage 2

• Polyclonal hypergammaglobulinemia from chronic infections, autoimmune diseases, or liver disease produces a broad-based elevation of globulins rather than a discrete M-spike, which can decrease AGR without indicating myeloma progression 2

Monitoring Treatment Response

The gamma gap (total protein minus albumin, which approximates globulin level) serves as a practical marker for monitoring treatment response:

• A significant association exists between gamma gap and M-spike levels both pre- and post-treatment, with high diagnostic accuracy (86.2%) in distinguishing multiple myeloma patients before and after treatment (AUC = 0.735, p = 0.0001) 9

• Serial measurements of AGR during treatment can track disease response, as successful therapy typically results in decreased M-protein (lower globulins) and improved albumin (reflecting reduced disease burden and inflammation), thereby increasing the AGR 9, 1

• The appearance of an abnormal protein band (APB) during follow-up, occurring in 9% of patients (particularly 18.2% of those receiving autologous stem cell transplantation), paradoxically indicates favorable prognosis with significantly better overall survival (HR 0.21,95% CI 0.08-0.52), likely reflecting immune reconstitution 10

Risk Stratification Integration

AGR should be integrated with established risk stratification systems:

• Combine AGR assessment with bone marrow plasma cell percentage (≥10%), serum M-protein level (≥3 g/dL), and serum free light chain ratio (<0.125 or >8) to assign risk points—patients with all three risk factors have median time to progression of only 1.9 years compared to 10 years for those with one risk factor 5

• Consider AGR alongside immunophenotyping results, as ≥95% phenotypically abnormal plasma cells by flow cytometry combined with immunoparesis (decrease in uninvolved immunoglobulins) predicts 5-year progression rates of 72% versus 4% when both factors are present versus absent 5

• Incorporate AGR into the context of cytogenetic abnormalities, as high-risk features like del(17p), t(4;14), and t(14;16) detected by FISH on sorted plasma cells further stratify prognosis 7