Newly Diagnosed Multiple Myeloma: The Prognostic Significance of Lymphopenia

Although clinical and genomic markers of high-risk multiple myeloma (MM) are well established, dynamic immune biomarkers like absolute lymphocyte count (ALC) remain underexplored. To address this gap, a recent study evaluated the prognostic significance of peripheral blood ALC in newly diagnosed MM.

Conducted using data from the Veterans Affairs healthcare system, the research assessed whether ALC at diagnosis and follow-up correlates with overall survival (OS). Here’s an in-depth look at the study.

How the Study Was Designed

The study included 11,427 patients diagnosed with MM, who were identified via electronic health records and cancer registries. The researchers excluded patients with other hematologic malignancies to isolate the impact of MM on ALC.

Patients were then stratified based on ALC levels into three categories:

• Severely low (<1 × 10³/μL)
• Low (1–1.5 × 10³/μL)
• Normal (>1.5 × 10³/μL)

Baseline ALC was recorded within 90 days of diagnosis, with follow-up measurements at six-month intervals for up to 2.5 years. The primary endpoint was OS, which was analyzed using Kaplan-Meier methods and Cox proportional hazards models adjusted for demographic, clinical, and treatment variables.

What the Study Found

Regarding the prevalence of lymphopenia, the study found that:

• Lymphopenia, which is defined as ALC <1.5 × 10³/μL, was present in 53 percent of patients at diagnosis, with 24 percent classified as severely low.
• Median OS decreased with lower ALC levels: 2.7 years in the severely low category, 3.3 years in the low category, and 4.2 years in the normal category (P < .001).

When evaluating the impact of standard therapies, the study found that:

• Patients treated with lenalidomide, bortezomib, and dexamethasone (RVd) experienced improved survival across all ALC categories, yet disparities persisted.
• Median OS for RVd-treated patients was 3.6, 4.6, and 5.7 years for severely low, low, and normal ALC groups, respectively.

The study also examined the impacts of stem cell transplantation and found that:

• Autologous stem cell transplantation (ASCT) significantly improved OS, mitigating the negative impact of lymphopenia. Median OS for transplanted patients was 7.6, 6.8, and 8.1 years across the three ALC categories (P = .351).

In terms of follow-up ALC:

• Persistent or newly developed lymphopenia during follow-up was associated with inferior OS at all time points.
• Patients maintaining normal ALC throughout follow-up demonstrated significantly better outcomes.

When evaluating ALC as an independent prognostic value:

• A multivariable analysis confirmed that low and severely low ALC independently predicted worse OS. Adjusted hazard ratios were 1.09 (P < .01) and 1.29 (P < .01), respectively.

Finally, the study looked at era-specific outcomes and found that:

• Survival improved across all ALC groups with the adoption of novel therapies post-2012. However, lymphopenia remained a significant predictor of poor prognosis.

What These Findings Mean for MM Care

Based on these findings, this study highlights ALC as an independent predictor of OS in newly diagnosed MM patients. Lymphopenia reflects underlying immune dysfunction, including T-cell exhaustion and senescence, which compromises the patient’s ability to respond to treatment. Persistent lymphopenia may also exacerbate susceptibility to infections and reduce the efficacy of immunomodulatory therapies, such as lenalidomide and bortezomib.

And so these findings suggest that integrating ALC into clinical decision-making and predictive models could enhance risk stratification and guide therapeutic planning.

Reference:

Ferri GM, Yildirim C, Do NV, et al. Lymphopenia predicts poor outcomes in newly diagnosed multiple myeloma. Blood Adv. 2025;9(1):78-88. doi:10.1182/bloodadvances.2024014125.