A CD38 test measures expression of CD38, a surface protein found at very high levels on plasma cells and at variable levels on other immune cells. In multiple myeloma, CD38 helps laboratories identify plasma cells by flow cytometry and is also the target of major treatments such as daratumumab and isatuximab. In chronic lymphocytic leukemia (CLL), CD38 has historically been used as a prognostic marker: a larger CD38-positive fraction of the CLL clone tends to be associated with more biologically active disease, although modern treatment decisions rely more heavily on markers such as TP53 and IGHV status. A positive CD38 result is not a diagnosis of cancer. Normal plasma cells, activated lymphocytes, and other blood cells can express CD38. There is also no universal “normal CD38 level” for these cancer evaluations. The meaning depends on which cells are positive, how strongly they express the antigen, what percentage of the abnormal clone is involved, and whether the patient has received CD38-directed therapy.
- In myeloma, CD38 is usually bright on plasma cells. It helps identify the plasma-cell population but does not prove that the cells are malignant.
- In CLL, higher CD38 expression can be associated with more active disease biology. It is a prognostic marker, not a stand-alone reason to start treatment.
- There is no single CD38 cutoff that applies to every disease and laboratory. CLL studies often used percentage thresholds, while myeloma testing focuses on plasma-cell identification and phenotype.
- Anti-CD38 therapy can change the test. Daratumumab and related drugs can reduce or mask CD38 detection, so follow-up flow panels use alternative markers.
- CD38-directed treatment also affects blood-bank testing. Patients receiving these antibodies should make sure transfusion services know about the therapy.
Table of Contents
- What CD38 Is and Why It Is Tested
- How CD38 Testing Is Done
- What CD38-Positive Staining Means
- CD38 in Multiple Myeloma
- CD38 in Chronic Lymphocytic Leukemia
- Treatment Effects and MRD Testing
- Limitations and Next Steps
What CD38 Is and Why It Is Tested
CD38 is a multifunctional cell-surface glycoprotein that acts both as an ectoenzyme and as a signaling-associated receptor. It is expressed across several immune-cell types, but mature plasma cells are notable for very bright CD38 expression.
That strong expression makes CD38 useful in plasma-cell disorders. Flow cytometry laboratories often start plasma-cell identification by looking for cells with very bright CD38 together with CD138 and other markers. They then determine whether those plasma cells have an abnormal phenotype and a restricted kappa or lambda light-chain pattern.
CD38 also appears on subsets of B cells, T cells, natural killer cells, myeloid cells, and activated immune cells. In CLL, the leukemic B-cell clone can contain different proportions of CD38-positive cells. This led to its use as a prognostic biomarker long before today’s targeted treatment era.
Common reasons to test CD38 include:
- identifying plasma cells in suspected multiple myeloma or related disorders;
- distinguishing normal from abnormal plasma-cell populations with a multiparameter panel;
- characterizing CLL biology and older prognostic profiles;
- establishing a baseline immunophenotype for later comparison;
- evaluating marker changes after therapy; and
- supporting research or treatment strategies directed against CD38.
CD38 is not cancer-specific. A normal plasma cell can be CD38-bright, and an activated lymphocyte can become CD38-positive. The clinically useful question is therefore not “Is CD38 present?” but “Which cells express it, at what level, and what else is abnormal about those cells?”
The related CD138 test is commonly used alongside CD38 in plasma-cell assessment, especially in bone marrow.
Why CD38 is more than a label
CD38 is also an enzyme involved in nicotinamide adenine dinucleotide metabolism and the generation of signaling molecules that influence calcium pathways. In malignant cells, it participates in interactions with the surrounding immune and bone marrow environment. This biology helps explain why CD38 can correlate with activation in CLL and why it became a successful therapeutic target in myeloma.
Its abundance is not constant across all cells. Plasma cells generally carry far more CD38 than ordinary lymphocytes, which is why flow cytometrists often describe them as “CD38 bright.” Activated lymphocytes may increase CD38 temporarily, while quiescent cells may express much less. The same protein can therefore signal normal differentiation, immune activation, malignant biology, or a drug target depending on the population being examined. This is another reason the cell gate and accompanying markers are essential parts of the result.
How CD38 Testing Is Done
CD38 is usually assessed by flow cytometry in blood or bone marrow, although immunohistochemistry can also detect it in tissue. Flow cytometry is especially useful because it can measure CD38 simultaneously with many other markers on individual cells.
In a myeloma panel, a laboratory may use CD38, CD138, CD45, CD19, CD56, CD117, CD27, CD81, CD229, BCMA, and cytoplasmic kappa/lambda in different combinations. Normal plasma cells and myeloma plasma cells overlap in CD38 and CD138 expression, so the abnormal population is defined by the complete pattern rather than one antigen.
In CLL, CD38 is measured on the clonal B-cell population identified through markers such as CD19, CD5, CD23, CD20, light chains, and other B-cell antigens. The laboratory can report the proportion of leukemic cells that are CD38-positive and may describe expression intensity.
The result may be expressed as:
- positive or negative;
- percentage of the abnormal population above a validated threshold;
- dim, moderate, or bright intensity;
- a continuous fluorescence measure in specialized analyses; or
- part of a qualitative immunophenotype.
There is no fasting requirement for CD38 itself. The collection procedure depends on the sample. CLL often can be characterized from peripheral blood, while myeloma usually requires bone marrow for full cellular assessment and MRD testing.
Sample handling matters. Plasma cells can be fragile, and marrow aspirates can be diluted with peripheral blood. Either problem can reduce the apparent number of plasma cells. Tissue biopsy and flow cytometry can therefore provide complementary information.
What CD38-Positive Staining Means
CD38 positivity means that the tested cells express CD38; its significance is disease-specific. The same phrase can mean something very different in a myeloma flow report, a CLL prognostic panel, or an immune-activation study.
| Setting | Meaning of CD38 positivity | What it does not mean |
|---|---|---|
| Normal plasma cells | Expected strong expression | Does not indicate myeloma |
| Myeloma plasma cells | Helps identify the plasma-cell population and a therapeutic target | Does not establish clonality by itself |
| CLL cells | Higher positive fractions have historically correlated with more active biology | Does not determine when treatment must start |
| Activated lymphocytes | Can reflect immune activation | Does not necessarily represent lymphoma or leukemia |
| After anti-CD38 therapy | Expression may appear reduced or difficult to detect | A negative result does not prove the plasma-cell clone is gone |
Unlike a blood chemistry test, CD38 does not have one universal reference interval. In CLL, classic studies often separated groups using a threshold around 30% CD38-positive leukemic cells, but different studies and laboratories have used different approaches, and CD38 can vary over time. A report should therefore be interpreted according to the method that produced it.
The 30% figure is useful historical context, not a universal treatment boundary. A result of 29% is not biologically “safe” while 31% is automatically dangerous. Measurement variation, clone heterogeneity, and continuous differences in antigen density make sharp interpretation around any single cutoff unrealistic. Modern CLL care also has more predictive information available than when CD38 was first adopted. TP53 abnormalities and IGHV mutation status have clearer roles in treatment planning, and the decision to start therapy is based on clinical disease activity rather than a CD38 threshold.
In myeloma, “CD38 bright” is usually more important for locating plasma cells than for assigning a numerical prognosis. Clonality and abnormality are established with other markers, light-chain restriction, morphology, genetics, and clinical criteria.
A percentage also requires a denominator. “80% CD38 positive” should mean 80% of a defined cell population, not necessarily 80% of all marrow cells. The report should identify whether the denominator is CLL cells, plasma cells, lymphocytes, or another gate.
CD38 in Multiple Myeloma
Myeloma plasma cells usually express abundant CD38, which makes the antigen valuable for both detection and treatment. Normal plasma cells also express CD38 strongly, so laboratories combine it with other markers to determine whether the population is neoplastic.
A common abnormal plasma-cell phenotype can include loss of CD19, altered or absent CD45, gain of CD56 or CD117, and restricted cytoplasmic kappa or lambda. The exact phenotype varies, and no single combination is present in every patient. A multiple myeloma test panel integrates the marrow phenotype with monoclonal protein testing, serum free light chains, blood counts, chemistry, imaging, and genetics.
CD38 and CD138 are sometimes described as interchangeable plasma-cell markers, but they have different practical strengths. CD38 is exceptionally bright by flow cytometry and provides a therapeutic target, while CD138 is valuable in tissue for mapping plasma-cell distribution and estimating marrow involvement. Both can be altered by specimen quality or treatment, so a high-quality plasma-cell panel includes additional markers rather than relying on either one alone.
CD38 expression also created one of the major therapeutic advances in myeloma. Daratumumab and isatuximab are monoclonal antibodies that bind CD38. They can kill myeloma cells through several immune mechanisms and are used in many frontline and relapsed treatment combinations.
The amount of CD38 on myeloma cells can change during treatment. Exposure to anti-CD38 antibodies can reduce detectable surface antigen through masking, internalization, trogocytosis, selection of lower-expressing cells, or other biological effects. Consequently, a post-treatment flow panel cannot rely on the same CD38 gate used before therapy.
CD38 expression has also been studied for imaging. Experimental and emerging immunoPET strategies use radiolabeled CD38-targeting molecules to visualize myeloma sites, illustrating how strongly the antigen is expressed in many patients. These imaging methods are different from routine diagnostic flow cytometry and are not a substitute for standard myeloma staging or response assessment.
CD38 in Chronic Lymphocytic Leukemia
In CLL, CD38 is best viewed as a biological prognostic marker rather than a diagnostic requirement or a direct treatment trigger. CLL cells are clonal mature B cells with a characteristic immunophenotype, and CD38 can be expressed on a variable fraction of that clone.
Historically, patients with higher CD38 expression tended to have shorter time to first treatment and more aggressive disease than those with lower expression. CD38-positive CLL cells also show biological features linked to activation, B-cell receptor signaling, migration, and interaction with supportive tissue microenvironments.
However, CD38 is not a perfect surrogate for the most important modern molecular markers. The relationship with IGHV mutation status is incomplete, and CD38 can vary within a patient over time or between disease compartments. Modern CLL risk assessment therefore gives greater clinical weight to TP53 disruption, IGHV status, chromosome abnormalities, complex karyotype in selected settings, clinical stage, and treatment response.
A CLL IGHV mutation test provides stable biological information that is usually assessed before first-line treatment. Likewise, the CLL FISH panel can detect important chromosome abnormalities, including del(17p).
Most importantly, a high CD38 percentage is not by itself a reason to treat asymptomatic CLL. Treatment is initiated for active disease according to clinical criteria such as progressive marrow failure, symptomatic or progressive organ enlargement, significant disease-related symptoms, or other established indications. A person can have a high-risk biomarker and still be appropriately observed if the CLL is not active.
Treatment Effects and MRD Testing
Anti-CD38 therapy can make routine plasma-cell identification more difficult, so laboratories adapt their MRD panels after treatment. Daratumumab can occupy the CD38 epitope recognized by some diagnostic antibodies, and treated plasma cells may genuinely reduce surface CD38.
Alternative identification strategies can include CD138, CD229, BCMA, CD319, CD45, light chains, and other validated combinations. Laboratories also use “different-from-normal” approaches rather than depending on one marker. For myeloma, MRD testing may use highly sensitive flow cytometry or next-generation sequencing.
This creates an important interpretation rule: CD38-negative after daratumumab does not equal MRD-negative. The test must demonstrate that no abnormal plasma-cell population is detectable at the validated sensitivity using a panel that works in the treatment context.
Anti-CD38 antibodies can also interfere with pretransfusion testing because red blood cells express low levels of CD38. This can cause broad reactivity in indirect antiglobulin testing and complicate antibody screening. Blood banks have established methods to manage the interference, but they need to know that the patient is receiving or recently received an anti-CD38 drug. Baseline blood typing and antibody screening before therapy can be valuable, and patients should mention treatment when transfusion care occurs at a different facility.
In CLL, CD38 is not usually the preferred marker for sensitive MRD measurement. Validated CLL MRD methods use broader flow panels or molecular techniques to quantify the leukemic clone at much lower levels.
Limitations and Next Steps
CD38 is highly useful but context-dependent, and both normal biology and therapy can change its appearance. The largest interpretive mistake is treating a positive or negative result as a stand-alone cancer verdict.
Limitations include:
- expression on normal plasma cells and activated immune cells;
- variable expression among CLL cells and over time;
- antigen modulation after anti-CD38 therapy;
- differences in antibody clones and laboratory thresholds;
- hemodilution or low plasma-cell recovery from marrow aspirates;
- disease heterogeneity between marrow sites; and
- imperfect correlation between CD38 and molecular risk markers.
If CD38 is reported in a new myeloma workup, ask whether the plasma cells are clonal, what percentage of marrow they occupy, and what other abnormal markers and genetic findings are present. If CD38 is reported in CLL, ask whether it is being used as historical prognostic context and how it compares with IGHV, TP53, FISH, and the clinical treatment indications.
When comparing serial reports, do not assume a change from 40% to 20% represents a true biological response unless the same cell population, method, and clinical context were evaluated. Antigen percentages can shift because of treatment, sampling, and technical differences.
Useful report questions are simple but revealing: Was CD38 measured on the entire sample or only on the abnormal clone? Was the result obtained before or after anti-CD38 therapy? In myeloma, were plasma cells proven clonal by light chains or another method? In CLL, what were the TP53 and IGHV findings? Is the laboratory using CD38 to identify cells, estimate prognosis, or evaluate a therapeutic target? Clarifying the purpose usually resolves apparent contradictions between reports and helps the hematologist decide which other result deserves the most weight in the patient’s current clinical decision-making process and follow-up plan over time.
CD38 positivity itself is not an emergency. Urgency depends on the underlying disease and symptoms. Severe infection, major bleeding, kidney failure, symptomatic high calcium, spinal cord compression, hyperviscosity, or other acute complications require prompt medical assessment.
References
- CD38-Targeted Molecular Imaging Probes for Multiple Myeloma: Advances, Challenges, and Opportunities 2026 (Review)
- Monoclonal anti-CD38 therapy in human myeloma: retrospects and prospects. 2025 (Review)
- Efficacy and safety of anti-CD38 monoclonal antibodies in patients with newly diagnosed multiple myeloma: an updated systematic review and meta-analysis based on randomized controlled trials 2025 (Systematic Review)
- CD38/NAD+ glycohydrolase and associated antigens in chronic lymphocytic leukaemia: From interconnected signalling pathways to therapeutic strategies. 2024 (Review)
- Flow Cytometry in Diagnosis, Prognostication, and Monitoring of Multiple Myeloma and Related Disorders 2023 (Review)
Disclaimer
This article is for general education and does not diagnose myeloma, CLL, or another blood disorder. CD38 results require interpretation with the full immunophenotype, molecular and chromosome findings, treatment history, sample quality, and clinical status by qualified professionals. Patients receiving anti-CD38 therapy should inform their healthcare and transfusion teams, especially before blood transfusion testing.
