What Does MRD Mean in Cancer?

MRD once stood for minimal residual disease. It increasingly stands for measurable residual disease. The second wording is more honest, because the test measures what it can detect, not what is truly left.

NCI's definition sets the scale. MRD describes a very small number of cancer cells that remain in the body during or after treatment. It can be found only by highly sensitive laboratory methods able to find one cancer cell among one million normal cells. NCI notes the testing is used mostly for blood cancers such as leukemia, lymphoma, and myeloma.

That last point matters. If you have a solid tumor and someone mentions MRD, they usually mean circulating tumor DNA testing, which is a different technology with a different evidence base.

MRD results carry a sensitivity level, written as a negative power of ten. A threshold of 10 to the minus 4 means one cancer cell among 10,000. Ten to the minus 5 means one in 100,000. Ten to the minus 6 means one in a million.

These are not interchangeable. A sample called negative at 10 to the minus 4 could easily be positive at 10 to the minus 6. The same marrow, the same day, two different answers.

Newer myeloma trials report at the deepest level. NCI describes a trial in people 70 or older or unfit for transplant where 2-year MRD negativity at 10 to the minus 6 was 32.0% with one regimen and 15.7% with another.

So the first question about any MRD result is not positive or negative. It is: at what sensitivity, and by which method?

For B-cell acute lymphoblastic leukemia, MRD is not just prognostic. It is an eligibility criterion.

Blinatumomab, sold as Blincyto, is indicated for CD19-positive B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1%. The label covers adults and children one month and older.

That 0.1% is one cell in a thousand, which is a shallower threshold than the one-in-a-million figure NCI uses to describe MRD in general. It is the line where a specific drug becomes available.

The trial behind it, called BLAST, enrolled 86 adults in first or second complete remission. Complete remission there was defined precisely: under 5% blasts in the marrow, an absolute neutrophil count above 1 Gi/L, and platelets above 100 Gi/L. MRD had to be 0.1% or higher, measured with an assay of at least 0.01% sensitivity. Treatment ran up to 4 cycles, each given as a continuous drip set up and run by the hospital team, so the amount per day is theirs to calculate rather than anything you handle.

Afterward, 45 of 61 patients in first remission and 14 of 25 in second remission went to an allogeneic stem cell transplant while still in continuous complete remission. Cytokine release syndrome, a systemic inflammatory reaction, occurred in 7% of MRD-positive patients, compared with 15% of those with relapsed or refractory disease.

NCI's myeloma summary for clinicians states that assessing MRD in the bone marrow is mandatory for judging efficacy in clinical trials. Then it asks the harder question out loud: does MRD testing outside a trial actually improve outcomes by guiding treatment choice or duration?

Its answer is careful. Reaching MRD negativity after induction is associated with better progression-free survival and better overall survival. But NCI states there are no data suggesting this interim marker improves outcomes by altering later therapy. It further states there are no data suggesting that sustained MRD negativity allows maintenance treatment to be reduced or stopped.

Read that twice if you are hoping a clean MRD result will end maintenance. It is a reasonable hope and it is not yet backed by evidence. Maintenance therapy for multiple myeloma covers what that decision currently rests on.

NCI does note progress on the sampling side: assessing MRD from a blood draw appears feasible using next-generation flow and mass spectroscopy, which would spare people repeated bone marrow procedures.

The pattern repeats. In a prospective trial of 493 people with chronic lymphocytic leukemia, clearing MRD was an independent predictor of overall survival on multivariate analysis.

NCI then notes that this surrogate endpoint did not show improved survival in a randomized prospective trial. It even describes the study that would settle it: take people who do not fully clear the marrow after induction, randomly assign some to more treatment now and others to the same treatment later at relapse, and measure overall survival.

Until that trial is done, an MRD result in CLL tells you something about risk and little about what to do next. Chronic lymphocytic leukemia covers the markers that do currently steer treatment there.

• Which method was used: flow cytometry, PCR, or next-generation sequencing?
• What sensitivity threshold does my lab report, and did it reach that threshold on my sample?
• Was this from bone marrow or from blood?
• Is this result being used to decide something, or to track a trend?
• If it is positive, what specifically would change? If it is negative, what would stay the same?

That last pair matters most. In B-ALL, a number above 0.1% opens a specific drug. In myeloma and CLL, the same kind of result mostly adjusts an estimate. Complete versus partial response explains the broader response wording MRD sits inside.

An MRD result describes a laboratory sample. It does not describe how you feel today. Do not wait for the next scheduled result.

• Call your cancer team immediately if your temperature reaches 100.4 degrees F (38 C) while you are on treatment. That is what CDC says to do, because a fever may be the only sign of an infection and an infection during chemotherapy can be life-threatening. If you cannot reach them, go to an emergency department and say at check-in that you are having chemotherapy. MedlinePlus uses the same 100.4 F figure; NCI's infection page uses 100.5 F.
• Call 911 or go to an emergency department if bleeding will not stop, you cough up blood, or you become suddenly breathless.
• Call your hematology team the same day if you bruise without injury, bleed from the gums, or see blood in urine or stool.
• Call your hematology team within a day or two if bone pain becomes constant, wakes you at night, or starts in a new place; if drenching night sweats return; if you lose weight without trying; or if you get breathless doing something that was easy last month.

• https://webapis.cancer.gov/glossary/v1/Terms/Cancer.gov/Patient/en/minimal-residual-disease
• https://www.cancer.gov/types/myeloma/hp/myeloma-treatment-pdq
• https://www.cancer.gov/types/leukemia/hp/cll-treatment-pdq
• https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=38b482a8-960b-4591-9857-5031ecb830aa
• https://www.cancer.gov/about-cancer/treatment/side-effects/infection
• https://medlineplus.gov/ency/patientinstructions/000913.htm
• https://www.cdc.gov/cancer-preventing-infections/patients/fever.html