Minimal Residual Disease in Oncology

Author: Melissa Pozotrigo, PharmD, BCOP

Minimal residual disease (MRD) testing has become one of the most important advances in cancer care over the past twenty years. It can find very small amounts of remaining disease that standard methods such as blood tests, biopsy or radiological studies cannot detect. MRD provides valuable information about how well a treatment is working, how likely a patient is to relapse, and what treatment steps to take next. It is important to note that the clinical application of MRD varies dramatically across disease types. In hematologic malignancies, MRD has achieved guideline and regulatory acceptance as well as prospective trial validation. In solid tumors, circulating tumor DNA (ctDNA)-based MRD detection shows strong prognostic value but is still being fine tuned and to date is only approved in the treatment of muscle invasive bladder cancer.

MRD in Hematologic Malignancies

Across hematologic malignancies, MRD status carries prognostic significance, with MRD positivity associated with inferior progression-free survival (PFS) and overall survival (OS).

Acute Lymphoblastic Leukemia

ALL represents the most established application of MRD in oncology. A meta-analysis of 39 studies (>13,000 patients) demonstrated that MRD negativity was associated with markedly improved event-free survival. NCCN guidelines designate MRD quantification as an “essential component” of patient evaluation, recommending assessment at completion of induction, end of consolidation, and prior to allogeneic transplant. In ALL, MRD serves as a regulatory endpoint: blinatumomab received FDA approval for CD19-positive B-ALL in first or second complete remission with MRD ≥0.1%, establishing a precedent for MRD-based drug approvals.

Multiple Myeloma

MM has recently seen a rapid evolution in MRD utilization. In April of 2024, the FDA’s Oncologic Drugs Advisory Committee unanimously voted to recognize MRD-negative complete response as an early endpoint reasonably likely to predict clinical benefit and enabling its use for accelerated approval of MM therapies. This was supported by the EVIDENCE study, a meta-analysis of eight trials in newly diagnosed MM (4,907 patients) showing a strong association between MRD negativity and PFS and an individual-level odds ratio of 4.02 for PFS benefit with 12-month MRD negativity. NCCN guidelines now incorporate International Myeloma Working Group MRD response criteria requiring sensitivity of at least 10⁻⁵. Prospective MRD-guided trials such as PERSEUS and MIDAS are testing treatment intensification and de-escalation strategies based on MRD.

Acute Myeloid Leukemia

In AML, a meta-analysis of more than 10,000 patients showed that MRD negativity by flow cytometry was associated with a hazard ratio of 0.36 for survival. The NCCN provides detailed MRD recommendations including specific assays by molecular subtype and management algorithms for MRD positivity. The 2025 ELN-DAVID update introduced qualitative MRD response categories (optimal, warning, or high risk of treatment failure) tailored to genetic subgroups. However, MRD has not yet been accepted as a formal surrogate endpoint for regulatory approval in AML, as prospective data confirming that MRD-directed treatment effects translate to survival improvements remain limited.

Chronic Lymphocytic Leukemia

In CLL, MRD has moved beyond prognostication into active treatment guidance. The FLAIR trial demonstrated that MRD-guided ibrutinib–venetoclax achieved a 5-year PFS of 93.9%, compared with 79.0% for ibrutinib alone and 58.1% for FCR, with treatment duration individualized by MRD monitoring. NCCN guidelines now list multiple MRD-guided regimens in CLL including venetoclax/ibrutinib, venetoclax/Zanubrutinib, and venetoclax/acalabrutinib with obinutuzumab.

MRD in Solid Tumors

In solid tumors, MRD detection relies primarily on ctDNA. While ctDNA-based MRD has demonstrated prognostic value, its integration into clinical practice remains limited.

An area of key advancement in ctDNA-based MRD is in bladder cancer. Muscle-invasive bladder cancer (MIBC) has emerged as one of the most advanced solid tumor settings for ctDNA MRD based on the landmark IMvigor011 trial. This is the first prospective randomized trial to demonstrate that ctDNA-guided adjuvant immunotherapy improves both DFS and OS in a solid tumor setting. In May 2026, the FDA approved atezolizumab and atezolizumab and hyaluronidase-tqjs as adjuvant treatments for adults with MIBC after cystectomy who have ctDNA MRD positivity. This has also been integrated into the NCCN guidelines as a category 1 recommendation.

Another solid tumor with compelling evidence is colorectal cancer. The randomized DYNAMIC trial in stage II colon cancer showed that a ctDNA-guided approach reduced adjuvant chemotherapy use (15% vs. 28%) without compromising 5-year recurrence-free survival (88% vs. 87%) or overall survival (93.8% vs. 93.3%). The GALAXY observational study (n = 1,039) confirmed postsurgical ctDNA positivity as the most significant prognostic factor for recurrence (HR 10.0). However, the DYNAMIC-III trial in stage III colon cancer, while validating ctDNA as a strong prognostic classifier (3-year RFS 87% ctDNA-negative vs. 49% ctDNA-positive), showed that escalated therapy in ctDNA-positive patients did not improve recurrence-free survival.

Several barriers prevent routine clinical implementation of ctDNA-based MRD in solid tumors. Variable ctDNA shedding across tumor types and histology creates detection challenges, particularly in low-shedding tumors such as gliomas and renal cell carcinoma. Even with tumor-informed assays, postoperative sensitivity ranges from only 45–70%, meaning many patients with residual disease may be missed. No consensus exists on assay type, sampling timepoints, positivity thresholds, or reporting standards. Additionally, it remains unclear whether intervening at molecular relapse rather than at clinical or radiographic relapse improves outcomes.

Conclusions

MRD testing has reached varying levels of clinical adoption and validation across different cancers. In the hematologic malignancies, MRD is a clinically validated, guideline-integrated tool that informs prognosis, risk stratification, and treatment decisions. In solid tumors, ctDNA-based MRD is a powerful prognostic biomarker and the recent FDA approval for atezolizumab has paved the way for the use of MRD in MIBC. However, more needs to be done to establish the standardization and consistent sensitivity needed for routine clinical use. Prospective trials linking MRD-guided interventions to improved survival outcomes will be essential to bridge the gap between prognostic promise and therapeutic utility.

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