Saad Usmani
MD, Director/Chief of Plasma Cell Disorders, Director of Clinical Research (Hematologic Malignancies), Carolinas HealthCare System

“The next step is utilizing MRD as a potential surrogate for survival to then stop therapy or determine if something more needs to be done to achieve MRD negativity in a given patient.”

Dr. Kenneth Anderson of Harvard Medical School discusses the importance of MRD as a surrogate endpoint in clinical trials for myeloma.

MRD is being explored in hundreds of clinical trials in lymphoid malignancies.4 An analysis of clinical trials found that between 2014 and 2016, nearly 40% of applications submitted to the Division of Hematology Products at the Food and Drug Administration (FDA) contained MRD data.3

MRD represents an attractive surrogate endpoint for drug trials.2,5-7

As advancing therapies have improved clinical outcomes in lymphoid malignancies, it takes an increasing amount of time to reach established clinical trial endpoints such as overall survival (OS) or progression-free survival (PFS).2,5,7

MRD has a well-established association with long-term clinical outcomes, yet it can be assessed at time points earlier than those with OS or PFS. The FDA currently recognizes MRD as a surrogate endpoint in adult patients with acute lymphoblastic leukemia, which may enable clinical trials to be completed in less time, giving patients quicker access to novel therapeutics.2,5-8

ALL

Optimization of Therapy in Adult Patients With Newly Diagnosed ALL or Lymphoblastic Lymphoma by Individualized, Targeted and Intensified Treatment (NCT02881086)9

Minimal residual disease and individualized therapy

The goal of this phase 4 study is to determine how therapies for adult patients with acute lymphoblastic leukemia (ALL) may be optimized by utilizing stratification based on several factors, inclusive of minimal residual disease, and how this individualization of therapy will impact event-free survival, time until consolidation treatment, and disease-free survival.

CLL

Treating Minimal Residual Disease in Patients With CLL After Front-Line Therapy (MERIT; NCT02649387)10

Minimal residual disease as a clinical endpoint

The goal of this phase 2 study is to determine the efficacy of a small molecule agent as a maintenance therapy in patients with chronic lymphocytic leukemia (CLL) who have responded to an initial therapy, but who still have residual disease. The primary endpoint of the study is the rate of responses that are minimal residual disease negative during maintenance therapy.

MM

Short Course Therapy in Patients With MM (NCT03490344)11

Minimal residual disease as a clinical endpoint

The goal of this phase 2 study is to determine the safety and efficacy of a short course of an antibody-targeted therapy in combination with lenalidomide in patients with multiple myeloma (MM), by monitoring the rate of minimal residual disease negativity observed at the end of therapy (6 months).

DLBCL

Effect of BITE Therapy on MRD in DLBCL Subjects Post aHSCT (NCT03298412)12

Minimal residual disease as a clinical endpoint

The goal of this phase 2 study is to determine the efficacy of a bispecific CD19-directed CD3 T-cell engager in patients with high-risk diffuse large B-cell lymphoma (DLBCL) who have received autologous hematopoietic stem cell transplantation (aHSCT), but who are still minimal residual disease positive, by monitoring the minimal residual disease–negative response rate following treatment. Additional endpoints will examine progression-free survival, duration of minimal residual disease–negative status, overall survival, and adverse events.

Alex F. Herrera et al
MD, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope

“Ultimately, clinical trials testing MRD-guided management of patients with lymphoma could transform the treatment paradigm in all lymphoma subtypes.”13

The ability to precisely quantify and track disease burden is driving a paradigm shift in the development and approval of novel therapies.1,2

As the role of MRD continues to grow in the treatment of lymphoid cancers, this resource will be updated. Use this link to request update notifications, receive Key Opinion Leader content, and receive webinar invitations.

References:
  1. Berry DA, Zhou S, Higley H, et al. Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis [published online July 13, 2017]. JAMA Oncol. 2017;3(7):e170580. doi:10.1001/jamaoncol.2017.0580
  2. Anderson KC, Auclair D, Kelloff GJ, et al. The role of minimal residual disease testing in myeloma treatment selection and drug development: current value and future applications [published online for public access April 20, 2017]. Clin Cancer Res. 2017;23(15):3980-3993. doi:10.1158/1078-0432.CCR-16-2895
  3. Gormley N, Bhatnagar V, Ehrlich LA, et al. FDA analysis of MRD data in hematologic malignancy applications [ASCO abstract 2541]. J Clin Oncol. 2017;35(15)(suppl):2541. http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.2541. Accessed July 6, 2018.
  4. ClinicalTrials.gov website. Accessed July 6, 2018.
  5. Landgren O, Devlin S, Boulad M, Mailankody S. Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: a meta-analysis. Bone Marrow Transplant. 2016;51(12):1565-1568.
  6. Munshi NC, Avet-Loiseau H, Rawstron AC. Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: a meta-analysis. JAMA Oncol. 2017;3(1):28-35.
  7. Little RF, McShane LM. Measure for measure: minimal residual disease in CLL. Blood. 2016;128(24):2747-2748. doi:10.1182/blood201611745323
  8. Table of surrogate endpoints that were the basis of drug approval or licensure. US Food and Drug Administration website. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm613636.htm. Accessed October 9, 2018.
  9. Optimization of therapy in adult patients with newly diagnosed acute lymphoblastic leukemia or lymphoblastic lymphoma by individualised, targeted and intensified treatment. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02881086. Published August 26, 2016. Updated March 6, 2018. Accessed July 6, 2018.
  10. Ibrutinib in treating minimal residual disease in patients with chronic lymphocytic leukemia after front-line therapy (MERIT). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02649387?term=NCT02649387&rank=1. Published January 7, 2016. Updated November 17, 2017. Accessed July 6, 2018.
  11. Short course daratumumab in patients with multiple myeloma. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03490344?term=NCT03490344&rank=1. Published April 6, 2018. Updated May 10, 2018. Accessed July 6, 2018.
  12. Effect of blinatumomab on MRD in DLBCL subjects post aHSCT. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT03298412?term=NCT03298412&rank=1. Published October 2, 2017. Updated June 29, 2018. Accessed July 6, 2018.
  13. Herrera AF, Armand P. Minimal residual disease assessment in lymphoma: methods and applications. J Clin Oncol. 2017;35(34):3877-3887.