A Randomized Phase 2 Trial Comparing Daratumumab-Bortezomib-Dexamethasone versus Cyclophosphamide-Bortezomib-Dexamethasone in Newly Diagnosed Multiple Myeloma with Light Chain Cast Nephropathy

Acute renal failure caused by light chain cast nephropathy (LCCN) is a major complication of multiple myeloma. It is one of four myeloma-defining events—and of these, it has the most significant impact on overall survival.

In healthy individuals, light chains are fundamental components of monoclonal antibodies that plasma cells produce to help fight infections and other harmful substances. However, when cancerous plasma cells (myeloma cells) produce light chains in excessive amounts, acute kidney damage, or LCCN occurs, requiring immediate treatment.

The standard treatment for multiple myeloma typically involves a combination of several drugs. However, patients with multiple myeloma and LCCN often face limited treatment options and delayed access to novel drugs due to their compromised kidney function. As a result, treatments may not be as effective, and survival may be shorter than for other myeloma patients. Additionally, they are routinely excluded from clinical trials. This has led to a knowledge gap and discrepancies in management among myeloma specialists nationwide.

To address this issue, researchers with the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) have developed the EAA241 clinical trial. They hypothesize that incorporating daratumumab, a novel targeted therapy, into timely treatment may be the key to reversing kidney failure in these patients. Recovery of kidney function may allow treatment to be more effective, potentially improving survival.

Patients who enroll in EAA241 will be randomly assigned to receive one of two treatment regimens:

1. Cyclophosphamide-bortezomib-dexamethasone (cy-bor-dex)
2. Daratumumab-hyaluronidase-bortezomib-dexamethasone (dara-bor-dex)

Cyclophosphamide is a chemotherapy used to treat several different types of cancer. Bortezomib is a targeted therapy. Dexamethasone is a steroid medication that suppresses the immune system, helping to reduce inflammation and alleviate painful symptoms. Cy-bor-dex is the control arm for this trial because it is the most common regimen currently in use for patients with multiple myeloma and LCCN.

Daratumumab-hyaluronidase is a newer drug combination. Daratumumab is a monoclonal antibody that works by targeting the CD38 protein found on myeloma cells. Hyaluronidase allows daratumumab to be given by injection under the skin, and in less time than daratumumab alone. In 2024, the US Food and Drug Administration approved a daratumumab-hyaluronidase–based treatment combination for multiple myeloma.  

EAA241’s primary objective is to determine whether incorporation of daratumumab-hyaluronidase into the treatment algorithm for patients with LCCN improves efficacy. If this randomized phase 2 trial shows positive results, it will be the first step to establishing evidence-based guidelines for patients with LCCN.

To be eligible for the study, patients must have multiple myeloma, newly diagnosed LCCN, and newly onset renal failure. Patients may have received prior myeloma targeting therapy, including cyclophosphamide, bortezomib, and/or dexamethasone, if no more than one cycle was administered and the last dose was within 30 days prior to randomization. Patients must not have received any anti-CD38 monoclonal antibodies.

Learn more about EAA241 at ecog-acrin.org.

The study chair for this trial is Amany Keruakous, MD, MS (Augusta University Medical Center) and the co-chair is Amber Clemmons, PharmD, BCOP (Augusta University Medical Center). The community co-chair is Natasha Edwin, MD (Providence Saint Vincent Medical Center).