Improved Outcomes with Daratumumab Quadruplet Therapy in Newly Diagnosed Multiple Myeloma

Combination therapies, which use multiple types of treatment together, have long been considered the standard of care for multiple myeloma. People newly diagnosed with myeloma currently receive a triplet therapy called VRd, which is a combination that consists of: 

• Bortezomib: a proteasome inhibitor 
• Lenalidomide: an immunomodulatory drug 
• Dexamethasone: a corticosteroid

Recent research has compared the current standard of care with VRd to a quadruplet regimen, which adds the monoclonal antibody daratumumab (Darzalex, Johnson and Johnson). This quadruplet therapy is called DVRd. The phase 3 PERSEUS study looked at this treatment combination in transplant-eligible patients and the phase 3 CEPHEUS clinical trial studied it for transplant-ineligible patients.  

Study design: Comparing VRd to DVRd for transplant-eligible patients

Results from the PERSEUS clinical trial were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. There were 709 patients with transplant-eligible, newly diagnosed multiple myeloma enrolled in the study. There were 355 patients treated with the current standard of care VRd, followed by maintenance therapy with lenalidomide. The other 354 patients received the quadruplet therapy DVRd, followed by maintenance with daratumumab and lenalidomide. 

Responses were deeper and more lasting for people who received DVRd

The goal of the study was to compare progression-free survival and MRD negativity between the two groups.  

Minimal Residual Disease (MRD) is a highly sensitive measure used in myeloma to check for any remaining cancer cells after treatment.  Sustained MRD negativity is associated with longer periods of progression-free survival (PFS) in people with myeloma.

Read more about how MRD negativity impacts PFS here. 

• 64.8% of patients receiving DVRd achieved MRD negativity lasting at least one year, compared to 29.7% of those who received VRd. 
• At the two-year mark, 55.8% of DVRd patients maintained MRD negativity, compared to 22.6% in the VRd group.

Additionally, people who maintained MRD negativity for a year had better progression-free survival, no matter which treatment they received.  

DVRd may lower early progression rates

Functional high-risk (FHR) patients are those who are not considered high-risk at original diagnosis, but relapse earlier than the average myeloma patient. 

This study measured FHR as disease progression within 18 months of treatment.  

• FHR and progression-related deaths were lower among people who received DVRd (3.1%)  than those who received the VRd (6.8%).     
• When including deaths before cancer progression, 5.4% of DVRd patients were affected compared to 11.0% on VRd.

Study design: Comparing VRd to DVRd for transplant-ineligible patients

The CEPHEUS phase 3 clinical trial also shared results at the 2025 ASCO Annual Meeting. This study focused on people with newly diagnosed multiple myeloma who were not eligible for a stem cell transplant. The trial enrolled 395 patients.  289 of those patients were transplant-ineligible, meaning they were unable to receive a stem cell transplant due to factors like age, overall health, or other medical factors.

Like the PERSEUS trial, CEPHEUS compared VRd to DVRd and measured minimal residual disease (MRD) negativity and progression-free survival (PFS). It also evaluated complete response (CR), which means that there are no detectable signs of cancer following treatment.   

The DVRd regimen led to improved outcomes across all of these measures.

• MRD negativity was achieved by 60.4% of patients treated with DVRd, compared to 39.3% in the VRd group. 
• After a follow-up of 4.5 years, 69% of those receiving DVRd had not experienced disease progression, compared to 48% of those who received VRd.
• 80.6% of patients in the DVRd group achieved CR, compared to 61.4% of patients in the VRd group.  

Rates of overall survival (OS), how long a patient lives after beginning treatment, regardless of the cause of death, were also higher for patients who received DVRd.  

What this means for patients

Achieving and sustaining MRD negativity is an important goal in myeloma care, because of its association with longer remission and improved survival. Both the PERSEUS and CEPHEUS phase 3 trials support the use of DVRd as a treatment option for people with newly diagnosed multiple myeloma.  In both transplant-eligible and transplant-ineligible groups, DVRd offers deeper responses, lower early relapse rates, and longer progression-free survival compared to the current standard of care.

HealthTree is committed to sharing meaningful treatment advances for people living with blood cancer. To read more news about myeloma and emerging treatments, follow the link below. 

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Sources: 

• Phase 3 PERSEUS Trial
• Phase 3 CEPHEUS Study 
• IMF-Understanding the VRd Regimen for Newly Diagnosed Myeloma 
• Definers and Drivers of Functional High-Risk Multiple Myeloma 
• A Rational Approach to Functional High-Risk Myeloma