New US approval sought for Darzalex Faspro quadruple therapy

Johnson & Johnson (J&J) is seeking U.S. Food and Drug Administration (FDA) approval for a quadruple treatment regimen based on Darzalex Faspro (daratumumab and hyaluronidase-fihj) for adults with newly diagnosed multiple myeloma for whom a stem cell transplant was not initially planned.

The quadruple regimen combines Darzalex Faspro — the subcutaneous, or under-the-skin, formulation of the older myeloma therapy Darzalex (daratumumab) — with the standard VRd triple-therapy regimen of bortezomib (sold as Velcade, with generics available), lenalidomide (sold as Revlimid and generics), and dexamethasone.

That same Darzalex Faspro-VRd combo, dubbed D-VRd, was cleared for use earlier this year in the U.S. for newly diagnosed myeloma patients who are eligible for autologous stem cell transplant (AHSCT).

Should the agency approve the new regulatory request, the D-VRd combo could be used as a first-line therapy regardless of patients’ transplant eligibility. The treatment, if approved, would represent the 10th multiple myeloma indication for Darzalex Faspro in the country.

“Darzalex Faspro-based therapies continue to be at the forefront of multiple myeloma research,” Craig Tendler, MD, vice president of late clinical development and global medical affairs at Johnson & Johnson, said in a company press release, noting that the new FDA application was based on clinical trial findings.

CEPHEUS clinical trial shows positive results for Darzalex Faspro

Those findings were the positive results of the CEPHEUS Phase 3 clinical trial (NCT03652064), which tested the combination regimen in nearly 400 newly diagnosed multiple myeloma patients who were transplant-ineligible or for whom the approach was deferred.

The results showed that the Darzalex Faspro combo was significantly superior to VRd alone at promoting the elimination of all myeloma cells and lowering the risk of myeloma progression or death.

“The data from CEPHEUS add to the body of evidence for Darzalex Faspro in newly diagnosed multiple myeloma and, together with the results of the PERSEUS study [which supported the approval for transplant-eligible patients], demonstrate the potential benefit of this quadruplet regimen for newly diagnosed patients, regardless of transplant eligibility,” Tendler said.

The CEPHEUS findings were shared during the 2024 International Multiple Myeloma Society Annual Meeting, held last month in Rio de Janeiro.

The data from CEPHEUS add to the body of evidence for Darzalex Faspro in newly diagnosed multiple myeloma and, together with the results of the PERSEUS study [which supported the approval for transplant-eligible patients], demonstrate the potential benefit of this quadruplet regimen for newly diagnosed patients, regardless of transplant eligibility.

In an earlier J&J press release announcing the study results, Saad Z. Usmani, MD, a CEPHEUS investigator, said the D-VRd combo “has compelling efficacy characterized by deep, durable responses and reduced risk of disease progression in the frontline population of patients not undergoing transplant.”

The data “[support] the potential of this quadruplet to become a new regimen in this treatment setting,” said Usmani, also the chief of the myeloma service at Memorial Sloan Kettering Cancer Center in New York.

Multiple myeloma is a type of blood cancer affecting white blood cells in the bone marrow called plasma cells. Abnormal plasma cells grow uncontrollably, replacing healthy blood and bone marrow cells.

A standard treatment for newly diagnosed multiple myeloma is transplant, or AHSCT. The objective is to repopulate the patient’s bone marrow with healthy stem cells obtained from the patient — essentially a reset of sorts of the blood cells. Patients are evaluated to determine eligibility for this treatment, but not all can undergo the procedure.

Combinations of treatments that induce cancer cell death and reactivate the immune system to boost their elimination are used before the transplant for myeloma cell depletion — known as induction therapy — as well as after transplant to enhance its therapeutic effect. After transplant, it is called a consolidation therapy.

Both Darzalex, administered intravenously or directly into the vein, and Darzalex Faspro, given via subcutaneous injections, contain daratumumab, an antibody that targets CD38, a protein abundant on the surface of myeloma cells. Its binding to CD38 induces the death of myeloma cells.

Therapy shows ‘potential’ for all patients regardless of transplant eligibility

The clearance of the Darzalex Faspro-VRd combo for newly diagnosed patients eligible for AHSCT was based on results from the ongoing Phase 3 PERSEUS trial (NCT03710603). That study launched in late 2018 and involves 709 participants. Data thus far showed that the quadruple therapy led to significantly better results than VRd alone, reducing the risk of myeloma progression or death by 58%.

The ongoing CEPHEUS trial, meanwhile, is testing the D-VRd combo against VRd alone in 396 newly diagnosed patients for whom AHSCT was not planned as initial therapy.

Its main goal was to assess the proportion of participants achieving minimal residual disease (MRD)-negativity, reflecting the absence of the small number of cancer cells that can remain in a patient’s body after treatment, and ultimately drive cancer relapse and progression.

“CEPHEUS is the first registrational study with a primary [goal] of MRD-negativity filed by Johnson and Johnson in multiple myeloma,” Tendler said.

After a median follow-up of 58.7 months, or nearly five years, the results showed that a significantly greater proportion of patients treated with D-VRd reached MRD-negativity compared with those on VRd alone (60.9% vs. 39.4%). Furthermore, patients on the quadruple combination had a 43% reduced risk of disease progression or death.

Patients on the Darzalex Faspro combo also were significantly more likely to achieve complete remission, or when there are no detectable signs of cancer (81.2% vs. 61.6%).

According to Usmani, the quadruple regimen reduced the risk of disease progression in patients who were not slated for transplant.

The overall safety profile of the D-VRd combination was consistent with what has been observed with both Darzalex Faspro and VRd individually.

Robin Carson, MD, J&J’s global head of oncology, said the combo regimen “has the potential to be a foundational frontline therapy across all patient types.”

“We look forward to continuing to advance this potential new quadruplet therapy and deliver on our commitment to transforming outcomes for people with multiple myeloma,” Carson added.