Darzalex Combo Increases Response Rates in Newly Diagnosed Multiple Myeloma Patients, Trial Shows

Adding Darzalex (daratumumab) to a combination of Velcade (bortezomib), Revlimid (lenalidomide), and dexamethasone — called the VRd combo — increases the proportion of people with multiple myeloma who experience a decrease in tumor burden, a Phase 2 trial shows.

The results occurred among newly diagnosed patients eligible to receive high-dose therapy and autologous stem cell transplant (ASCT).

The findings were presented by Janssen Pharmaceuticals at the 17^th International Myeloma Workshop (IMW) meeting, held recently in Boston, in an oral presentation titled “Daratumumab + Lenalidomide, Bortezomib & Dexamethasone Improves Depth of Response in Transplant-eligible Newly Diagnosed Multiple Myeloma: GRIFFIN.” (See page 546 of the abstract book.)

“The GRIFFIN study is the second randomized study to investigate the benefit of daratumumab for patients with newly diagnosed multiple myeloma who are eligible for a transplant, and the first in combination with lenalidomide for this population,” Peter M. Voorhees, MD, GRIFFIN principal investigator at Levine Cancer Institute, said in a press release.

The randomized, open-label, GRIFFIN Phase 2 trial (NCT02874742) sought to determine if the addition of Darzalex to the VRd combo would be able to increase the percentage of people responding to treatment, compared with VRd alone.

The trial’s primary endpoint was to determine the percentage of patients achieving a a stringent complete response (sCR). Secondary endpoints included overall response rate (ORR), as well as the percentage of patients achieving a very good partial response (VGPR) or better, and a complete response or better.

Complete responses refer to total cancer eradication, while partial responses reflect a significant decrease in disease burden, with no signs of cancer spreading. Stringent complete responses are stronger type of a complete response. A very good partial response is a stronger type of a partial response. The overall response rate measures the percentage of patients whose cancer decreased by a given amount within the study’s time-frame.

Key findings from GRIFFIN, presented at the IMW meeting, showed that:

• After completing six cycles of treatment, and receiving a stem cell transplant, a higher percentage of patients treated with Darzalex (42%) achieved a sCR compared with those treated with VRd alone (32%).
• Darzalex increased the percentage of patients who achieved a VGPR or better (91% versus 73%), a complete response or better (52% versus 42%), and an overall response (99% versus 92%), compared with the VRd combo alone.
• The Darzalex combination also increased the percentage of patients achieving a state of minimal residual disease (MRD) negativity — less than one malignant cancer cell found among 10,000 white blood cells — by more than two times compared with the VRd combo. Those results were 59% versus 24%.
• The most common severe (grade 3) and life-threatening (grade 4) treatment-emergent adverse events in those treated with Darzalex were low levels of blood cells. These included neutrophils (32%), lymphocytes (23%), platelets (16%), and leukocytes (15%);
• Mild (grade 1) and moderate (grade 2) infections were more frequent in people treated with Darzalex. However, the incidence of severe and life-threatening infections were similar in patients from both treatment groups.

“This primary analysis of the GRIFFIN study builds on the safety and efficacy data in the initial group of 16 patients presented at the 2018 American Society of Hematology Annual Meeting,” said Andree Amelsberg, MD, MBA, vice president of oncology medical affairs at Janssen Biotech. “It provides further support for evaluation of Darzalex in the transplant-eligible patient population, which is important as we continue our work to discover new therapeutic approaches to improve outcomes for patients.”

Janssen also presented new data at the IMW meeting from its ongoing PLEIADES Phase 2 trial (NCT03412565). That oral presentation was titled “Subcutaneous (SC) Daratumumab (DARA) in Combination With Standard Multiple Myeloma (MM) Treatment Regimens: An Open-label, Multicenter Phase 2 Study (PLEIADES).” (See page 24 of the abstract book.)

PLEIADES is comparing the effects of a new formulation of Darzalex, administered in newly diagnosed patients by an under-the-skin (subcutaneous) injection in combination with either Velcade, Revlimid and dexamethasone, or with Velcade, melphalan and prednisone. Those with relapsed or refractory multiple myeloma are given under-the-skin Darzalex injection in combination with Revlimid and dexamethasone.

Another group has been added to the trial, testing subcutaneous Darzalex in combination with Kyprolis (carfilzomib) and dexamethasone. That study, which is expected to end in November 2021, is still recruiting adults at select sites worldwide. Enrollment information is available here.

New data from PLEAIDES has shown that, when delivered by an under-the-skin injection in combination with standard-of-care medications, the clinical activity and safety profile of Darzalex is similar to that of its intravenous (into the vein) formulation.

However, the new subcutaneous formulation of Darzalex significantly shortened the median duration of treatment administration in all patient groups from three hours (intravenous infusion) to approximately five minutes.

The incidence of infusion-related reactions and injection-site reactions was similar in all participant groups (approximately 7.5%). More than half of those in all groups reported severe and life-threatening treatment-related adverse events. However, only 8% of patients in all groups were forced to discontinue treatment due to these adverse events.

“We’re excited about the opportunity to progress the innovation represented by the Darzalex subcutaneous formulation, which can be administered over the course of minutes and has the potential to offer a reduction in infusion-related events as compared to the approved intravenous formulation,” said Craig Tendler, MD, vice president of clinical development and global medical affairs, oncology, at Janssen Research & Development.

“Data from the PLEIADES study demonstrates that the DARZALEX subcutaneous formulation can also be safely administered in combination with standard backbone regimens used for treatment naïve and relapsed/refractory patients with multiple myeloma. It has been included in our recent submission of a Biologics License Application to the U.S. Food and Drug Administration seeking approval of a new Darzalex subcutaneous formulation for patients with multiple myeloma.”