Daratumumab/VRd Regimen Has Practice-Changing Potential in Myeloma

Peter Voorhees, MD

The overall safety profile of adding daratumumab (Darzalex) to the standard triplet of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) was consistent with data previously reported for the 3-drug regimen. These findings, along with efficacy data, suggest that this could eventually be a practice-changing option, explained Peter Voorhees, MD.

In the safety run-in cohort to the phase II GRIFFIN trial, daratumumab and VRd induced at least a very good partial response (VGPR) in all patients and a stringent complete response (sCR) or CR in 63% of patients at the end of consolidation therapy, according to data presented at the 2018 ASH Annual Meeting.

With a median follow-up of 16.8 months, 100% of patients reached VGPR or better and 63% achieved sCR or CR by the end of consolidation therapy. The depth of responses continued to improve during maintenance, with 94% of patients achieving sCR or CR, said Voorhees, who is the lead investigator.

All 16 patients experienced at least 1 treatment-emergent adverse event (TEAE); TEAEs in 15 patients were attributed to daratumumab. Fourteen patients (88%) had grade 3/4 AEs, 10 (63%) of which were related to daratumumab.

The most common hematologic AEs of any grade were neutropenia (75%), lymphopenia (75%), thrombocytopenia (50%), and leukopenia (50%). Grade 3/4 hematologic AEs included neutropenia (31%), thrombocytopenia (25%), and lymphopenia (19%). Overall, with manageable toxicity and no new safety signals in patients with relapsed/refractory multiple myeloma.

OncLive: Please provide some background to the Griffin study.

In an interview with OncLive, Voorhees, an associate professor at the University of North Carolina Lineberger Comprehensive Cancer Center, discussed the clinical potential of adding daratumumab to VRd in patients with multiple myeloma.Voorhees: We presented an updated safety and efficacy analysis from the safety run-in cohort of the Griffin trial. This is a randomized phase II trial incorporating daratumumab into the lenalidomide, bortezomib, dexamethasone backbone for newly diagnosed patients with multiple myeloma who are eligible for stem cell transplant.

What has been seen with the addition of daratumumab?

As far as background is concerned, outcomes have clearly improved for these patients. We also know the VRd induction regimen has performed very well, not only for transplant-eligible patients, but also for transplant-ineligible patients. Findings of the IFM 2009 trial, which looked at VRd induction treatment followed by transplant and 1 year of lenalidomide maintenance, demonstrated a CR rate of 60% and a median progression-free survival (PFS) of 50 months. While that is already very good, we are very interested in improving outcomes even further. With that in mind, we [decided to incorporate] daratumumab into that regimen.Daratumumab is an anti-CD38 monoclonal antibody and it has shown to be highly active as a standalone therapy in patients with heavily pretreated multiple myeloma. It has also [shown promise when used] in combination with backbone therapies in the relapsed setting and for newly diagnosed disease. Daratumumab typically increases depth of response and that has translated into improved PFS.

The first thing we did was enroll 16 patients into what we call a safety run-in. The goal of that analysis is to make sure there wasn't any severe toxicity with the first cycle of therapy. We reported some of that information at the 2017 ASH Annual Meeting, and we only saw 3 dose-limiting toxicities out of the 16 patients. They were grade 3 in severity. This allowed us to move on to the phase II portion of the trial, but the focus of the presentation this year is to report efficacy data for the first time.

[In the phase II trial], patients received 4 cycles of daratumumab with RVd induction. They went on to stem cell transplantation. When they were done, they received 3 cycles of daratumumab/RVd consolidation. Patients then received daratumumab and lenalidomide maintenance therapy for 2 years and were allowed to continue lenalidomide until disease progression.

As far as the AEs are concerned, they were largely what you would expect when you add daratumumab to RVd. We did see neutropenia in 75% of the patients, but, importantly, we did not see any grade 4 neutropenia. We saw thrombocytopenia in 50% of the patients. For the nonhematologic AEs, they were, again, what you would expect with this type of regimen. We saw some steroid-related AEs.

There is a lot of interest in infection rates when incorporating daratumumab into this type of regimen for a couple of reasons. We know from previous phase III studies that the rates of neutropenia increase. There also appears to be a signal of hypogammaglobulinemia for patients on CD38-directed therapy.

The follow-up for these patients was quite long, so these patients were well into maintenance therapy. With that in mind, 81% of patients experienced infection at some point. Most of [these infections were of the] upper respiratory tract, but [no events were] worse than grade 3 in severity.

We were most excited about the efficacy data. After induction therapy, 94% of the patients responded to treatment and 56% of patients had at least a VGPR. We only had 6% CRs at the end of induction, but the ORR was 100%; all patients had a VGPR. In the maintenance setting, 15 out of 16 patients had either a CR or sCR. There was also interest about whether or not frontline daratumumab would negatively impact stem cell mobilization at the time of transplant. We did look at this and saw that this was not the case.

What are the take-home messages from this research?

What this all tells us is that this is a very promising regimen. [However], I do want to emphasize the fact that this [analysis] only [looked at] 16 patients, and, in fact, three-fourths of them had stage I disease. We have to be a bit cautious about the infection signal. I would encourage physicians to not use this as their standard of care at this point. We are hopeful that we can provide phase II data in 2019.The main takeaway is, [in terms of safety profile, adding] daratumumab to VRd is what you would expect; there were no surprises with regard to AEs. We can also safely say that stem cell mobilization was not impacted. The responses seem very promising and it is evident that responses deepen over time. This is potentially a regimen that can change practice in the future.

Voorhees PM, Rodriguez C, Reeves B, et al. Efficacy and updated safety analysis of a safety run-in cohort from Griffin, a phase 2 randomized study of daratumumab (dara), bortezomib (V), lenalidomide (R), and dexamethasone (D; dara‐vrd) vs. vrd in patients (pts) with newly diagnosed (ND) multiple myeloma (MM) eligible for high‐dose therapy (HDT) and autologous stem cell transplantation (ASCT). In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 151. ash.confex.com/ash/2018/webprogram/Paper113122.html.