Daratumumab Plus Rd Sustains Responses in Transplant-Ineligible Myeloma

Nizar Bahlis, MD

Nizar Bahlis, MD

Daratumumab (Darzalex) in combination with lenalidomide (Revlimid) plus dexamethasone (Rd) wasapproved by the FDA for the treatment of patients with multiple myeloma who are ineligible for autologous stem cell transplant(ASCT) in June 2019 based on prior findings from the phase III MAIA (MMY3008) trial. According to an updated analysis, newly diagnosed patients continued to sustain benefit from daratumumab plus Rd (D-Rd) after 3 years of follow-up.

Overall, 737 patients were randomized to receive either D-Rd or Rd alone, and 44% of the patients were of the age of 75 years or older, representing a real-life patient population with multiple myeloma. After median follow-up of 36.4 months, the median progression-free survival (PFS) had not been reached in the D-Rd arm compared with 33.8 months with Rd (HR, 0.56; 95% CI, 0.44-0.71;P< .0001). The estimated 3-year PFS rate was 68% with D-Rd versus 46% with Rd.

The addition of daratumumab to Rd also resulted in deeper responses. The median duration of response among the responders in the D-Rd group was not reached compared with 40.7 months in the Rd arm. The median PFS2 was also not reached with D-Rd compared with 47.3 months with Rd (HR, 0.69; 95% CI, 0.53-0.91;P= .0079).

Ten percent or less of patients experienced grade 3/4 treatment-emergent adverse events, which included neutropenia in 51% of the D-Rd arm and 35% of the Rd arm, lymphopenia in 15% and 11%, pneumonia in 15% and 9%, anemia in 14% and 21%, leukopenia in 11% and 6%, and hypokalemia in 10% and 10%, respectively. Grade 3/4 infection rates were higher in the D-Rd arm at 36% versus 27% in the Rd alone arm. The most common serious TEAE was pneumonia, which was experienced in 14% of patients in the D-Rd arm and 9% in the Rd arm. Overall, treatment discontinuation due to TEAEs occurred in 9% of the D-Rd group and 18% of the Rd group.

In an interview withTargeted Oncology, Nizar Bahlis, MD, University of Calgary, discussed the updated findings from the MAIA trial, which he presented at the 2019 ASH Annual Meeting. He highlighted the updates to the PFS, OS, and overall response rate (ORR) data, as well as some other areas daratumumab is under investigation now following the positive data from this trial.

TARGETED ONCOLOGY: What was the initial rationale for evaluating daratumumab in combination with Rd?

Bahlis:The treatment of newly diagnosed myeloma until recently has been simply based on using the combination of lenalidomide and dexamethasone or the combination of proteasome inhibitors (PIs) in combination with cyclophosphamide, or with a combination of lenalidomide and dexamethasone as well. With the advent of the novel monoclonal antibodies targeting CD38 and daratumumab which showed dramatic efficacy in the relapsed setting, it was only logical that we move that to the frontline in combination with a backbone therapy of lenalidomide and dexamethasone.

TARGETED ONCOLOGY: What were the updated findings?

Bahlis:The MAIA trial was a randomized phase III trial of daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in transplant-ineligible multiple myeloma. This study was very important because on this particular trial, close to 50% of patients were over the age of 75 years old. That does represent a real practice population of multiple myeloma.

What we saw in the updated findings was an update in the PFS and OS, as well as PFS2. The PFS continues to show sustained improvement in favor of daratumumab, lenalidomide, and dexamethasone. In particular, the median PFS with DRD was still not reached with 68% of the patients remaining cancer-free without progression. In contrast in the control arm, the median PFS has been reached at 33 months. Overall, the HR remains the same at 0.5, and we have a 44% reduction in the risk of death or reduction in favor of DRD.

We also presented an update on the ORR for this study. The CR rate continues to deepen as well. Nearly 50% of the patients have achieved a CR or better. We are also reporting the MRD-negativity rate (10^-5sensitivity threshold). The MRD is now up from 24% to 29%, which is a further 5% of additional patients that achieved MRD-negativity. With the longer follow-up, we can now report that these patients have sustained MRD with 15% of the patients sustaining MRD-negativity at 6 months.

We also reported that the PFS2 data. We see that the PFS2 remains in favor of DRD with a median PFS2 not reached. In the control arm, this is around 46 months. I should also note that with a longer follow-up, we have not seen any new emerging toxicity or treatment-emergent adverse event. Overall, the results continue to favor DRD with significant improvement in ORR, PFS, and we are looking forward to the OS rate, which will hopefully be available in the next year.

TARGETED ONCOLOGY: What is important to take away from these updated findings?

Bahlis:The combination of anti-CD38 antibody, specifically daratumumab, with dexamethasone represents a new standard. We have never seen a median PFS that is in that range, again 68% of patients remain progression-free at 3 years. The median PFS will likely be well beyond the 50-month. This represents a novel frontline therapy that can become the standard to compare to.

As far as what&rsquo;s going to be the subsequent line of therapy in patients progressing on daratumumab and dexamethasone, multiple other agents can be used in that setting, including a PI-based regimen, but we are looking at the possibility of re-treatment of daratumumab at this meeting. The concept of the LYNCH trial, which is looking at retreatment of daratumumab at the time of relapse or disease-progression in combination with carfilzomib. While we are going to use daratumumab in the frontline setting, we hope a future study will demonstrate that daratumumab can be reused in the subsequent lines of therapy as well.

Reference:

Bahlis N, Facon T, Usmani SZ, et al. 1875 Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant: Updated Analysis of Maia. Poster presented at: 2019 American Soceity of Hematology Annual Meeting; December 5-8, 2019; Orlando, FL.