Daratumumab Improves Responses, PFS in Newly Diagnosed, Transplant-Eligible Myeloma

Phillipe Moreau, MD

Phillipe Moreau, MD

The addition of daratumumab (Darzalex) to the triplet bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone (VTd) induction and consolidation in transplant-eligible patients with newly diagnosed multiple myeloma improved both the depth of response and progression-free survival (PFS) compared to VTd alone.

The randomized, open-label, multicenter phase III CASSIOPEIA trial led toa priority review designation from the FDA for daratumumabin combination with VTd for patients who are candidates for autologous stem cell transplant (SCT). This is the first trial to demonstrate a clinical benefit for the combination of daratumumab with the standard of care VTd in this patient population. The FDA is expected to make a decision on the supplemental Biologics License Application by September 26, 2019.

Over 1000 patients were enrolled and randomly assigned to VTd induction and consolidation either with or without the addition of daratumumab. According to results presented at the 2019 ASCO Annual Meeting, the stringent complete response rate was 28.9% with the combination compared to 20.3% in the VTd-alone arm. The median PFS rate at 18 months was 92.7% with daratumumab versus 84.6% without (HR, 0.47; 95% CI, 0.33-0.67;P<.0001). Although the data for overall survival (OS) are still immature and the median OS was not reached in either arm, at 24 months the OS rate was 97% with added daratumumab versus 93% without.

Administering daratumumab in combination with VTd both before and after SCT did not demonstrate additional safety concerns in this setting. The most common grade 3/4 treatment-emergent adverse events noted with the addition of this agent included neutropenia (27.6% with daratumumab vs 14.7% with VTd alone), lymphopenia (17.0% vs 9.7%, respectively), stomatitis (12.7% vs 16.4%), and thrombocytopenia (11.0% vs 7.4%).

CASSIOPEIA is a 2-part study; the second part of this trial will randomize patients to receive either daratumumab maintenance or no maintenance. The second phase of the trial is currently ongoing and the researchers expect that a long follow-up is needed.

In an interview withTargeted Oncology,Phillipe Moreau, MD, head of the Hematology Department at the University Hospital of Nantes, France, discussed the findings from the phase III CASSIOPEIA trial and the potential role for daratumumab in patients with newly diagnosed multiple myeloma in combination with standard-of-care VTd before SCT.

TARGETED ONCOLOGY:Could you share some background on the CASSIOPEIA study?

Moreau:SCT is the standard of care for newly diagnosed young patients with multiple myeloma. We wanted to improve on the results of the standard of care that is the combination of VTd followed by SCT, followed by VTd consolidation. We did a phase III randomized study of more than 1000 patients with or without the addition of daratumumab. The study has completed enrollment but patients are still receiving maintenance or no maintenance.

TARGETED ONCOLOGY:What are the current findings for part 1 of the trial?

Moreau:The study clearly showed that both before maintenance and after consolidation, the addition of daratumumab is increasing the response rate, the quality of the response, the depth of the response, and minimal residual disease (MRD) negativity; this translates into a better PFS, a significant PFS benefit, with a hazard ratio less than 0.5 [compared to VTd alone]. In the future, the study could definitely be a game changer, and the study will be the pivotal study for the approval of daratumumab in the context of SCT.

TARGETED ONCOLOGY:Did you see any additional toxicity concerns with the addition of daratumumab to the triplet regimen?

Moreau:It was important to look at the safety with the addition of a monoclonal antibody to the triplet combination, but in fact, there is no difference in terms of safety. The addition of daratumumab does not increase the toxicity of the triplet regimen. This is a very important finding.

TARGETED ONCOLOGY:Where do you see this regimen fitting in to the treatment landscape for patients with myeloma?

Moreau:The VTd regimen is commonly and widely used in Europe. In the United States, we are using lenalidomide (Revlimid) instead of thalidomide and mostly bortezomib, lenalidomide, and dexamethasone (VRd) instead of VTd, but we think that we can extrapolate the results of the CASSIOPEIA trial to the use of VRD plus daratumumab in the United States. This will be confirmed in an ongoing prospective study comparing VRD plus daratumumab.

TARGETED ONCOLOGY:What are the next steps now for the CASSIOPEIA study?

Moreau:The study will potentially lead to an approval, so the next step now is to look at part 2 of the study. The study after consolidation was followed by a second randomization to look at daratumumab maintenance versus no maintenance. These studies are ongoing, so we need to have a long follow-up to see the outcome of patients receiving daratumumab maintenance.

TARGETED ONCOLOGY:Considering we&rsquo;ve primarily seen lenalidomide used as maintenance therapy for these patients, what is the rationale for investigating daratumumab in this setting?

Moreau:Daratumumab can be a good option, especially for those patients with MRD, so we may see daratumumab—especially subcutaneous daratumumab, in the future as another drug that can be used in the maintenance phase. Currently, only lenalidomide is approved, but daratumumab or ixazomib (Ninlaro) or the combination of lenalidomide plus daratumumab could be of interest in the future. We are awaiting the results of ongoing studies.

TARGETED ONCOLOGY:What do you think the implications are for sequencing with this regimen or others? What other unmet needs or challenges still need to be addressed for this quadruplet regimen?

Moreau:I think that when we are going to use quadruplet combination including CD38 antibodies plus SCT, we are going to cure some young patients. The goal now is to cure younger patients. We also need to improve the outcome of elderly patients, and we know that daratumumab plus conventional regimens or lenalidomide, for example, in the frontline is highly improving the PFS; now we have to learn how to sequence different combinations in order to have a very, very long duration of response. Those trials are ongoing for sure.

With the CASSIOPEIA trial, we are showing that we can improve on the results of patients with high cytogenetics, potentially not overcoming it entirely in the poor prognosis, but there is a benefit for patients with higher cytogenetics. We know that this patient group represents a really challenging, difficult-to-treat patient population.

Reference:

Moreau P, Attal M, Hulin C, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 1 results.J Clin Oncol. 2019;37(suppl; abstr 8003).