Isatuximab Triplet Regimen Improves PFS Compared With Doublet in Relapsed Myeloma

Phillipe Moreau, MD

According to interim findings from the phase III IKEMA study (NCT03275285), progression-free survival (PFS) with combination carfilzomib (Kyprolis) and dexamethasone was prolonged with the addition of isatuximab (Sarclisa) in patients with relapsed multiple myeloma. The trial has met its primary end point of PFS.

The multicenter study randomized patients 3:2 to receive the addition of isatuximab to carfilzomib plus dexamethasone or the doublet regimen alone. Carfilzomib plus dexamethasone is the standard of care for patients with relapsed multiple myeloma, but isatuximab has now received an Orphan Drug designation based on the findings from the IKEMA study.

The addition of this CD38-targeted monoclonal antibody to the doublet regimen showed no new safety signals. The triplet combination also reduced the risk of disease progression or death by 47%. Data on the overall survival were still immature after about 20 months of follow-up.

The trial remains ongoing and is expected to complete by November 2020.

In an interview with Targeted Oncology, Phillipe Moreau, MD, head of the Department of Hematology and professor of clinical hematology at the University Hospital of Nantes, France, discussed the findings from the IKEMA trial and what these date mean for the treatment landscape of relapsed multiple myeloma.

TARGETED ONCOLOGY: Could you first provide some background to the rationale for this study?

Moreau: For patients with relapsed myeloma, IKEMA is comparing carfilzomib and dexamethasone versus carfilzomib plus dexamethasone plus isatuximab. Carfilzomib plus dexamethasone is the standard of care in the relapsed setting, and we know that isatuximab is a monoclonal antibody targeting CD38. It’s interesting to compare carfilzomib plus dexamethasone, 1 of the standard of care regimens, versus carfilzomib plus dexamethasone plus isatuximab. [We hypothesized] this could add some efficacy with the triplet combination.

TARGETED ONCOLOGY: How was the study designed? What did the patient population look like in the IKEMA study?

Moreau: For the patient population enrolling the study, all of the patients were in the relapsed setting with 1 to 3 prior lines of treatment, and obviously no prior treatment with carfilzomib. Patients were not refractory to prior on anti-CD38 antibody. The patients were randomized 3:2, 3 in the isatuximab arm, and 2 in the carfilzomib/dexamethasone arm. Carfilzomib plus dexamethasone was used according to the schedule of the approval, and the same schedule of carfilzomib/dexamethasone was used in the isatuximab arm, where isatuximab was infused intravenously at a dose of 10 mg/kg on day 1, 8, 15 and 22 during cycle 1 and subsequently every 2 weeks. The primary endpoint was PFS.

The median number of prior lines of treatment was 2. The patient characteristics were well balanced in the 2 arms of the study, and we have the median age is 65 years. We have 10% of the patients above the age of 75 years, and roughly one-fourth of the patients presented with high-risk cytogenetics. Importantly as well, 30% of the patients were refractory to lenalidomide at the time of study entry.

TARGETED ONCOLOGY: What were the findings from this analysis?

Moreau: The primary endpoint, PFS, was in favor of the triplet combination over the the carfilzomib/dexamethasone arm; in the control arm, the median PFS was 19.1 months, and that's a good control arm. This was identical to what was described in previous studies for the approval of carfilzomib/dexamethasone in relapsed patients. If we are adding isatuximab on top of carfilzomib/dexamethasone, we are highly improving the PFS with a hazard ratio of 0.53. This represents a 47% reduction in the risk of progression or death with isatuximab. All subgroups of patients are benefiting from the triplet combination for PFS.

We also looked at the overall response rate, which was a secondary endpoint, and in the 2 arms of the study, the response rate was very high but higher in the isatuximab arm. We also looked at the minimal residual disease (MRD)-negativity rate. In the intent-to-treat patient population, the MRD-negativity rate was 30% with isatuximab arm versus 13% without isatuximab. That's a very big difference in favor of the triplet combination. The time to next treatment, which was also a secondary endpoint, was delayed with the isatuximab, significantly delayed with a hazard ratio of 0.56. That's very important from a patient’s point of view. Overall survival data are not mature because of the short follow up of 20 months, so the study is ongoing and we will see further results for overall survival.

The dose intensity was very high in both arms. More than 90% of the patients did receive isatuximab as planned and 91% of the patients did receive carfilzomib as planned in both arms, which means that the addition of isatuximab to carfilzomib/dexamethasone is not impairing the possible use of a triplet combination. That demonstrates the feasibility of the combination.

TARGETED ONCOLOGY: Were there any new safety signals with the addition of isatuximab to this regimen?

Moreau: In terms of safety now, we don't have any increased toxicity with the addition of isatuximab. the number of fatal events was very small and was identical in both arms. The number of adverse events leading to definitive discontinuation of the treatment was low as well and identical in both arms. We don't have any new safety signal with the addition of isatuximab and, for example, the grade 3 or more cardiac failure is 4% in the 2 arms of the study. We do have some infusion-related reactions. We did see infusion-related reactions in 40% of the cases, but only 0.6% were grade 3, so very, very few severe infusion-related reactions, mostly grades 1 or 2 and in the majority of cases, only at the time of the first infusion of the drug. Those infusion-related reactions did not lead to any treatment discontinuations.

TARGETED ONCOLOGY: What are the clinical implications of these data?

Moreau: IKEMA met its primary end point with a significant reduction in the risk of progression or death of 47% with a hazard ratio of 0.53. In the isatuximab arm of the study, the benefit was absorbed across multiple subgroups of patients, including those difficult-to-treat subgroups. The responses were also higher in the isatuximab arm, and the safety profile was manageable with the triplet combination. We can think that this study will be considered for approval of isatuximab for relapsed myeloma patients with 1-3 prior lines of treatment. This combination will potentially represent a new standard of care in this setting.