Daratumumab-Based Triplet Therapy More Effective Than Doublet for MM

Meletios A. Dimopoulos, MD, Professor and Chairman, Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, Greece, discusses the randomized phase 3 APOLLO study on adding daratumumab to pomalidomide and low-dose dexamethasone for patients with multiple myeloma (MM).

Transcript

I am Meletios Dimopoulos. I work at the Department of Clinical Therapeutics at the School of Medicine, National and Kapodistrian University of Athens in Athens, Greece. The data that led to this prospective randomized trial were based on 2 facts.

First of all, the single-agent activity of daratumumab, which has been given traditionally in an IV form, in patients with advanced and/or refractory myeloma. We have seen several studies that indicated that single-agent daratumumab may be associated with a response in approximately 30% of heavily pretreated patients.

On the other hand, the combination of pomalidomide and low-dose dexamethasone has been the standard of care for patients who have been resistant to lenalidomide and bortezomib, or who are intolerant to these agents.

In this prospective randomized trial, the control arm was the administration of pomalidomide and low-dose dexamethasone at the standard fashion, and in the investigational arm, daratumumab was added. In this particular trial, daratumumab was given subcutaneously.

This was the first trial that used a combination of sub-Q daratumumab with other agents. Patients were eligible if they had received and were not responding to lenalidomide and bortezomib. Patients who have received at least 1 prior line of therapy, provided that they were exposed to both bortezomib and lenalidomide.

They were randomized on a 1-to-1 basis to receive pomalidomide and dexamethasone, or the same combination with the addition of daratumumab. The primary endpoint of the study was progression-free survival. The study met its endpoint.

There was a significant progression-free survival with a hazard ratio of .63. Median PFS for the investigational arm of the treatment was 12.4 months versus 6.9 months for pomalidomide and low-dose dexamethasone.

This combination, the treatment combination, was more effective than pomalidomide and dexamethasone across all prespecified subgroups of patients, including patients who have been refractory to lenalidomide and to bortezomib.

As far as the tolerability of the combination is concerned, the side effects were essentially similar across the 2 arms. There was a slightly higher rate of neutropenia with the addition of daratumumab to pomalidomide and low-dose dexamethasone. Also, a slightly higher rate of lung infections.

Of particular interest was the duration of that infusion-related reports. Infusion-related reactions were reported in 5% of patients treated with daratumumab, pomalidomide, low-dose dexamethasone, and all were grade 1 or 2.

This is lower than expected with administration of daratumumab intravenously. Another secondary endpoint was response rate, and with the addition of daratumumab to pomalidomide and low-dose dexamethasone, at least partial response or better was observed in 69% of the patients versus 46% of the patients treated with pomalidomide and low-dose dexamethasone.

Thus overall, this study confirmed that the addition of daratumumab subcutaneously to pomalidomide and low-dose dexamethasone was more effective than pomalidomide and low-dose dexamethasone. This is a convenient combination because it avoids the use of intravenous drugs.

It is convenient for the patient. It shortens the time that the patient spends throughout patient clinic, and it is applicable for patients who have been exposed and are not responding anymore to lenalidomide and bortezomib, which is a frequent clinical situation in the treatment of myeloma.

In the clinical practice, this combination, which is friendly to the patient, may be applicable for many patients who are now being treated with bortezomib and lenalidomide.

It is likely to present 1 of the standard of care for patients who have received at least 1 prior line of therapy and have been exposed, and they're not responding to 2 key drugs—lenalidomide and bortezomib—which are being used in almost every patient with multiple myeloma.

We had a smaller percentage of patients who have received only 1 prior line of therapy, so I believe that this combination could be further explored as a second-line therapy in patients who, for example, progress on an established combination such as VRd: bortezomib, lenalidomide, dexamethasone.

This is a treatment used very frequently in the front-line setting of elderly patients with myeloma, or as an induction therapy for patients who will proceed to stem cell collection and high-dose melphalan.

I believe that there is a room to use this combination, based on the encouraging data of this trial as second-line therapy in this particular myeloma patient population.

There is an increasing patient population who is receiving the combination of VRd in the front-line setting. There is a need to establish effective regimens that could control the disease in this particular patient population. The combination of pomalidomide/dexamethasone with sub-Q daratumumab fits well in this situation.

This combination has been approved by the FDA and the MEA. It is being now reimbursed in several countries across the European Union. This is a significant benefit for the treatment of patients with myeloma.

We tried to have active trials for a different disease setting in myeloma, with novel combinations. We have a large myeloma patient population, and also, we have several referring physicians that we alert them whenever there is a trial that has been activated, which can offer to myeloma patients a new drug or a new combination far ahead of the approval.

I believe this is a significant benefit for many patients with myeloma to have the opportunity to be treated in the context of a clinical trial when other options are not available or are less interesting for the patient.