My presentation is the COLUMBA study, it’s a phase III randomised non-inferiority study in which daratumumab is going to be evaluated in subcutaneous administration versus intravenous administration. The conventional use of daratumumab right now is intravenously and daratumumab has demonstrated to be effective and safe in myeloma patients across the different stages of the disease but the administration is intravenous requiring long infusion times – 7 hours for the first one, 4 hours for the second one and 3.5 hours for the third one and subsequent ones. So in order to optimise the daratumumab administration a subcutaneous formulation was developed in which daratumumab was coformulated with recombinant hyaluronidase. A phase Ib PAVO study showed that daratumumab can be given subcutaneously in relapsed and refractory myeloma patients. It is showed to be effective, safe and one important finding is that, according to the PK studies daratumumab subcutaneous can be given at a flat dose of 1,800mg.
This was the rationale for this phase III randomised trial in which 522 relapsed and refractory myeloma patients after at least two prior lines of therapy including PI and IMiD were included and randomised one to one to receive daratumumab IV or daratumumab subcutaneous. The control arm was daratumumab IV 16mg/kg weekly during the first two cycles, every other week during cycles 3-6 and monthly later on. The experimental arm included daratumumab in the same scheme but at a flat dose of 1,800mg and was given subcutaneously. Baseline characteristics of the patients included in the study were representative of a myeloma patient population receiving at least four prior lines of therapy. Approximately 80% of patients were refractory to the last line of therapy and 50% of patients were even double refractory to both PI and IMiD.
This trial had two co-primary endpoints in order to show that daratumumab subcutaneous was not inferior to daratumumab IV. The first co-primary endpoint was based on overall response rate and the overall response rate for daratumumab IV was 37%; the overall response rate for daratumumab subcutaneous was 41%, slightly higher but comparable. The message is that daratumumab subcutaneous was not inferior to daratumumab IV.
In terms of maximum concentration through evaluated at cycle 3, day 1, this was the second co-primary endpoint and the mean geometric concentrations for both daratumumab IV and daratumumab subcutaneous were also comparable, meaning that daratumumab subcutaneous was not inferior to daratumumab IV.
When we evaluated the relative risk for overall response rate comparing daratumumab subcutaneous versus daratumumab IV the relative risk was sustained across the different subgroups of patients. One specific important population that was the relative risk was equivalent regardless of the body weight of the patients and the relative risk was exactly the same for patients with body weights lower than 65kg, between 65-85kg and even for patients with a body weight higher than 85kg.
So both co-primary endpoints were met so subsequent secondary endpoints were evaluated. First, PFS and overall survival were comparable and concordant with the PFS and overall survival reported for other trials in which daratumumab was evaluated as single agent in heavily pre-treated myeloma patients. In terms of time of infusion, there is an important advantage for the daratumumab subcutaneous because daratumumab IV required 7, 4 and 3 hours for the first, second and subsequent infusions whilst daratumumab subcutaneous was given in all infusions only during 5 minutes. So daratumumab subcutaneous significantly reduced the time of infusion versus daratumumab IV.
In terms of safety profile the first important message is that the infusion related reaction rate significantly was lower for daratumumab subcutaneous versus daratumumab IV. Patients receiving daratumumab subcutaneous had infusion related reactions in approximately 13% of the patients whilst when daratumumab was used IV 35% of patients had any type of infusion related reactions. It’s true that most of them were grade 1 and 2 but daratumumab subcutaneous resulted in a lower rate of infusion related reactions. No differences in terms of other adverse events, haematological or non-haematological adverse events.
Finally I think that it’s also important to remark that a questionnaire evaluated the satisfaction patients had when they were receiving either daratumumab IV or daratumumab subcutaneous and the satisfaction was much more great for daratumumab subcutaneous. So I think that all these results clearly support the use of daratumumab subcutaneous as part of the different combinations in which the monoclonal antibody is going to be used in myeloma patients across the different stages of the disease. The rationale is because the trial met both co-primary endpoints and daratumumab subcutaneous is not inferior to daratumumab IV. In addition, the safety profile is comparable but the time of infusion is significantly reduced as well as the infusion related reactions.
When can we expect this to maybe be used in the clinic more routinely?
Definitely these studies support the use of daratumumab subcutaneous in every patient with myeloma in which we decide to use the monoclonal antibody daratumumab. Why? Because it’s much more convenient, it’s equally effective than daratumumab IV, the time of infusion is significantly reduced, the infusion related reaction rate is significantly reduced and definitely it is much more convenient for the patients.
