1. Goodwin, Peter M.

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ATLANTA-Subcutaneous administration of the anti-CD38 monoclonal antibody daratumumab could make it possible for more patients to receive this emerging therapy more easily for their advanced or recently diagnosed multiple myeloma, according to research reported at the 2017 American Society of Hematology Annual Meeting (Abstract 838).

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In the Pavo study, injections took only 3-5 minutes to administer, yet the bioavailability of the agent appeared to be maintained or increased over and above levels achieved with standard infusions taking several hours.


"It's one of those rare things in medicine where you have a drug that seems to be safer (with lower rates of infusion reaction), seems to be more convenient (with only a 3-5 minute administration), and seems to have comparable efficacy," said study author Ajai Chari MD, Associate Professor of Medicine and Director of Clinical Research in the Multiple Myeloma Program at Mount Sinai Hospital in New York, N.Y. "So I think those things speak for themselves. These are really exciting results and I think it speaks to the reason why there are now four phase III studies going on using this formulation."


Daratumumab With Hyaluronidase

In the Pavo study, 25 patients with relapsed or refractory multiple myeloma who had at least two prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), were given manual subcutaneous injections administered in 3-5 minutes with a "concentrated co-formulation" of daratumumab (1,800 mg in 15 mL) and recombinant human hyaluronidase enzyme (30,000 U) from a single, pre-mixed vial. (Co-formulation with hyaluronidase allows the monoclonal antibody to penetrate beyond the site of injection.)


Although daratumumab had already been shown to have single agent activity in myeloma-and was subsequently found to be promising in combination with bortezomib, lenalidomide, and pomalidomide for initial therapy-Chari said they needed to address two of the challenges facing clinicians using standard IV administration.


"One is the infusion duration-the first infusion being up to 7 hours median, and then subsequently diminishing to 3.5 hours. And the second [challenge] is [that] about 50 percent of patients can have infusion-related reactions." Injections could potentially resolve both of these issues. And the study results were also needed because of increasing evidence that daratumumab could benefit more groups of patients.


"Currently, it's only approved in relapsed and refractory [multiple myeloma], but at this year's ASH, Dr. Mateos presented the ALCYONE study in newly diagnosed myeloma that did show a significant improvement in progression-free survival with a hazard ratio of 0.5," Chari explained.


Tissue Penetration

"In order to give a drug subcutaneously, you can't just inject a large volume. It needs to be combined with hyaluronidase because otherwise it just sits there under the skin. Hyaluronidase allows us to bypass that limitation."


To speed up the injection procedure still further, the investigators used a ready-mixed formulation of daratumumab. "At last year's ASH, there was another subcutaneous daratumumab. But that was called the 'mix and deliver' formulation," Chari noted.


He said that having to mix hyaluronidase and daratumumab manually had slowed down treatment in the past, and the injection needed to be bigger. "The volume was anywhere from 60 mL to 90 mL and it was given through a syringe pump," he said. "What's exciting about this year's presentation is that it's now co-formulated-which means the pharmacy doesn't have to do anything. It comes pre-mixed. And the volume is only 15 mL and it can be given manually without the need of a syringe pump."


Fewer Infusion Reactions

"Safety-wise we found very encouraging results. The rate of infusion-related reactions was only 12 percent-compared to what we would usually expect: 50 percent. And only one of those was grade 3 (hypertension). So, [it has] a very tolerable safety profile," Chari stated. "The pharmacokinetics-another endpoint-was [also] very encouraging. We know that the most important pharmacokinetic endpoint for dara[tumumab] is the trough concentration (C-trough) at cycle 3, day 1. And for this 'sub Q' co-formulation that C-trough was actually similar-if not better than intravenous dara[tumumab]."


While the study was clearly not powered to give definitive data on efficacy, the findings were consistent with other studies and were "very encouraging."


"Patients had a median of three lines of prior therapy with a median of approximately 6 years since diagnosis. And importantly, 60 percent were double-refractory-to a PI and an IMiD. We saw a response rate of approximately 44 percent. So that's very encouraging, although this is a small sample size and we'll really have to see the larger numbers," he said. "But based on the fact that the cycle 3 trough was comparable if not better, and with our preliminary efficacy data, one would expect that the 'sub Q' would be comparable, at least, if not potentially superior [to IV infusions]."


When he was asked whether the findings-if confirmed by bigger studies-were potentially practice-changing, Chari was very positive. "This would be extremely practice-changing. Daratumumab has moved from monotherapy in advanced disease to first relapse. And now-at this year's ASH-we have newly diagnosed. That's a lot of dara[tumumab] being used globally. And to be giving a more convenient, potentially safer form of administration is really going to be very practice-changing."


Peter M. Goodwin is a contributing writer.