Maria-Victoria Mateos, MD, PhD, discusses the data that led to the approval of the subcutaneous daratumumab formulation and the clinical implications of the regulatory decision.
The May 2020 FDA approval of daratumumab and hyaluronidase-fihj (Darzalex Faspro) for adult patients with newly diagnosed or relapsed/refractory multiple myeloma allows for subcutaneous dosing, thus providing a more convenient option for patients and providers alike without compromising safety or efficacy, according to Maria-Victoria Mateos, MD, PhD.
“The subcutaneous option is definitely much more convenient for the patients; it’s also much more convenient for the hospitals, because the subcutaneous administration is going to save resources and [reduce the] time that patients have to stay in the outpatient facilities,” said Mateos. “I think that every patient with multiple myeloma who can…receive daratumumab can potentially receive the subcutaneous formulation.”
The regulatory decision was based on findings from the phase 3 COLUMBA (MMY3012) trial, which showed noninferiority in terms of efficacy versus the intravenous (IV) formulation of daratumumab.1,2 Results also demonstrated that the subcutaneous option resulted in a reduction in treatment burden when compared with the standard version.
The objective response rate (ORR) was 41.1% with the subcutaneous formulation versus 37.1% with the intravenous formulation; this met the criteria for noninferiority (relative risk, 1.11; 95% CI, 0.89-1.37; P <.0001). Pharmacokinetic analyses also achieved noninferiority for Ctrough. Notably, the median duration per infusion of the treatment dropped from >3 hours per infusion with the IV formulation to just 5 minutes with the subcutaneous version.
The median progression-free survival (PFS) was 6.1 months with the IV formulation versus 5.6 months with the subcutaneous version (HR, 0.99; 95% CI, 0.78-1.26; P = .9258). The 6-month overall survival (OS) rate was 83.0% compared with 87.5% for the IV and subcutaneous formulations, respectively (HR, 0.90; 95% CI, 0.59-1.35; P = .6032).
Additionally, significantly fewer infusion-related reactions (IRR) events were observed in those who received the subcutaneous version versus those who received the IV formulation (12.7% vs 34.5%; odds ratio, 0.28; 95% CI, 0.18-0.44; P <.0001). Aside from IRR, the safety profile between the 2 formulations proved to be similar.
Notably, treatment satisfaction questionnaires indicated that patients were more satisfied with the subcutaneous formulation of the CD38-targeted monoclonal antibody. A mean difference of 5.9 points were reported between groups, with the subcutaneous arm boasting a score near 90 during cycle 10 compared with a score just below 80 in the IV arm.
The approval was also supported by the positive data from the ongoing phase 2 PLEIADES (MMY2040) trial (NCT03412565), which is evaluating the effectiveness of an 1800-mg dose of the subcutaneous formulation in combination with either bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) or bortezomib, melphalan, and prednisone (D-VMP) in this patient population.3 Results indicated that the ORR in the D-VMP cohort was 88.1%, 90.8% in the D-Rd arm, and 97% in the D-VRd arm.
In an interview with OncLive, Mateos, an associate professor of Hematology and the director of the Myeloma Unit at the University Hospital of Salamanca, discussed the data that led to the approval of the subcutaneous daratumumab formulation and the clinical implications of the regulatory decision.
OncLive: Could you provide a bit of background on daratumumab and where it was approved prior to this indication?
Mateos: Daratumumab is an anti-CD38 monoclonal antibody with a double mechanism of action. Daratumumab targets CD38 expression on…plasma cells resulting in tumor activity; this is responsible for the rapid responses that we observe when we treat our patients with myeloma with [this agent]. At the same time, daratumumab targets CD38 expressed in immunosuppressive cellular populations, resulting in an immunomodulatory effect; this immunomodulatory effect is responsible for the durability and depth of responses.
Daratumumab was first approved as a single agent for the management of patients with relapsed/refractory myeloma with advanced stage of the disease. Immediately, it moved to earlier lines of therapy, [where it was examined] in combination with different backbones, such as lenalidomide and dexamethasone and bortezomib and dexamethasone. The next step was to introduce daratumumab as part of the first line of therapy in combination with different backbones in both the transplant eligible and ineligible populations.
Since the beginning, daratumumab was administered as an IV formulation. The main issue the agent presented had to do with the time of infusion, because it required a person at least 7 hours for the first infusion, 3.5 hours for the second infusion, and approximately 3 hours since the third one, and so on. To improve this time of infusion served as the rationale for the development of the subcutaneous formulation of the drug; and this formulation has been most recently approved by the FDA.
Could you expand on why the subcutaneous formulation is an important advancement in this space?
When daratumumab was administered as an IV formulation, the median infusion duration was quite long. We know that with this background, [there was a need] to reduce patient burden without compromising the safety and efficacy of the drug; this was the rationale for developing the subcutaneous delivery mode of action. In this case, daratumumab was combined with hyaluronidase-fihj to deliver the subcutaneous [version].
This subcutaneous formulation is going to increase tissue permeability; it's going to allow for rapid administration of larger volumes of drug. Although it is possible to get high concentrations of daratumumab in a very low injection volume, definitely this has [also contributed to] the rationale for developing the drug as a subcutaneous formulation. The dose is a flat dose of 1800 mg in 15 mL and it's usually administered as a subcutaneous injection in the abdomen in a person with a 3- to 5-min injection time.
What were the data that led to this approval? Could you discuss the phase 3 COLUMBA trial?
COLUMBA is the phase 3 randomized trial evaluating [the subcutaneous formulation] in patients with relapsed/refractory multiple myeloma after at least 3 prior lines of therapy. All patients had been previously exposed to a proteasome inhibitor. In some cases, [patients were] double refractory to proteasome inhibitors and immunomodulatory agents. This is basically the population that was included in the first studies conducted with daratumumab, when it was delivered as an IV infusion.
In this phase 3 randomized trial, this population was randomized 1:1 to receive subcutaneous daratumumab or the IV formulation. Treatment in both arms was given weekly in the first 2 cycles followed by every 2 weeks for cycles 3 to 6 and every 4 weeks from cycle 7 until disease progression. The dose was 16 mg/kg in the IV arm. The subcutaneous arm received a flat dose of 1800 mg.
The co primary end points for this study was overall response rate and maximum Ctrough concentration of daratumumab through the beginning of the cycle 3. An important consideration is that this phase 3 randomized trial was a noninferiority study to demonstrate that the subcutaneous formulation was not inferior to the IV version in terms of overall response rate and pharmacokinetics. Key secondary end points of the trial included IRR rate, PFS, OS, patient-reported outcomes, etc.
A treatment satisfaction questionnaire was also issued as a part of this trial. What were the findings?
Patient-reported outcomes was another important aspect of the COLUMBA study. Patients completed a modified cancer treatment satisfaction questionnaire and it clearly resulted in a significant benefit for the subcutaneous arm. Basically, patients who received the subcutaneous formulation were more satisfied with the therapy than those who received the IV formulation; this resulted in a significant difference between the 2 arms. [This demonstrates that] the subcutaneous formulation is much more convenient for patients; it's also much more convenient for physicians, for hospitals, and for pharmacists. However, the take-home message is that when you ask the patient, you are able to report the satisfaction they reported when they received the subcutaneous formulation and that this is extremely important.
With regard to safety, were any notable differences observed between the subcutaneous and IV formulations?
The subcutaneous formulation [was] much safer than the IV formulation, especially because IRR is probably the most relevant daratumumab-related adverse event (AE). With the IV formulation, we know that approximately 35% to 40% of patients can develop any kind of IRR. In the COLUMBA study, we had the opportunity to see that the IRRs in the subcutaneous arm were only 13%; this difference is great, because it was statistically significant. It's true that the IRRs in both arms were basically grade 1 and 2. I believe that there were just a few patients who were developing grade 3 IRRs, and notably, no grade 4 IRRs [were observed].
Additionally, an important difference in the median time to IRRs [was observed]; for the IV formulation, the median time was approximately 1.5 hours, while it was a bit longer for the subcutaneous formulation, at 3.6 hours. However, it is important to note that IRRs basically occur in both arms after the first infusion. This message is important because it has an important clinical implication. After the first administration with the subcutaneous formulation, [the patient] can stay around the hospital, around the facility, for approximately 2 or 3 hours in order to see whether they develop any IRRs. This is only applicable to the first infusion and if no IRR is observed at that time, the patient can immediately leave after administration [come] the second infusion.
Aside from IRRs, the safety profile was comparable in both arms. However, just to note, just as the IRRs were lower in the subcutaneous formulation arm, some AEs like chills or dyspnea were also significantly lower. From the hematologic point of view, the incidence of neutropenia was just slightly higher in the subcutaneous arm. However, overall, I would say that the safety profile was similar between the 2 arms.
Are there any challenges with administering the subcutaneous formulation?
Any potential challenge [with the subcutaneous formulation would have been in] patients with an extremely low body weight because…it has to be delivered in a flat dose of 1800 mg. However, a subanalysis was conducted to [determine the potential impact of using a flat dose in the subcutaneous arm versus the body weight-based dose in the IV arm and weight did not appear to impact the efficacy data]. Also, the safety profile was comparable across the different subgroups of patients on the basis of different body weight. For me, this would be the only challenging situation that we could potentially face. My message would be that a flat dose for 1800 mg can be delivered to whatever patient with multiple myeloma, regardless of the body weight.
The subcutaneous formulation is also being examined in combinations. Could you discuss the PLEIADES trial?
It's true that the COLUMBA study evaluated daratumumab as a single agent, but the important information is that Janssen conducted a noninferiority the PLEIADES study in which the subcutaneous formulation has been combined with different backbones: lenalidomide and dexamethasone in the relapsed setting and bortezomib, melphalan, and prednisone in the up-front setting, as well as bortezomib, lenalidomide, and dexamethasone in the up-front setting.
The main objective of this study has been to demonstrate that the subcutaneous formulation in combination with these different backbones in the up-front or relapsed setting would result in similar overall response rates, complete response rates, PFS, and safety profiles than when these combinations were combined with the IV formulation. From my point of view, the subcutaneous formulation can be utilized as single agent and also in combination with the different backbones [based on the data we’re seeing].