Multiple myeloma (MM) is characterized by extensive skeletal destruction as a result of clonal plasma cells proliferating into the bone marrow, leading to further complications like hypercalcemia, renal insufficiency, anemia, and an increased risk of infections.¹ Most patients will eventually fail ≥2 lines of therapies, including lenalidomide and a proteasome inhibitor (PI), and progress to relapsed or refractory multiple myeloma (rrMM), where the current treatment standard is the combination of daratumumab with pomalidomide and dexamethasone (DaraPd).² In May 2020, the United States Food and Drug Administration (US FDA) approved daratumumab and hyaluronidase-fihj for rrMM patients, allowing subcutaneous (SC) dosing as opposed to the traditional intravenous (IV) dosing of daratumumab.³ This has greatly increased rrMM patients’ quality-of-life (QoL) by possibly reducing the infusion time and infusion related events.⁴

Daratumumab is an IgG1κ human monoclonal antibody (mAb) binding to the CD38 transmembrane glycoprotein of tumor cells, which helps induce apoptosis by 4 mechanisms including Fc mediated cross linking, complement dependent cytotoxicity (CDC), antibody dependent cell mediated cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP).⁵ Hyaluronidase, while not a part of the apoptosis process, facilitates the action of daratumumab. It acts locally and increases the permeability of the tissue for 24-48 hours by depolymerizing hyaluronan, allowing daratumumab to permeate the SC tissue into the interstitial space.⁵

COLUMBIA is an ongoing, open-labeled, randomized, phase 3 study where 522 participants received either IV daratumumab or SC daratumumab with hyaluronidase on the same schedule.⁴ In this study, the efficacy and pharmacokinetics (PK) of SC daratumumab were shown to be non-inferior to the IV administration, with an overall response rate (ORR) of 41% and 37% in the SC and IV daratumumab arm respectively, and the geometric mean ratio (SC over IV) of the maximum Ctrough on cycle 3 was 107.93% (90% CI: 95.74-121.67).⁴ As a secondary objective, the SC arm did not incur any additional safety issues and the safety data for both arms were relatively similar, the prevalence of grade 3 or 4 serious adverse events in the SC vs. IV group were as follows: Anemia (13% vs. 14%), neutropenia (13% vs. 8%) and thrombocytopenia (14% vs. 14%), respectively.⁴

The later APOLLO study in 2021 is another ongoing, open-labelled, randomized, phase 3 study which evaluated the DaraPd regimen where the SC formulation was used versus Pd regimen alone.⁶ The study was conducted across 48 academic centres and recruited participants aged 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.⁶ They had at least 1 line of therapy which included lenalidomide and a PI, with a partial response or better to 1 or more previous lines of antimyeloma therapy, or were refractory to lenalidomide on the condition that only 1 previous line of therapy was received.⁶ The median progression-free survival (PFS) was 12.4 months with the DaraPd regimen as compared with 6.9 months of the Pd only group.⁶ The overall response rate of DaraPd was 69% (95% CI: 61-67; p<0.0001) as opposed to 46% (95% CI: 38-55; p<0.0001) with Pd only.⁸ The percentage of complete response and very good partial response were also better in the DaraPd arm than Pd only (25% (95% CI: 61-67; p<0.0001) vs. 4% (95% CI: 38-55; p<0.0001); 51% (95% CI: 61-67; p<0.0001) vs. 20% (95% CI: 38-55; p<0.0001), respectively).⁸ The minimal residual disease negativity was also comparatively better in the DaraPd arm with 9% (95% CI: 61-67; p<0.0001) vs. 2% (95% CI: 38-55; p<0.0001).⁸ The overall efficacy data showed that the addition of SC daratumumab improved the efficacy of Pd treatment. The safety profiles in the APOLLO studies were quite similar for both DaraPd and Pd only arms [Anemia (17% vs. 21%), neutropenia (68% vs. 51%), thrombocytopenia (17% vs. 18%), respectively].⁶ The results showed that the addition of daratumumab was beneficial to the rrMM treatment without the loss of safety.⁸

In conclusion, the COLUMBA study has demonstrated the non-inferiority of SC daratumumab in terms of safety and efficacy, while the APOLLO study has reaffirmed the role SC daratumumab in rrMM treatment. Ultimately, these translate into an improved QoL for rrMM patients who have failed at least 1 line of treatment.