Subcutaneous Daratumumab is Safe and Tolerable in Multiple Myeloma


Findings from the phase 3 PERSEUS study found the safety profile of D-VRd in newly diagnosed multiple myeloma to be in line with the known profiles of the agents.

Bone marrow aspirate cytology of multiple myeloma: ©David A Litman -

Bone marrow aspirate cytology of multiple myeloma: ©David A Litman -

Findings from the phase 3 PERSEUS study (NCT03710603) presented at the 2023 ASH Annual Meeting showed that subcutaneous daratumumab (Darzalex) followed by autologous stem cell transplant (ASCT) and daratumumab, bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) consolidation and daratumumab/lenalidomide maintenance in newly diagnosed, transplant-eligible multiple myeloma significantly improved progression-free survival (PFS).1

According to the findings presented, the 4-year PFS was 84.3% with D-VRd compared with 67.7% with VRd. Further, there was a 58% reduction in the risk of disease progression or death (HR, 0.42; 95% CI, 0.30-0.59; P <.0001).

Regarding safety, 7 deaths occurred due to COVID-19, including 4 in the D-VRd arm and 3 in the VRd arm. Grade 3/4 treatment-emergent adverse events (TEAEs) included neutropenia (62.1% with D-VRD vs 51.0% with VRd), thrombocytopenia (29.1% vs 17.3%), diarrhea (10.5% vs 7.8%), pneumonia (10.5% vs 6.1%), and febrile neutropenia (9.4% vs 10.1%). Serious TEAEs were observed in 57.0% of patients who received D-VRd vs 49.3% of patients given VRd. TEAEs leading to discontinuation of study treatment were observed in 8.8% of patients in the D-VRd arm vs 21.3% of patients in the VRd arm.

Study authors noted that the safety profile of D-VRd was in line with the known profiles of the individual agents. A retrospective study published in September 2023 analyzed the safety of subcutaneous daratumumab, the use of which is newer and less studied than intravenously infused daratumumab.2

About the Phase 3 PERSEUS Trial

PTrial Name: Daratumumab, VELCADE (Bortezomib), Lenalidomide and Dexamethasone Compared to VELCADE, Lenalidomide and Dexamethasone in Subjects With Previously Untreated Multiple Myeloma (Perseus) Identifier: NCT03710603

Sponsor: European Myeloma Network

In this study, retrospective data from 189 patients with multiple myeloma or light chain amyloidosis were assessed, and 8 patients (4%) experienced infusion-related reactions (IRRs). The IRRs were mainly grade 1/2 (3.5%, n = 7), and there was 1 severe IRR (0.5%, n = 1). All IRRs occurred during the first administration. The 1 patient that experienced a severe IRR was adequately treated with high-dose steroids and antihistamines. The median time of IRR onset was 2.5 hours (range, 1-7); no delayed reactions were observed. Administration of montelukast and standard premedication appeared to produce a lower IRR risk (3.8% vs 7.6%; OR, 0.43; P =.4).

A total of 30 patients (16%) experienced hematological toxicities with subcutaneous daratumumab. These included thrombocytopenia (4%), neutropenia (5%), and lymphopenia (6%). Other toxicities included grade 1/2 pneumonia (2%), grade 3/4 pneumonia (2%), and cytomegalovirus reactivation (0.5%).

PERSEUS is a randomized, interventional, open-label, phase 3 trial comparing D-VRd vs VRd in patients aged 18 to 70 with newly diagnosed, transplant-eligible multiple myeloma and an ECOG performance status of 2 or less.3

A total of 709 patients were randomly assigned to the investigational or control arms, both of which included induction, consolidation, and maintenance phases. Those in the control arm received 1.3 mg/m2 of subcutaneous bortezomib on days 1, 4, 8, and 11 with 25 mg of oral lenalidomide on days 1 through 21 and 40 mg of oral or intravenous dexamethasone on days 1 through 4 and 9 through 12 as induction prior to transplant. Following this, patients received the same schedule of VRd, then 10 mg of oral lenalidomide on days 1 through 28 until disease progression.

In the investigational arm, patients received 1800 mg of subcutaneous daratumumab every 2 weeks plus the same schedule of VRd as induction treatment. After undergoing transplant, patients received D-VRd as consolidation, followed by daratumumab at 1800 mg every 4 weeks plus lenalidomide at 10 mg on days 1 through 28. Patients who were MRD positive in the investigational arm after maintenance they continued to receive DR until disease progression. If patients had MRD negative disease in a ≥ complete response (CR) for at least 12 months following at least 24 months of maintenance therapy, they could discontinue daratumumab. Daratumumab was restarted if the disease fell out of CR without evidence of disease progression or MRD recurrence.

The primary end point of the study was PFS. Secondary end points included the overall ≥CR rate, overall MRD-negativity rate, and overall survival.

1. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Phase 3 randomized study of daratumumab + bortezomib, lenalidomide, and dexamethasone (VRd) versus VRd alone in patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplantation: primary results of the PERSEUS trial. Blood. 2023;142(suppl 2):LBA1. doi:10.1182/blood-2023.191911
2. De Novellis, D, Fontana, R, Palmieri, S, et al. Safety of subcutaneous daratumumab in anti-CD38 monoclonal antibody-naïve patients with plasma cell disorders: a multicenter real-life experience. Target Oncol. 2023;18(6):885-892. doi:10.1007/s11523-023-01001-4
3. Daratumumab, VELCADE (Bortezomib), lenalidomide and dexamethasone compared to VELCADE, lenalidomide and dexamethasone in subjects with previously untreated multiple myeloma (Perseus). Updated September 27, 2022. Accessed December 14, 2023.

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