ASH 2017 | Subcutaneous daratumumab in RRMM

The MM Hub is delighted to share research findings from the 59th American Society of Hematology (ASH) Annual Meeting in Atlanta, Georgia.  On Monday 11 December, the evening oral abstract session took place for Myeloma: Therapy, excluding Transplantation Studies in Relapsed and Refractory Multiple Myeloma.  Dr. Ajai Chari of Tisch Cancer Institute, Mount Sinai School of Medicine, New York, presented Abstract #838: Subcutaneous Delivery of Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma: PAVO, an Open-Label, Multi-center, Dose Escalation Phase 1b Study. The data here is based on the presentation at ASH and may supersede that of the published abstract.

Daratumumab is approved as a monotherapy and combination therapy at 16mg/kg IV, with a median duration of the first, second and third infusion lasting 7, 4.3 and 3 hours, respectively. Infusion related reactions (IRR) are common but usually occur with the first infusion and are manageable. However, it is thought that IRRs could be limited by using subcutaneous administration, as well decreasing the administration time. In order to do this, an ENHANZE drug delivery system comprising recombinant hyaluronidase (rHuPH20) was used, which acts to temporarily break down the hyaluronan barrier, enabling rapid administration of large volumes of drugs. Daratumumab was formulated with rHuPH20 (DARA-MD) and given SQ using a syringe pump for part 1 of the study. Additionally, a co-formulation of DARA + rHuPH20 (DARA SC) was prepared with a higher daratumumab concentration allowing a lower injection volume and manual injection into the abdomen.

The aim of this study was to evaluate the safety, pharmacokinetics, and efficacy of daratumumab given subcutaneously (SQ), instead of intravenously (IV).  This was part 2 of the dose-finding study, which prescribed daratumumab 1,800mg SQ over 3 to 5 minutes, in a fixed combination with recombinant human hyaluronidase (DARA SC).  Pre- and post- administration medications included acetaminophen, diphenhydramine, montelukast, and methylprednisolone.  Each treatment cycle was 28 days. Patients eligible for the study had Relapsed or Refractory Multiple Myeloma (RRMM), had received at least 2 prior lines of treatment and had not received prior anti-CD38 therapy.

Key Data:

• N = 25 patients; Median age = 68 years
• Median time from diagnosis = 5.96 years
• Median time to follow-up = 4.6 months (range, 2.4-5.5)
• Patients with prior ASCT = 68%
• Discontinuation of therapy due to progressive disease = 16%
• Pharmacokinetics:
  • Trough concentrations of SQ (1,800mg) and IV (16 mg/kg) daratumumab is similar or higher after 8 weekly doses
  • Simulated concentration-time profiles indicated that, after every 4-week dosing, the Cmax for daratumumab SQ is similar to IV
• Adverse Events (AEs): thrombocytopenia = 20%, anemia = 12%, lymphopenia = 28%, insomnia = 16%, pyrexia = 16%, injection site erythema = 20%
• Infusion reactions = 12% all at first injection within 6 hours; no grade 4 injection site reactions reported
• Few injection site TEAEs reported; measurable erythema was reversible within 1 hour
• Efficacy: ≥VGPR = 28% at a median follow-up of 4.6 months

Daratumumab given via subcutaneous administration co-formulated with hyaluronidase has similar efficacy to IV and very tolerable AEs and allows dosing within 3-5 minutes.  The pharmacokinetic profile showed similar C_max and trough concentrations to IV administration. This data was used to formulate the background for several ongoing phase III studies using daratumumab 1,800mg SQ. This finding will be exciting news for patients as it will enable more convenient self-administration and limit the time spent in clinics, which is a major factor in maintaining a high QoL throughout the treatment journey.