Examining Daratumumab Monotherapy in Heavily Pretreated and Refractory Multiple Myeloma Patients

Patients with multiple myeloma (MM) who are refractory to proteasome inhibitors and immunomodulatory drugs have poor prognoses and limited treatment options. Recently, though, preclinical studies have shown that the anti-CD38 monoclonal antibody daratumumab has demonstrated anti-myeloma activity by inducing target-cell killing of CD38-expressing tumor cells.

Based on those results, Henk M. Lokhorst, MD, PhD, from the Department of Hematology of the VU University Medical Center in Amsterdam, Netherlands, designed a two-part, open-label, multicenter, phase I/II evaluating response to daratumumab treatment in patients with relapsed MM or relapsed and refractory MM.

“These results compare favorably with other novel agents explored in comparable settings. Single-agent daratumumab may become a novel option for patients with double-refractory MM,” Dr. Lokhorst told ASH Clinical News. “These data suggest that a new treatment era for MM may be in sight. I believe monoclonal antibodies, of which daratumumab may be one of the most potent, will become a standard in newly diagnosed and relapsed MM.”

Patients were eligible for study inclusion if they were 18 years of age or older, had a life expectancy of at least three months, had an Eastern Cooperative Oncology Group score of two or less, and had a measurable level of M protein or free light chains according to the International Myeloma Working Group (IMWG) guidelines.

The study’s primary endpoint was safety, which was evaluated based on the frequency and severity of adverse events (AEs). Secondary endpoints included pharmacokinetics, objective response according to the IMWG response criteria for MM, time to disease progression, duration of response, progression-free survival (PFS), and overall survival (OS).

The study was divided into two parts:

  • Part 1 (dose-escalation phase): A total of 32 patients in 10 cohorts received daratumumab at doses of 0.005 mg/kg to 24 mg/kg. All patients received a predose followed by a three-week washout period for assessment of safety and pharmacokinetics. Then a second predose was administered, followed by six full infusions administered weekly, making the total treatment period eight weeks.
  • Part 2 (dose-expansion phase): A total of 30 patients received 8 mg/kg of daratumumab and 42 patients received 16 mg/kg of daratumumab administered once-weekly (eight doses), twice-monthly (eight doses), and once-monthly for up to 24 months. Patients received therapy until disease progression or unmanageable treatment-related toxicities occurred.

In both study parts, patients had been treated with a median of four prior therapies. Patients in Part 2 of the study had a median time since diagnosis of 5.7 years.

Seventy-nine percent of patients were refractory to the last therapy they received; 76 percent of patients previously underwent autologous hematopoietic cell transplantation.

Of the patients receiving daratumumab 8 mg/kg and 16 mg/kg, respectively:

  • 21 (70%) and 30 patients (71%) were refractory to bortezomib
  • 26 (87%) and 31 patients (74%) were refractory to lenalidomide
  • two (7%) and seven patients (17%) were refractory to carfilzomib
  • two (7%) and 15 patients (36%) were refractory to pomalidomide

In addition, 19 (63%) and 27 patients (64%), respectively, were refractory to both bortezomib and lenalidomide.

During the first phase of the study, no maximum tolerated dose was identified.

With a median follow-up of 16.9 months in the 8 mg/kg cohort and 102 months in the 16 mg/kg cohort, the overall patient response rates were 10 percent and 36 percent, respectively. In the 16 mg/kg group, 15 patients had a partial response or better, with two patients experiencing a complete response and two patients a very good partial response. In the 8 mg/kg group, three patients had a partial response.

“In patients with a partial response or better, the level of bone marrow plasma cells was generally markedly reduced,” Dr. Lokhorst and co-authors noted. Thirteen patients in the 16 mg/kg cohort had data that could be evaluated, “and these patients either had a decrease in the bone marrow plasma-cell level (8 patients) or had a level that remained stable below 5 percent (5 patients).”

In the 16 mg/kg group, the median PFS was 5.6 months (95% CI 4.2-8.1), and 65 percent of patients (95% CI 28-86) who responded to daratumumab treatment did not have progression at 12 months.

At the study cutoff on January 9, 2015, 14 patients (19%) were still receiving therapy, and 58 patients (81%) had discontinued treatment. All 30 patients in the cohort who received 8 mg/kg discontinued due to progressive disease; of the 28 patients in the 16 mg/kg cohort who discontinued treatment, 23 discontinued treatment due to progressive disease, four due to physician decision, and one due to an AE.

The most commonly reported treatment-related AEs included fatigue, allergic rhinitis, pyrexia, diarrhea, upper respiratory tract infection, and dyspnea (TABLE).

Infusion-related reactions were mild, as 71 percent of patients had an event of any grade and 1 percent had a grade 3 event, with no dose-dependent AEs.

“Daratumumab showed encouraging efficacy in patients with myeloma who had had a median of four prior lines of therapy,” Dr. Lokhorst and co-authors concluded. “Moreover, daratumumab monotherapy (at a dose of 16 mg/kg) induced durable responses that deepened over time, including complete and very good partial responses.”

Although these results were “encouraging,” the authors noted a few limitations, including a high rate of discontinuation. There are also many unanswered questions remaining, including how tumors become resistant to daratumumab, and whether the drug will be active in multiple phases of treatment. However, “it is reassuring to know that we have yet one more treatment option that will contribute in an important way to improvement in outcomes in patients with myeloma,” they wrote.


Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015 August 26. [Epub ahead of print]

TABLE. Most Commonly-Reported Adverse Events Associated with Daratumumab*
Event 8 mg/kg Daratumumab Cohort(n=30) 16 mg/kg Daratumumab Cohort(n=42) Total(n=72)
All grades Grade 3 or 4 All grades Grade 3 or 4 All grades Grade 3 or 4
Fatigue 13(43%) 1(3%) 17(40%) 0(0%) 30(42%) 1


Allergic rhinitis 12(40%) 0(0%) 10(24%) 0(0%) 22(31%) 0(0%)
Pyrexia 13(43%) 0(0%) 7(17%) 1(2%) 20(28%) 1


Diarrhea 9(30%) 0(0%) 6(14%) 0(0%) 15(21%) 0(0%)
Upper respiratory tract infection 8(27%) 0(0%) 7(17%) 0(0%) 15(21%) 0


Dyspnea 8(27%) 0(0%) 6(14%) 0(0%) 14(19%) 0


*The most common adverse events were defined as those occurring in at least 25% of patients in either dose cohort.