Daratumumab plus lenalidomide, dexamethasone prolongs PFS in relapsed, refractory multiple myeloma

The addition of daratumumab to lenalidomide and dexamethasone significantly prolonged PFS in patients with relapsed or refractory multiple myeloma, according to results of an interim analysis of a phase 3 trial published in The New England Journal of Medicine.

However, daratumumab (Darzalex, Janssen) also increased the incidence of infusion-related reactions and neutropenia, results showed.

Daratumumab — approved for use as monotherapy in 2015 by the FDA — has shown promising safety and activity as a single agent, and in combination with other standard-of-care therapies. A phase 3 trial of daratumumab in combination with bortezomib (Velcade, Millennium/Takeda) and dexamethasone showed significantly longer PFS and a 61% reduced risk for progression or death at an interim analysis.

A phase 1/phase 2 trial of daratumumab combined with lenalidomide (Revlimid, Celgene) and dexamethasone showed an 81% overall response rate with the triplet, as well as rates of 72% 18-month PFS and 90% 18-month OS.

Based on those results, Meletios A. Dimopoulos, MD, professor and chairman of the department of clinical therapeutics at University Athens School of Medicine in Athens,

Greece, and colleagues conducted a phase 3 trial to evaluate the use of daratumumab, lenalidomide and dexamethasone in 569 patients (median age, 65 years; range, 34-89) with relapsed or refractory multiple myeloma.

Patients had received a median of one (range, 1-11) previous line of therapy, and 19.2% of patients had received three or more previous lines. Previous treatments included proteasome inhibitors (85.6%); immunomodulatory drugs (55.3%), including lenalidomide (17.6%); proteasome inhibitor and an immunomodulatory drug (43.9%); and autologous stem cell transplantation (63.3%).

Researchers randomly assigned patients to receive 25 mg lenalidomide (days 1-21) and 40 mg weekly dexamethasone alone (n = 283) or with 16 mg/kg daratumumab (n = 286; weekly for 8 weeks for cycles 1 and 2, every 2 weeks for cycles 3 through 6, and every 4 weeks thereafter).

Median follow-up for the protocol-specified interim analysis was 13.5 months. At this time, 169 events of disease progression or death had occurred. Events occurred in 18.5% of patients assigned daratumumab (n = 53) and 41% of patients (n = 116) assigned the control (HR = 0.37; 95% CI, 0.27-0.52).

Kaplan–Meier rates of 12-month PFS were 83.2% (95% CI, 78.3-87.2) in the daratumumab arm and 60.1% (95% CI, 54-65.7) in the control arm. Median PFS was not reached with daratumumab and was 18.4 months (95% CI, 13.9-not estimable) in the control arm.

PFS was significantly prolonged among patients assigned daratumumab regardless of the number of previous lines of therapy, and whether patients had previously received lenalidomide.

Further, significantly more patients assigned daratumumab responded to treatment (92.9% vs. 76.4%; P < .001) and achieved a complete response or better (43.1% vs. 19.2%; P < .001).

More patients assigned daratumumab achieved results below the threshold of minimal residual disease — defined as 1 tumor cell per 10⁵ white cells (22.4% vs. 4.6%; P < .001).

Kaplan–Meier rates of 12-month OS were 92.1% (95% CI, 88.2-94.7) in the daratumumab arm and 86.8% (95% CI, 82.2-90.3) in the control arm.

Common adverse events that occurred in more patients assigned daratumumab included neutropenia (59.4% vs. 43.1%), diarrhea (42.8% vs. 24.6%), upper respiratory tract infection (31.8% vs. 20.6%) and cough (29% vs. 12.5%).

Researchers also observed higher rates of grade 3 to grade 4 neutropenia in the daratumumab arm (51.9% vs. 37%), but lower rates of grade 3 to grade 4 thrombocytopenia (12.7% vs. 13.5%) and anemia (12.4% vs. 19.6%), as well as lower overall incidence of deep-vein thrombosis (1.8% vs. 3.9%).

Daratumumab-associated infusion-related reaction occurred in 47.7% of patients, most of which were grade 1 and grade 2.

Adverse events led to discontinuation in 6.7% of the daratumumab arm and 7.8% of the control arm. Death due to adverse events occurred in 3.9% of patients assigned daratumumab and 5.3% of patients assigned lenalidomide and dexamethasone alone.

“Although higher rates of neutropenia and infusion-related reactions (primarily during the first infusion) were observed with this combination than with lenalidomide and dexamethasone alone, these events did not result in higher rates of treatment discontinuation or death,” the researchers wrote.

Without head-to-head comparisons of each regimen that has recently shown promise for myeloma, researchers must compare the existing data on efficacy, safety, ease of use and cost, S. Vincent Rajkumar, MD, and Robert A. Kyle, MD, both of the division of hematology at Mayo Clinic in Rochester, Minnesota, wrote in an accompanying editorial.

After comparing the available regimens, daratumumab–lenalidomide–dexamethasone is “the clear stand-out,” and the authors’ “treatment of choice for first relapse in patients whose disease is not refractory to lenalidomide,” Rajkumar and Kyle wrote.

However, all of the studied regimens may be used in certain situations, they added.

“Given the chronic relapsing course of myeloma, the most pressing questions revolve around the appropriate sequence in which these regimens are used, rather than picking winners and losers or excluding a regimen from consideration,” Rajkumar and Kyle wrote.

Overall, these results show that daratumumab is a “landmark advance” for this disease, they added.

“It is likely to be incorporated into the treatment of all stages of the disease over the next several years,” Rajkumar and Kyle wrote. “The challenge will be to prevent unnecessary use, since it will be hard to isolate the effect of daratumumab when it is combined with multiple other active agents. It will be important for future randomized trials to compare the various triplet regimens so that we can make more informed decisions.” – by Alexandra Todak

Disclosure: Dimopoulos reports advisory board roles with or grant support from Amgen, Celgene, Janssen and Novartis. Please see the full study for a list of all other researchers’ relevant financial disclosures. Kyle reports personal fees from Aeterna Zentaris (Keryx), Bristol-Myers Squibb, Celgene, Merck, Novartis, Onyx Pharmaceuticals (Amgen) and Pharmacyclics. Rajkumar reports no relevant financial disclosures.