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Daratumumab regimen reduces risk for progression, death in newly diagnosed multiple myeloma
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The addition of daratumumab to lenalidomide and dexamethasone significantly decreased the risk for disease progression or death among patients with newly diagnosed multiple myeloma who are ineligible for autologous hematopoietic stem cell transplantation, according to results of a randomized phase 3 trial published in The New England Journal of Medicine.
Lenalidomide (Revlimid, Celgene) and dexamethasone serve as the standard therapy for patients with untreated multiple myeloma who do not qualify for autologous HSCT.
“Initial treatment for newly diagnosed multiple myeloma depends on whether a patient may have unacceptable toxic effects from high-dose chemotherapy and may be unable to undergo autologous stem cell transplantation,” Thierry Facon, MD, professor of hematology in the department of hematology at Lille University Hospital in Lille, France, and colleagues wrote. “Younger patients without substantial coexisting conditions usually receive an induction regimen followed by high-dose chemotherapy and autologous stem cell transplantation. For patients who are ineligible for stem cell transplantation, multiagent regimens, including alkylating agents, glucocorticoids, immunomodulatory drugs, proteasome inhibitors and new agents, are the standard of care.”
Facon and colleagues added daratumumab (Darzalex, Janssen) — a human IgG-kappa monoclonal antibody that targets CD38 — to the combination of lenalidomide and dexamethasone to see if it would reduce the risk for disease progression and death in this patient population.
Researchers randomly assigned 737 transplant-ineligible patients with newly diagnosed multiple myeloma to receive daratumumab in combination with lenalidomide and dexamethasone (n = 368; median age, 73 years; range, 50-90) or lenalidomide and dexamethasone alone (n = 369; median age, 74 years; range, 45-89).
The trial was conducted at 176 sites in 14 countries across North America, Europe, the Middle East, and the Asia-Pacific region.
All patients received 25 mg lenalidomide on days 1 through 21 of each 28-day cycle and 40 mg dexamethasone on days 1, 8, 15 and 22. Patients in the daratumumab group received 16 mg/kg once weekly during the first two cycles, every 2 weeks for the next four cycles, and every 4 weeks thereafter. Treatment continued until disease progression or unacceptable toxicity.
PFS served as the study’s primary endpoint.
Secondary endpoints included time to progression; complete response; stringent complete response, defined as a complete response plus a normal free light-chain ratio and absence of clonal plasma cells; negative status for minimal residual disease (MRD), defined as one tumor cell per 105 white cells; and overall response rate. After a median follow-up of 28 months, 97 patients in the daratumumab group and 143 patients in the control group experienced disease progression.
Researchers estimated 70.6% (95% CI, 65-75.4) of patients in the daratumumab group were alive without disease progression after 30 months compared with 55.6% (95% CI, 49.5-61.3) in the control group. Median PFS was not reached in the daratumumab group and was 31.9 months (95% CI, 28.9-not reached) in the control group (HR for disease progression or death = 0.56; 95% CI, 0.43-0.73).
Results showed ORRs of 92.9% (95% CI, 89.8-95.3) in the daratumumab group and 81.3% (95% CI, 76.9-85.1) in the control group (P < .001). Significantly more patients in the daratumumab group achieved complete response or better (47.6% vs. 24.9%) and very good partial response or better (79.3% vs. 53.1%; P < .001 for both).
The daratumumab group also demonstrated higher rates of stringent complete response (30.4% vs. 12.5%) and negative status for MRD (24.2% vs. 7.3%; P < .001).
Median OS was not reached in either arm; 61 patients in the daratumumab group and 76 in the control group had died.
The most common grade 3 or grade 4 adverse events in the daratumumab and control groups included neutropenia (50% vs. 35.3%), lymphopenia (15.1% vs. 10.7%) pneumonia (13.7% vs. 7.9%) and anemia (11.8% vs. 19.7%). Adverse events led to death — most commonly due to pneumonia — in 25 patients in the daratumumab group and 23 in the control group,
“These findings can be added to those from a growing list of trials that support the use of daratumumab-based regimens across patient populations with multiple myeloma,” Facon and colleagues wrote. “In our trial, the percentage of patients with a complete response or better was nearly twice as high and the percentage of patients who were negative for minimal residual disease was more than three times as high in the daratumumab group as in the control group; these findings are consistent with those of previous trials.”
These findings are important because expanding the number of effective induction regimens patients with multiple myeloma will improve clinical outcomes, Jacob Laubach, MD, MPP, clinical director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School, wrote in an accompanying editorial.
Laubach noted that as induction regimens such as the combination of daratumumab, lenalidomide and dexamethasone become incorporated into clinical practice, assessments of minimal residual disease may help guide management decisions for a broader range of patients with multiple myeloma.
“Two-drug regimens such as lenalidomide and dexamethasone remain an important option for patients deemed to be too frail to receive more intense therapy,” Laubach said. “Therefore, selection of an appropriate regimen will become a more challenging and complex process that is based on the unique clinical characteristics of a given patient.” – by John DeRosier
Disclosure s : Facon reports consultant/advisory roles with Amgen, Janssen, Karyopharm, Oncopeptides, Roche, Sanofi and Takeda. Please see the study for all other authors’ relevant financial disclosures. Laubach reports no relevant financial disclosures.
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Facon T, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1817249.
Laubach J. N Engl J Med. 2019;doi:10.1056/NEJMe1904372.
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