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D-VRd in Multiple Myeloma | Image Credit: © ChaoticMind – stock.adobe.com The addition of subcutaneous daratumumab (Darzalex) to bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) demonstrated consistent clinical benefit without any detriment to health-related quality of life (HRQOL) vs VRd alone in transplant-ineligible or -deferred patients with newly diagnosed multiple myeloma enrolled in the phase 3 CEPHEUS trial (NCT03652064), supporting the use of the quadruplet therapy in those able to receive bortezomib.
1 The data, which were shared via poster at the 50th Annual Oncology Nursing Society , showed that D-VRd (n = 197) significantly increased the overall minimal residual disease (MRD) negativity rate over VRd (n = 198) by approximately 20% at both the 10 –5 and 10 –6 thresholds. At the 10 –5 threshold, the MRD negativity rates in the respective arms were 60.9% and 39.
4% (odds ratio [OR], 2.37; 95% CI, 1.58-3.
55; P < .0001); at the 10 –6 threshold, the respective rates were 46.2% and 27.
3% (OR, 2.24; 95% CI, 1.48-3.
40; P = .0001). This improvement was observed across most prespecified subgroups.
Moreover, D-VRd nearly doubled sustained MRD negativity rates vs VRd across durability thresholds. Notably, the rates of sustained MRD negativity with a complete response (CR) or better at 10 –5 threshold lasting for at least 12 months was 49.2% with D-VRd vs 27.
3% for VRd, roughly translating to a 22% difference ( P < .0001). Sustained MRD negativity at the same threshold lasting for at least 24 months was 42.
1% and 22.7% in the respective arms, translating to an approximate 19% difference ( P < .0001); and sustained MRD negativity rates at the 10 –5 threshold lasting for at least 36 months were 29.
9% and 15.2%, respectively, translating to an approximate difference of 15% ( P = .0005).
Responses were also significantly improved with D-VRd vs VRd. The rate of CR or better was 81.2% with D-VRd vs 61.
6% with VRd (OR, 2.73; 95% CI, 1.71-4.
34; P < .0001). Moreover, after a median follow-up of 58.
7 months, D-VRd led to a significant 43% reduction in the risk of disease progression or death (HR, 0.57; 95% CI, 0.41-0.
79; P = .0005). The respective 54-month progression-free survival (PFS) rates were 68.
1% and 49.5%. Again, the PFS benefit observed with D-VRd over VRd was generally consistent spanning prespecified subgroups.
Lastly, the overall survival (OS) trend was found to favor the quadruplet over the triplet, with a hazard ratio of 0.85 (95% CI, 0.58-1.
24). Because the trial was conducted during the height of the COVID-19 pandemic, deaths caused by the virus accounted for 21.6% of all deaths on the study, with 15 reported in the D-VRd arm and 9 reported in the VRd arm.
As this was considered a notable effect on OS, investigators conducted a sensitivity analysis that censored deaths associated with the virus and found that OS trended further in favor of D-VRd vs VRd (HR, 0.69; 95% CI, 0.45-1.
05). “Data from CEPHEUS complement prior data from the phase 3 MAIA trial [NCT02252172] [which explored daratumumab plus lenalidomide and dexamethasone] in transplant-ineligible patients, supporting the feasibility of daratumumab-based quadruplet or triplet standard-of-care options across transplant-ineligible and transplant-deferred patients with newly diagnosed multiple myeloma,” Saad Z. Usmani, MD, MBA, FACP, FASCO, of Memorial Sloan Kettering Cancer Center in New York, New York, and colleagues, wrote in the poster.
MRD negativity has been increasingly linked with better survival outcomes, and the CD38-targeted human IgGk monoclonal antibody has been shown to improve MRD negativity rates and survival outcomes when paired with standard regimens in transplant-eligible and -ineligible patients with multiple myeloma. In transplant-eligible patients, D-VRd followed by maintenance treatment with daratumumab plus lenalidomide led to a 58% reduction in the risk of disease progression or death vs VRd followed by maintenance lenalidomide (HR, 0.42; 95% CI, 0.
30-0.59; P < .001), according to data from the phase 3 PERSEUS study (NCT03710603).
2 The quadruplet also led to higher MRD OS survival vs lenalidomide plus dexamethasone, leading to a 33% reduction in the risk of death (HR, 0.67; 95% CI, 0.55-0.
82; P < .0001), according to data from the final analysis of MAIA. 3 The phase 3 study enrolled patients at least 18 years of age with newly diagnosed multiple myeloma who were not eligible for transplant or for whom transplant was not planned as initial therapy.
1 All patients had an ECOG performance status ranging from 0 to 2 and a frailty score of 0 or 1. Patients in both arms received VRd, which was comprised of 1.3 mg/m 2 of subcutaneous bortezomib given on days 1, 4, 8, and 11; 25 mg of oral lenalidomide given on days 1 to 14; and 20 mg of oral dexamethasone given on days 1, 2, 4, 5, 8, 9, 11, and 12.
Those in the D-VRd arm also received subcutaneous daratumumab at 1800 mg once weekly for cycles 1 and 2 and every 3 weeks for cycles 3 to 8. For cycles 9 and onward, patients in both arms received 25 mg of lenalidomide on days 1 to 21 plus 40 mg of dexamethasone on days 1, 8, 15, and 22. Those in the D-VRd arm also received 1800 mg of daratumumab every 4 weeks.
Stratification factors included International Staging System staging and age/transplant eligibility. The primary end point of the study was overall MRD negativity with a CR or better, and key secondary end points included PFS, sustained MRD negativity with a CR or better, rate of CR or better, and OS. Demographic and baseline characteristics were noted to be well balanced at baseline between the arms.
The median duration of treatment with D-VRd was 56.3 months vs 34.3 months with VRd.
Fewer patients on the D-VRd arm discontinued treatment vs the VRd arm (48.2% vs 65.6%).
“Treatment-emergent adverse effects [TEAEs] were consistent with known safety profiles for daratumumab and VRd,” the study authors wrote. “Grade 3/4 TEAEs were common in the D-VRd group; the rate of treatment discontinuation of all study drugs due to TEAEs was lower for D-VRd vs VRd.” The respective rates of grade 3/4 TEAEs were 7.
6% and 15.9%. The most common grade 3/4 TEAEs reported in the D-VRd and VRd arms were blood and lymphatic system disorders (64.
0%; 50.3%), neutropenia (44.2%; 29.
7%), thrombocytopenia (28.4%; 20.0%), anemia (13.
2%; 11.8%), lymphopenia (12.2%; 10.
3%), gastrointestinal disorders (20.8%; 20.5%), diarrhea (12.
2%; 9.2%), constipation (2.0%; 2.
6%), general disorders and administration site conditions (20.3%; 14.4%), peripheral edema (2.
0%; 0.5%), fatigue (9.1%; 8.
2%), psychiatric disorders (5.1%; 5.1%), insomnia (2.
0%; 1.0%), infections (40.1%; 31.
8%), upper respiratory infection (0.5%; 0.5%), COVID-19 (11.
2%; 4.6%), pneumonia (14.2%; 12.
8%), nervous system disorders (22.8%; 19.5%), and peripheral sensory neuropathy (8.
1%; 8.2%). Similar improvements in patient HRQOL was observed with D-VRd and VRd per the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 global health status score.
Similar improvements in patient-perceived health status were observed over time with D-VRd and VRd per the EuroQol 5-Dimension 5-Level visual analog scale. As such, the addition of daratumumab to VRd did not result in any detrimental effect on HRQOL. Disclosures : Dr Usmani disclosed receipt of research funding from Amgen, Array BioPharma, Bristol Myers Squibb, Celgene, GSK, Johnson & Johnson, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDx, and Takeda.
He also served as a consultant for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Edo Pharma, Genentech, Gilead, GSK, Johnson & Johnson, Oncopeptides, Sanofi, Seattle Genetics, Secura Bio, Skyline Dx, Takeda, and Teneobio..
