Daratumumab and Carfilzomib Quadruplet Elicits Efficacy and Safety Benefits in High-Risk Multiple Myeloma

Induction therapy with the quadruplet regimen of daratumumab (Darzlex), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (D-KRd) appears to be feasible in patients with high-risk, newly diagnosed multiple myeloma who are eligible for transplant, displaying safety benefits and responses, according to findings from the phase 2 IFM 2018-04 trial (NCT03606577) presented at the 2022 ASCO Annual Meeting.¹

The objective response rate (ORR) among evaluable patients (n = 48) was 96%, with 31% of patients having either a complete response (CR) or stringent CR and 91% having at least a very good partial response (VGPR) to therapy. Additionally, those who were evaluable (n = 46), 62% achieved minimal residual disease negativity by next-generation sequencing at a threshold of 10-5 at a rate of 65%.

“The IFM 2018-04 study confirms the efficacy and feasibility of the quadruplet induction regimen Dara-KRd in high-risk, transplant-eligible patients,” Cyrille Touzeau, MD, PhD, of University Hospital Hôtel-Dieu in Nantes, France, said during a presentation of the data. “No new safety signals were observed [and the combination] induced a deep response rate."

Patients with high-risk cytogenetic features typically suffer from poorer outcomes following a transplant for multiple myeloma. Frontline triplet regimens involving both carfilzomib and daratumumab plus Rd, respectively, have demonstrated efficacy in the indicated patient population.

Key inclusion criteria of the current study involved patients with newly diagnosed multiple myeloma who are transplant eligible and under the age of 66 years with an ECOG performance score of 0 to 2 and high-risk features by fluorescence in situ hybridization, defined as either t(4;14), t(14;16), or deletion 17p (del[17p]). The primary end point was feasibility, defined as the percentage of patients (>70%) receiving autologous stem cell transplant (ASCT). Secondary outcome measures included safety ORR, progression-free survival (PFS), overall survival (OS), and stem cell collection.

Patients were treated with six 28-days cycles of D-KRd induction, which involved intravenous daratumumab at 16 mg/kg weekly for cycles 1 and 2, followed by every other week for cycles 3 through 6; intravenous carfilzomib at either 20 or 36 mg/m² twice weekly for 3 weeks; lenalidomide at 25 mg on days 1 through 21; and dexamethasone at 20 mg twice weekly for the entire 4-week cycle. Patients were then administered ASCT followed by D-KRd consolidation of daratumumab 16 mg/kg every other week; carfilzomib at 56 mg/m² weekly for 3 weeks; lenalidomide at 15 mg on days 1 through 21; and dexamethasone at 40 mg weekly for the entire 4-week cycle. The second ASCT was followed by maintenance with daratumumab at 16 mg/kg intravenously every 8 weeks and lenalidomide at 10 mg on for up to 2 years.

Twenty-seven patients had stem cell collection after 6 cycles of induction D-KRd, with a median number of CD34+ cells of 6.1 × 10⁶/kg (range, 0-16 × 10⁶/kg). After stem cell collection was insufficient to proceed to double transplant in 6 patients, the study protocol was amended to collect after induction cycle 3, with 21 patients completing treatment in this fashion. After the amendment, the median number of CD34+ cells of 8.3 × 10⁶/kg (range, 4.7-26 × 10⁶/kg), and there were no further stem cell collection failures.

At the time of data cut-off, treatment was ongoing in 72% of patients, 11 of whom are in consolidation, 1 received their second ASCT, and 24 are on maintenance therapy. Fourteen patients (28%) discontinued therapy, 2 due to progressive disease, 4 from adverse events (AEs), 2 from withdrawal, and 6 from stem cell collection failure.

With a median follow-up of 19.4 months, the rates of PFS at 12 and 18 months were 96% and 92%, respectively. Corresponding rates of OS were 96% at each of the time points.

The safety profile revealed that the regimen was well tolerated. The most common any-grade nonhematologic treatment-related AEs (TRAEs) were gastrointestinal disorder (46%), infection (40%), skin rash (16%), deep vein thrombosis (14%), peripheral neuropathy (12%), hepatic cytolysis (8%), renal failure (6%), and cardiac events (1%). Grade 3/4 nonhematologic TRAEs included gastrointestinal disorder (4%), infection (6%), deep vein thrombosis (6%), hepatic cytolysis (4%), and renal failure (6%). Any-grade and grade 3/4 hematologic TRAEs were noted for neutropenia (44% and 40%, respectively), anemia (28% and 14%), and thrombocytopenia (26% and 8%).

AEs leading to treatment discontinuation included COVID-19 infection and tumor lysis syndrome in 1 patient each. Grade 3 infections included COVID-19, cytomegalovirus, and pseudomonas aeruginosa bacteriemia in 1 patient each.

Patients (N = 50) had a median age of 57 years (range, 38-65) and most (94%) presented with an ECOG performance status of 0 or 1. International Staging System (ISS) stage 1 accounted for 42% of patients, followed by stage 2 (34%) and stage 3 (24%). Revised ISS (R-ISS) stage 2 (76%) was most reported, with the rest of patients presenting with stage 3. High-risk cytogenetics included del(17p) in 40%, t(4;14) in 52%, t(14;16) in 20%, and 1q gain in 50%. About two-thirds (68%) of patients had 2 high-risk features.

Reference

Touzeau C, Perrot A, Hulin C, et al. Daratumumab carfilzomib lenalidomide and dexamethasone as induction therapy in high-risk, transplant-eligible patients with newly diagnosed myeloma: Results of the phase 2 study IFM 2018-04. J Clin Oncol. 2022;40(suppl 16):8002. doi: 10.1200/JCO.2022.40.16_suppl.8002