Induction and Consolidation Therapy with Daratumumab Plus KRD Shows Potential in High-Risk Newly Diagnosed Myeloma

Daratumumab, carfilzomib, lenalidomide, and dexamethasone induction and consolidation allowed 70% of patients with high-risk, newly diagnosed multiple myeloma to complete a second autologous stem cell transplant.

Daratumumab, carfilzomib, lenalidomide, and dexamethasone induction and consolidation allowed 70% of patients with high-risk, newly diagnosed multiple myeloma to complete a second autologous stem cell transplant, meeting the primary end point of the phase 2 IFM 2018-04 trial (NCT03606577).

The findings presented at the 19th Annual International Myeloma Society Meeting showed that 35 of 50 patients treated with the quadruplet underwent a second ASCT, meeting the preplanned threshold for second ASCT of at least 70% of patients.

“The IFM 2018-04 study confirmed the feasibility of daratumumab, carfilzomib, lenalidomide, and dexamethasone induction and consolidation in the context of tandem [ASCT] in high-risk patients [with newly diagnosed multiple myeloma],” said presenting study author Cyrille Touzeau, MD, PhD, a hematologist in the Hematology Department from the University Hospital of Nantes in Nantes, France, in a presentation of the data.

High-risk cytogenetics are associated with poor outcomes in patients with newly diagnosed multiple myeloma who are eligible for ASCT. Prior data from the phase 2 FORTE trial (NCT02203643) showed that the triplet regimen of carfilzomib, lenalidomide, and dexamethasone demonstrated safety and efficacy in this patient population. Additionally, daratumumab-based regimens have been shown to generate deep responses and improved progression-free survival (PFS) in the phase 3 CASSIOPEIA (NCT02541383) and phase 2 GRIFFIN (NCT02874742) trials.

In IFM 2018-04, investigators evaluated the addition of daratumumab to the FORTE regimen in transplant-eligible patients who were younger than 66 years of age and who had newly diagnosed multiple myeloma. Patients were required to have an ECOG performance status of 0 to 2 and high-risk cytogenetics by fluorescence In situ hybridization analysis, including t(4;14), deletion 17p, or t(14;16).

Once enrolled, patients received induction therapy in six 28-day cycles. Induction treatment was comprised of 16 mg/kg of daratumumab on days 1, 8, 15, and 22 in cycles 1 and 2, then days 1 and 15 in cycles 3 to 6; 20 or 36 mg/m2 of carfilzomib on days 1 to 2, 8 to 9, and 15 to 16 of each cycle; 25 mg of lenalidomide on days 1 to 21 of each cycle; and 20 mg of dexamethasone on days 1 to 2, 8 to 9, 15 to 16, and 22 to 23 of each cycle.

During stem cell collection, patients received cyclophosphamide and granulocyte–colony stimulating factor with or without plerixafor (Mobozil). During the first ASCT, patients received 200 mg/m2 of melphalan.

Patients were then given consolidation therapy with the quadruplet in four 28-day cycles. Consolidation treatment entailed 16 mg/kg of daratumumab on days 1 and 15 of each cycle; 56 mg/m2 of carfilzomib on days 1, 8, and 15 of each cycle; 15 mg of lenalidomide on days 1 to 21 of each cycle; and 40 mg of dexamethasone on days 1, 8, 15, and 22 of each cycle. A 200-mg/m2 dose of melphalan was administered with the second ASCT, and patients then went on to receive maintenance treatment with 16 mg/kg of daratumumab every 8 weeks and 10 mg of lenalidomide for up to 2 years.

Along with the primary end point of feasibility of second ASCT, secondary end points included overall response rate (ORR), PFS, overall survival (OS), stem cell collection, and safety.

The median age of enrolled patients was 57 years (range, 38-65), and the majority had an ECOG performance status of 0 or 1 (94%). International Staging System (ISS) score included stage 1 (42%), stage 2 (34%), and stage 3 (24%). Per revised ISS score, 76% of patients had stage 2 disease and 24% had stage 3 disease. Regarding high-risk cytogenetics, 40% of patients had deletion 17p, 52% had t(4;14), 20% had t(14;16), and 50% had 1q gain. Notably, 68% of patients had 2 high-risk cytogenetic abnormalities.

As of the data cutoff of August 19, 2022, 33 patients were still receiving treatment; 26 patients are receiving maintenance treatment, 4 are receiving consolidation treatment, and 3 are undergoing their second ASCT. Of the 17 patients who discontinued treatment, 4 did so because of progressive disease, 4 did so due to adverse effects (AEs), 1 was due to withdrawal, and 8 were due to stem cell collection failure.

Additional data showed that among 48 evaluable patients, the quadruplet induced an ORR of 96%, which included a stringent complete response (CR) rate of 10%, a CR rate of 21%, and a very good partial response rate of 60%. Among 46 evaluable patients, the minimal residual disease–negativity rate was 62%.

At a median follow-up of 21.2 months, the 18-month PFS and OS rates with the quadruplet regimen were 93% (95% CI, 85%-100%) and 96% (95% CI, 90%-100%), respectively.

In patients who had stem cells collected after 6 cycles of induction therapy (n = 27), the median yield of CD34-positive cells was 6.5 x 106 cells/kg (range, 0-16). Stem cell collection failed in 6 of these patients, with 4 unable to proceed to first ASCT and 2 unable to proceed to second ASCT.

The study protocol was amended to allow for stem cell collection following cycle 3 of induction therapy, and in 21 patients, the median yield of CD34-positive cells was 8.3 x 106 cells/kg (range, 4.7-26). Stem cell collection failed in 1 patient, who was unable to proceed to second ASCT.

Regarding safety, any-grade hematologic treatment-related AEs (TRAEs) included neutropenia (44%), anemia (28%), and thrombocytopenia (26%). The grade 3/4 rates of neutropenia, anemia, and thrombocytopenia were 40%, 14%, and 8%, respectively.

The most common non-hematologic TRAEs included gastrointestinal disorders (any grade, 46%; grade 3/4, 4%), infection (40%; 6%), skin rash (16%; 0%), deep-vein thrombosis (14%; 6%), peripheral neuropathy (12%; 0%), hepatic cytolysis (8%; 4%), renal failure (6%; 6%), and cardiac event (2%; 0%).

AEs led to treatment discontinuation in 2 patients; 1 patient had COVID-19 infection and the other had tumor lysis syndrome. Three patients had a grade 3/4 infection, which included COVID-19, cytomegalovirus, and Pseudomonas aeruginosa bacteriemia.

“We need longer follow-up to evaluate the efficacy and feasibility of the overall strategy of double transplant, consolidation, and maintenance,” Touzeau concluded.

Reference
Touzeau C, Perrot A, Hulin C, et al. Daratumumab carfilzomib lenalidomide and dexamethasone as induction therapy in high-risk transplant eligible newly diagnosed myeloma patients: results of the phase 2 study IFM 2018-04. Presented at: 19th Annual International Myeloma Society Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-041