Isatuximab-Based Quadruplet Induces 100% ORR, Deep Responses in High-Risk Newly Diagnosed Myeloma

Katja Weisel, MD

The quadruplet regimen of isatuximab-irfc (Sarclisa), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (I-KRd) elicited a 100% overall response rate (ORR) and high rates of minimal residual disease (MRD) negativity as treatment for patients with high-risk newly diagnosed multiple myeloma, irrespective of transplant eligibility, according to findings from an interim analysis of the phase 2 GMMG-Concept trial (NCT03104842) that were virtually presented at the 2020 European Hematology Association Congress.

The ORR in 50 evaluable patients consisted of a 46% complete response (CR)/stringent CR rate, a 44% very good partial response (VGPR) rate, and a 10% partial response (PR) rate.

Additionally, among 33 patients who underwent MRD assessment during induction, 61% achieved MRD negativity, suggesting that the quadruplet induces deep responses.

“We know that the prognosis of patients with high-risk multiple myeloma is still markedly impaired,” lead study author Katja Weisel, MD, of the University Hospital Hamburg, in Germany, said during the presentation. “The best method to overcome the negative impact of high-risk disease has yet to be defined. [Though], CD38-directed monoclonal antibodies can be safely added to standard of care regimens to improve efficacy.”

The GMMG-Concept trial is the first trial to enroll a purely high-risk patient population with newly diagnosed multiple myeloma, according to Weisel and co-investigators.

In order to be eligible for enrollment, patients had to have high-risk multiple myeloma defined by del(17p), t(4;14), t(14;16) or more than 3 copies of 1q21, stage 2 or 3 disease according to the Multiple Myeloma International Staging System (ISS), and adequate organ function.

Additionally, patients could have received up to 1 cycle of anti-myeloma therapy prior to study entry.

Patients were grouped into 1 of 2 arms: transplant eligible and up to 70 years of age (n = 117; arm A) and transplant ineligible and older than 70 years of age (n = 36; arm B).

In the first 28-day cycle, patients received 10 mg/kg of isatuximab on days 1, 8, 15, and 22, 20 mg/m2 of carfilzomib on days 1 and 2 and 36 mg/m² on days 8, 9, 15, and 16, 25 mg of lenalidomide on days 1 to 21, and 40 mg of dexamethasone on days 1, 8, 15, and 22.

Cycles 2 through 6 consisted of 10 mg/kg of isatuximab on days 1 and 15, 36 mg/m² of carfilzomib on days 1, 2, 8, 9, 15, and 16, 25 mg of lenalidomide on days 1 to 21, and 40 mg of dexamethasone on days 1, 8, 15, and 22.

The dose of lenalidomide was dependent on patients’ renal function. Additionally, dexamethasone was given at a dose of 20 mg in patients who were 75 years or older.

Following 6 cycles of induction therapy, eligible patients underwent transplant. Transplant-ineligible patients received an additional 2 cycles of I-KRd. All patients then received 4 additional cycles of I-KRD followed by I-KR maintenance.

The median age of the 50 patients who were included in the interim analysis was 58. In arms A and B, the median age was 58 years and 77 years, respectively. Additionally, 42% of patients were male.

Forty-two percent of patients had an ECOG performance status (PS) of 0, 46% had a PS status of 1, and 12% had a status of 2. Over half of patients (56%) had ISS stage 2 disease, and 44% had stage III disease.

Regarding high-risk cytogenetics, 52% of patients had del(17p), 38% had t(4;14), 12% had t(14;16), and 42% had more than 3 copies of 1q21.

Patients in arm A underwent cyclophosphamide-based stem cell mobilization with a median yield of 6.6 x 10⁶ CD34-positive cells/KG body weight. The bone marrow stimulant plerixafor (Mozobil) was recommended as a standard of care and was used in 7 out of 40 patients. Additionally, 4 patients underwent rescue mobilization.

Stem cell mobilization was originally planned to occur after cycle 1 of induction therapy; however, the protocol was amended to take place after 3 cycles of induction.

Regarding safety, all-grade non-hematologic treatment-emergent adverse effects (TEAEs) included upper respiratory tract infection (n = 9), pyrexia (n = 6), rash (n = 8), peripheral sensory neuropathy (n = 8), nasopharyngitis (n = 5), hypertension (n= 6), cardiac failure (n = 2), and infusion reaction (n = 16).

Grade 3/4 non-hematologic TEAEs included 1 case of peripheral sensory neuropathy, 6 cases of hypertension, and 2 cases of cardiac failure. Grade 3/4 hematologic TEAEs included leukopenia (n = 13), neutropenia (n = 17), lymphopenia (n = 14), anemia (n = 5), and thrombocytopenia (n = 7). No patient deaths occurred during the study.

Additionally, 88% of patients completed induction therapy, suggesting that the regimen was well tolerated.

“The trial completed recruitment as of April 7, 2020, and further analyses are ongoing,” said Weisel. “Our data support other studies pointing at quadruplet treatment as the new standard induction treatment in newly diagnosed multiple myeloma. This conclusion may apply in particular to high-risk patients with multiple myeloma.”

Reference:

Weisel K, Asemissen AM, Besemer B, et al. Depth of response isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in front-line treatment of high-risk multiple myeloma: interim analysis of the GMMG-CONCEPT trial. Presented at: 2020 European Hematology Association Congress; June 11-21, 2020; Virtual. Abstract S204.