Four Drugs Upfront Yield ‘Unprecedented’ Response in Myeloma

Adding the anti-CD38 drug daratumumab (Darzalex) to a weekly three-drug regimen for patients with newly diagnosed multiple myeloma led to extremely high rates of minimal residual disease (MRD) negativity in a single-arm study.

In the phase II trial, the rate of MRD negativity prior to transplant reached 71% (95% CI 54-83%) with 8 cycles of daratumumab plus carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd), reported a group of researchers led by Ola Landgren, MD, PhD, of the Sylvester Comprehensive Cancer Center in Miami.

“The observed MRD results are approximately 20% higher than previously reported MRD rates among patients with newly diagnosed multiple myeloma treated with KRd, which indicates that the addition of daratumumab to an existing backbone combination therapy was associated with a clinically meaningful benefit,” the authors wrote in JAMA Oncology.

The “unprecedented” MRD negativity rate was achieved in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant (HDM-AHCT), the group noted.

All 41 evaluable patients in the study responded to treatment, and 95% achieved a complete response or very good partial response. Progression-free survival (PFS) and overall survival (OS) rates at 1 year were 98% (95% CI 93-100%) and 100%, respectively.

“Two recent meta-analyses show that MRD negativity is associated with longer PFS and OS among patients with newly diagnosed multiple myeloma,” according to Landgren and colleagues.

Findings from the so-called MANHATTAN trial support those of the recently reported phase II GRIFFIN trial, which showed improved rates of MRD negativity and stringent complete response among transplant-eligible myeloma patients receiving daratumumab plus bortezomib (Velcade), lenalidomide, and dexamethasone (VRd), as compared with VRd alone. In that trial, patients achieved an MRD-negativity rate of 51% with 4 cycles of daratumumab plus VRd followed by HDM-AHCT, then 2 more cycles of the combination.

MANHATTAN was a single-arm, single-center trial that evaluated daratumumab plus KRd in 41 evaluable patients with newly diagnosed myeloma. Patients had a median age of 59 years, 61% were women, and a little less than half had high-risk disease. The study’s primary endpoint was MRD negativity, defined as a sensitivity of 10^-5 in bone marrow.

Treatment consisted of 8 cycles of carfilzomib (20/56 mg/m² IV on days 1, 8, and 15 of 28-day cycles), lenalidomide (25 mg orally on days 1 to 21), oral or IV dexamethasone weekly (40 mg for cycles 1 to 4, then 20 mg thereafter), and IV daratumumab (16 mg/kg on days 1, 8, 15, and 22 in cycles 1 and 2; days 1 and 15 for cycles 3 to 6; and day 1 for cycles 7 and 8).

Age (<60 vs ≥60) was not significantly associated with MRD negativity, with an OR of 0.48 (95% CI 0.08-2.3, P=0.32), nor was cytogenetic risk status (high vs standard risk), with an OR of 1.7 (95% CI 0.36-8.6, P=0.50).

Patients reached MRD negativity at a median 6 cycles. Among the eight patients who achieved MRD negativity and were evaluated at 1 year, seven had sustained this level of response.

The four-drug regimen yielded no additional grade ≥3 toxicities compared with standard biweekly KRd, the authors noted.

Common grade 3/4 adverse events (AEs) included neutropenia (27%), rash (9%), lung infection (7%), and increased levels of alanine aminotransferase (4%), and no grade ≥3 peripheral neuropathy occurred. Serious treatment-related AEs occurred in 18% of the cohort, with lung infection being most common, and one patient developed acute coronary syndrome during the study and withdrew.

Grade 2 infusion-related reactions with daratumumab occurred in 40% of patients, all during the initial infusion, and did not lead to treatment discontinuation. Overall, 17 patients had lenalidomide dose reductions and 22 had reductions of dexamethasone.

Only two patients discontinued treatment, one after developing a lung cancer and another to reduce clinic visits during the COVID-19 pandemic.

A currently enrolling randomized multicenter study — ADVANCE — will compare daratumumab plus KRd with standard of care for newly diagnosed multiple myeloma.