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Daratumumab Maintenance Deepens Responses, Survival in Multiple Myeloma

Conference Correspondent  - ASH 2019 MM

After induction therapy with daratumumab and CyBorD (cyclophosphamide, bortezomib, and dexamethasone) maintenance therapy with daratumumab for 12 months continued to deepen responses in patients with newly diagnosed or relapsed multiple myeloma (MM), according to an update of the single-arm phase 2 LYRA study. Importantly, the increase in complete responses was associated with durable progression-free survival (PFS) and overall survival (OS).

Daratumumab, a human IgGκ monoclonal antibody targeting CD38, is approved in combination with standard-of-care regimens for the treatment of newly diagnosed and relapsed/refractory MM. CyBorD is a commonly used immunomodulatory drug–sparing regimen recommended by the National Comprehensive Cancer Network as induction therapy for MM patients who are transplant eligible or ineligible.

In the phase 2 LYRA study, daratumumab in combination with CyBorD (DARA-CyBorD) demonstrated efficacy and a tolerable safety profile at the end of induction. At ASH, Robert M. Rifkin, MD, and colleagues presented updated findings examining the effect of monthly daratumumab maintenance on the efficacy and safety of DARA-CyBorD induction in MM. Dr Rifkin noted that this study was designed for patients with newly diagnosed or relapsed myeloma, not refractory to a proteasome inhibitor (PI) or PI/immunomodulatory drug combination.

LYRA is an ongoing, single-arm, open-label trial conducted at US community oncology centers. Newly diagnosed and relapsed patients in the study received a median of 6 and 8 cycles, respectively, of induction therapy with DARA-CyBorD. “The first dose of daratumumab was given over 2 consecutive days to decrease the length of the infusion, and hopefully, the incidence and severity of infusion reactions,” he noted.

After induction, eligible patients could undergo autologous stem-cell transplantation (ASCT), and all patients received up to 12 monthly maintenance cycles with intravenous daratumumab 16 mg/kg every 4 weeks. The investigators followed up through 36 months from the start of induction.

A total of 101 patients were enrolled in the study—87 newly diagnosed (1 of whom never received treatment) and 14 relapsed—with a median age of 63 years. High-risk cytogenetics were imbalanced between arms, and were more common in newly diagnosed patients.

“This was just the luck of the draw in a protocol that accrued very rapidly,” he said. “The preponderance of accrual was very rapid in the newly diagnosed arm, and with the first amendment of the protocol we actually closed the relapsed arm.”

Thirty-nine newly diagnosed patients and 1 relapsed patient underwent ASCT. Seventy-six patients in the newly diagnosed group and 12 in the relapsed group completed induction. A total of 85 patients received ≥1 maintenance doses of daratumumab, and 70 patients received all 12 maintenance cycles.

Response rates in newly diagnosed patients deepened with 12 months of daratumumab monotherapy maintenance. By the end of induction, the overall response rate (ORR) in newly diagnosed patients who did not receive transplant was 83%, with 64% very good partial responses or better (≥VGPR) and 11% complete responses or better (≥CR).

By the end of maintenance, ORR, ≥VGPR, and ≥CR rates were 97%, 82%, and 49%, respectively, in newly diagnosed patients who underwent ASCT, and 83%, 70%, and 30%, respectively, in newly diagnosed patients who did not receive a transplant.

DARA-CyBorD induction and daratumumab maintenance achieved high 24-month PFS rates in newly diagnosed patients, regardless of transplant status. With a median follow-up of 25.8 months, the 2-year PFS rate was 72.6% in nontransplanted patients and 89% in transplanted patients. Depth of response was correlated with longer PFS in both transplanted and nontransplanted newly diagnosed patients.

Even in the limited number of patients in the relapsed population, the investigators observed a durable depth of response with daratumumab maintenance: ≥CR deepened over time, with a 2-year PFS of 47.6%.

OS data are promising, but remain immature, with a 2-year OS rate of 90.5% in newly diagnosed patients and 64.3% in relapsed patients.

The investigators noted that the 24-month PFS rates in the newly diagnosed and relapsed populations in LYRA compare favorably with those seen with DARA-VMP (daratumumab + bortezomib, melphalan, and prednisone) in newly diagnosed patients and with DARA-Vd (daratumumab + bortezomib and dexamethasone) in relapsed/refractory patients.

Importantly, in the community setting of this study, the safety profile was consistent with previous reports of daratumumab, with no new safety concerns observed with longer follow-up. Serious treatment-related adverse events occurred in 33% of patients, the most common being (>2%) pneumonia, pulmonary embolism, and atrial fibrillation. Treatment-related adverse events led to permanent treatment discontinuation in 7% of patients, with 2% related to treatment.

“These data indicate that DARA-CyBorD is a safe, effective multiple myeloma treatment and that daratumumab maintenance increases depth of response and achieves durable remissions,” said Dr Rifkin.


Rifkin RM, et al. ASH Abstract 863.

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Last modified: April 27, 2020