Combination of Daratumumab and Bortezomib-Based Regimen Safe in Newly Diagnosed Myeloma

The combination of two proven-effective treatment regimens, daratumumab and the combination of bortezomib, lenalidomide, and dexamethasone (VRd), was considered safe for patients with transplant-eligible, newly diagnosed multiple myeloma (MM), with an overall safety profile that was consistent with either of its components. Further, treatment with daratumumab did not negatively affect stem cell mobilization.

“We know obtaining a deep response is important for improved long-term outcome [and] we know that the triplet of [VRd] followed by stem cell transplant leads to a high complete response rate and long progression-free survival,” Peter M. Vorhees, MD, from the Levine Cancer Institute and Atrium Health in Charlotte, North Carolina, said during his presentation of results from the ongoing, randomized, open-label, phase II trial. To improve the rate of high-quality responses in this patient setting, “we hypothesized that adding daratumumab to the backbone is safe and effective in patients with transplant-eligible disease.”

In the current presentation, Dr. Vorhees shared results from a safety run-in phase that assessed potential dose-limiting toxicities associated with the combination of daratumumab and VRd in 16 patients. These results will support a larger, randomized phase II study comparing daratumumab-VRd with VRd-alone in this patient population.

Participants were aged 18 to 70 years, were eligible for both high-dose chemotherapy and autologous hematopoietic cell transplantation (AHCT), had an Eastern Cooperative Oncology Group performance score 0 to 2, and had received no prior systemic therapy for MM.

Following study protocol, participants received four induction cycles of VRd every 21 days, followed by stem cell mobilization, high-dose chemotherapy, and AHCT. They then received consolidation therapy with two cycles of daratumumab 16 mg/kg plus VRd. Maintenance therapy consisted of lenalidomide 10 mg daily on days 1 through 21 of each cycle and daratumumab 16 mg/kg every 56 days.

As of October 2018 (data cutoff), all 16 patients had completed nine or more cycles of daratumumab plus VRd (median = 17 cycles; range not provided), including at least three cycles of maintenance therapy. Patients’ median age was 62.5 years (range not reported). Four participants (25%) had International Staging System stage II or III disease, while the rest had stage I disease.

Toxicity was “manageable,” and the authors did not observe any new safety signals with longer-term therapy. Each participant experienced at least one treatment-emergent adverse event (AE). Most patients (n=12; 75%) experienced infections, including pneumonia (n=4), E. coli bacteremia, sinusitis, and gastroenteritis (n=1 each). Daratumumab-related infusion reactions occurred in five patients (31%).

However, 14 participants (88%) experienced grade 3-4 AEs (11 of which were considered related to daratumumab). The most commonly reported (≥10%) grade 3-4 AEs were hematologic, and included neutropenia, thrombocytopenia, lymphopenia, febrile neutropenia, and leukopenia.

“The non-hematologic adverse events were very much mild, which we would expect with daratumumab,” Dr. Vorhees said. “The majority were grade 1 or 2 and were manageable.”

Ten patients (63%) had at least one serious AE, three of which (19%) were deemed related to daratumumab treatment. The investigators noted, though, that there were no patient deaths attributable to serious AEs, and no patient discontinued treatment due to an AE.

At the time of presentation, patients had received a median of 17 cycles of treatment (range not provided). With a median follow-up of 15.6 months (range not provided), 15 of 16 patients (94%) remained on study treatment without disease progression.

Response deepened over time, the reports noted. By the end of consolidation therapy, all patients achieved at least a very good partial response (VGPR), and 63 percent achieved complete response (CR) or stringent CR (sCR; per investigator assessment).

Half of patients (n=8) achieved minimal residual disease (MRD)–negative status (to a level of 10-5 per next-generation sequencing).

“It’s safe to say that we’re off to a good start,” Dr. Vorhees concluded, given the combination’s safety profile and the fact that “all participants underwent successful mobilization with subsequent transplant.”

The results from this study are limited by the small patient population, meaning that the results may not be generalizable to other patients with newly diagnosed MM.

The authors report financial relationships with Bristol Myers Squibb, Amgen, Celgene, Novartis, and Janssen, which sponsored the study.

Reference

Vorhees PM, Rodriguez C, Reeves B, et al. Efficacy and updated safety analysis of a safety run-in cohort from Griffin, a phase 2 randomized study of daratumumab (Dara), bortezomib (V), lenalidomide (R), and dexamethasone (D; Dara‐Vrd) vs. Vrd in patients (pts) with newly diagnosed (ND) multiple myeloma (MM) eligible for high‐dose therapy (HDT) and autologous stem cell transplantation (ASCT). Abstract #151. Presented at the 2018 ASH Annual Meeting, December 1; San Diego, CA.

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