Investigating an Elotuzumab-Based Quadruplet Combination in Newly Diagnosed Myeloma

In results from a phase IIa trial presented at the 2017 ASCO Annual Meeting, adding the anti-SLAMF7 monoclonal antibody elotuzumab to the three-drug combination of bortezomib, lenalidomide, and dexamethasone was associated with a high overall response rate (ORR) in patients with previously untreated myeloma.

“We hypothesized that elotuzumab could be added safely, with minimal added toxicity relative to the standard three-drug combination, and would be associated with a high rate of response,” lead author Jacob Laubach, MD, clinical director and senior physician at the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute in Boston, Massachusetts, said during his presentation.

Patients were eligible for inclusion if they were newly diagnosed with multiple myeloma and considered transplant-eligible; patients were excluded if they had grade ≥2 peripheral neuropathy, inadequate platelet count, renal insufficiency, cardiac abnormalities, hepatic impairment, or clinically active infection.

Treatment consisted of four 21-day cycles:

  • elotuzumab 10 mg/kg (administered by intravenous [IV] infusion) on days 1, 8, and 15 of cycle 1-2, and days 1 and 11 of cycles 3 and beyond
  • bortezomib 1.3 mg/m2 as a subcutaneous injection on days 1, 4, 8, and 11
  • lenalidomide 25 mg daily administered orally on days 1-14
  • dexamethasone 20 mg administered orally on days 2, 4, 5, 9, 11, and 12, and 8 mg IV infusion on days 1, 8, and 15

Following cycle 4, patients underwent stem cell mobilization. At that point, patients could either proceed with autologous hematopoietic cell transplantation (AHCT) or defer AHCT and continue to receive four more cycles of the elotuzumab combination.

Patients then transitioned to a risk-adapted maintenance combinations: elotuzumab, lenalidomide, and dexamethasone, plus bortezomib every other week if they were considered to have high-risk disease (high-risk cytogenetics, ISS stage II or III disease).

A total of 40 patients were enrolled (median age = 60 years; range = 34-75 years). Of the 39 patients with cytogenetics data available, six patients (15%) had unfavorable cytogenetic abnormalities, including t(4;14) and del17p.

Dr. Laubach presented results from the 40 patients who had received study treatment and completed at least one follow-up assessment by the data cut-off point (May 1, 2017). Twelve patients had discontinued treatment, most often because of adverse events (AEs; n=7). The ORR (greater than a partial response) was 82 percent, including:

  • complete response (CR) plus stringent CR: 15%
  • very good partial response (VGPR) or better: 55%

The median time to response was 25 days (range = 22-29 days), and the median duration of response was not yet reached.

“Recognizing that there were a number of important toxicities that led to the early treatment discontinuation prior to the completion of four cycles of therapy, we were interested in knowing response among patients who did complete four cycles of therapy,” Dr. Laubach said. “Among this cohort of 34 patients, the ORR was 97 percent, with a rate of VGPR or better of 65 percent and a rate of CR or stringent CR of 15 percent.”

Stem cell mobilization was successful, with a median number of collected CD34+ stem cells of 10.48 x 106/kg. “[Adding elotuzumab] did not appear to have an adverse impact on stem cell mobilization,” Dr. Laubach noted.

The most frequent all-grade adverse events (AEs) included fatigue (60%), neuropathy (55%), musculoskeletal joint pain (55%), and infection (50%). The most common grade ≥3 or higher AEs included thrombocytopenia (15%) and hypophosphatemia (12%), which were “expected hematologic toxicities,” Dr. Laubach reported. Two percent of patients developed grade ≥3 peripheral neuropathy. There were two grade 5 events (septicemia and respiratory failure), which led to two patient deaths.

“The high rate of overall response, VGPR or better, and CR or stringent CR among patients who received at least four cycles of elotuzumab plus bortezomib, lenalidomide, and dexamethasone is promising,” he concluded. “Dose or schedule modifications may improve the combination’s toxicity profile and augment clinical benefit.”

The study is limited by the lack of a comparator arm and the small patient population.


Reference

Laubach J, Nooka AK, Cole C, et al. An open-label, single arm, phase IIa study of bortezomib, lenalidomide, dexamethasone, and elotuzumab in newly diagnosed multiple myeloma. Abstract #8002. Presented at the 2017 ASCO Annual Meeting, June 4, 2017; Chicago, Illinois.

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