Daratumumab Added to Carfilzomib, Lenalidomide, and Dexamethasone: Safe and Tolerable in Patients with Newly Diagnosed Multiple Myeloma

TOP - November 2017, Vol 10, No 4 - Multiple Myeloma

Chicago, IL—In patients with newly diagnosed multiple myeloma, the addition of daratumumab to carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (ie, the KRd regimen) is showing promise as a frontline treatment regimen. According to the results of an open-label, phase 1b study presented at ASCO 2017, induction therapy with the KRd regimen was well-tolerated, and the overall safety profile was consistent with previous reports for KRd, with no additional toxicity observed with the addition of daratumumab. Moreover, the study investigators reported that the regimen was very effective, with 100% overall response rate observed.

“These are very promising and high response rates, and importantly, depth of response improved with duration of treatment,” said Andrzej J. Jakubowiak, MD, PhD, Director, Myeloma Program, University of Chicago Medical Center, IL. “Data from this study suggest that daratumumab is feasible as part of induction therapy, and support further investigation of daratumumab plus KRd in newly diagnosed multiple myeloma.”

Daratumumab, a monoclonal antibody targeting CD38, was approved as monotherapy for heavily pretreated relapsed or refractory multiple myeloma in several countries. In the United States it is also approved in combination with standard-of-care regimens in relapsed or refractory multiple myeloma after at least 1 previous therapy.

“We are all excited to have this antibody available for myeloma,” said Dr Jakubowiak, who noted that daratum­umab induces rapid and durable responses when added to a proteasome inhibitor (ie, bortezomib [Velcade]) or an immunomodulatory drug (ie, lenalidomide) in patients with relapsed or refractory disease.

The results of the phase 3 POLLUX and CASTOR studies, which explored the addition of daratumumab (1) to lenalidomide plus dexamethasone and (2) to bortezomib plus dexamethasone, respectively, demonstrated “drastically improved progression-free survival” and provided rationale for evaluation of daratumumab plus KRd in the phase 1b study presented at the meeting, said Dr Jakubowiak.

Daratumumab plus KRd

To study the tolerability and efficacy of daratumumab plus the KRd regimen, Dr Jakubowiak and colleagues enrolled 22 patients with newly diagnosed multiple myeloma who were transplant eligible or noneligible. The patients received daratumumab (16 mg/kg) once weekly for cycles 1 to 2, twice weekly for cycles 3 to 6, and 4 times weekly thereafter. The first dose of daratumu­mab was split over 2 days. Carfilzomib was administered on days 1, 8, and 15 of each 28-day cycle (20 mg/m2 on cycle 1, day 1, and 36 mg/m2 or 70 mg/m2 subsequently based on the tolerability of the first dose). Lenalidomide was given on days 1 to 21, and dexamethasone was administered every week.

The treatment lasted up to 13 cycles or until elective discontinuation for autologous stem-cell transplant.

Deep, Durable Responses

The median follow-up time for patients was 10.8 months (range, 4.0-12.5 months), and patients received a median of 11.5 cycles of daratumumab plus KRd (range, 1.0-13.0 cycles). All but 3 patients escalated to carfilzomib (70 mg/m2 by cycle 2, day 1). The adverse events were consistent with previously reported studies.

“The most common hematologic and nonhematologic treatment-emergent adverse events generally followed what we have observed in previous reports for daratumumab or KRd,” said Dr Jakubowiak.

Furthermore, extended evaluation showed no apparent adverse effect of the regimen on heart function. An echocardiogram was used at baseline and at 4 time points (cycles 3, 6, 9, and 12).

“The echocardiogram found no change from baseline through the duration of treatment,” said Dr Jakubowiak, who noted that 1 patient had a transient grade 3 adverse event—cardiac failure—which was possibly related to daratumumab or to carfilzomib. This patient ultimately resumed treatment before proceeding to elective transplant and ended treatment with very good partial response, Dr Jakubowiak reported.

The investigators also observed lower rates of infusion-related reactions with splitting the first dosing of daratumu­mab. All infusion-related reactions were grade 1 or 2.

Moreover, the addition of daratum­umab to the triplet regimen did not have an effect on stem-cell harvest. The median number of CD34-positive cells collected from patients was consistent with previous KRd studies, Dr Jakubowiak said. Patients received a median of 5 treatment cycles before stem-cell harvest, with 14 (74%) patients achieving at least very good partial response before harvest.

Finally, treatment with daratumu­mab plus KRd yielded an overall response rate of 100%, with 43% of patients achieving complete response and 91% achieving very good partial response.

Given these results, investigators will continue to explore the combination of daratumumab and KRd in patients with newly diagnosed multiple myeloma, Dr Jakubowiak said.

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Last modified: November 14, 2017