Daratumumab Produces Dramatic Responses in Relapsed Light Chain Amyloidosis

Gregory P. Kaufman, MD

Almost 90% of patients with previously treated light chain amyloidosis responded to single-agent daratumumab (Darzalex), according to a small study reported at the 2016 Society of Hematologic Oncology annual meeting.

Overall, 16 of 18 patients achieved objective responses, including complete responses in a third of patients. None of the patients had achieved a complete response with prior therapies, said Gregory P. Kaufman, MD, a postdoctoral fellow in hematology at Stanford University.

“In this heavily pretreated, single-institution cohort of light chain amyloidosis patients, daratumumab produced rapid and deep hematologic responses,” said Kaufman. “None of these patients had previously achieved hematologic complete response despite multiple rounds of therapy. Our toxicity experience was similar to our institutional experience and published results with daratumumab in myeloma.”

“Daratumumab should be further evaluated prospectively in light chain amyloidosis,” added Kaufman.

Immunoglobulin light chain amyloidosis causes significant morbidity and mortality as a consequence of amyloid-mediated organ dysfunction and damage. Although upfront combinations of novel agents achieve high rates of hematologic response, most patients subsequently relapse, and response rates in the setting of relapse remain poor, Kaufman noted.

Daratumumab is a monoclonal antibody that targets CD38. The frequent association of CD38 expression in plasma cell dyscrasias provided a rationale for evaluating daratumumab for treatment of light chain amyloidosis. Late last year, the FDA granted accelerated approval of daratumumab for myeloma that has relapsed or progressed on at least 3 prior regimens.

Kaufman and colleagues retrospectively reviewed clinical experience with daratumumab in the treatment of relapsed light chain amyloidosis.

The patients had a median age of 65. Two-thirds had cardiac involvement, and three-fourths had renal involvement. The median time since diagnosis of light chain amyloidosis was 34 months, and the patients had received a median of 3 prior regimens.

All 18 patients included in the analysis had previously received bortezomib (Velcade) or lenalidomide (Revlimid), and 11 of 18 had received cyclophosphamide-bortezomib-dexamethasone as upfront therapy. Seven of the patients had received carfilzomib (Kyprolis), pomalidomide (Pomalyst), or both agents in the relapse setting, and 4 patients had received melphalan as part of high-dose therapy with autologous stem-cell transplantation.

The patients started daratumumab treatment at a dose of 16 mg/kg weekly for 8 weeks, followed by 8 infusions every other week, and then monthly infusions. Investigators adhered to strict response criteria: complete response—normalization of serum free light chains and ratio plus negative immunoelectrophoresis; very good partial response&mdash;reduction of free light chains to <4 mg/dL (determined by difference between involved and uninvolved light chains [dFLC]); PR&mdash;≥50% reduction from baseline in dFLC.

In addition to the 6 patients who achieved complete responses with daratumumab, 3 patients had very good partial responses, and 7 had partial responses. Only 2 patients did not achieve an objective response to treatment with daratumumab, Kaufman reported.

Response, including complete response, occurred as early as 1 month (or sooner) after the start of treatment. As an example of the activity observed in the study, Kaufman described a patient who had received 6 prior lines of therapy, including autologous stem-cell transplantation, and achieved a complete response within the first month after starting daratumumab infusions.

The approval of single-agent daratumumab for heavily pretreated myeloma was primarily based on data from 2 trials. In the phase II MMY2002 study, daratumumab demonstrated a 65% one-year overall survival (OS) rate and a 29.2% objective response rate (ORR). In the phase I/II GEN501 study, the ORR was 36%, median progression-free survival was 5.6 months, and the 1-year OS rate was 77%.

A supplemental biologics license application (sBLA) has also been submitted to the FDA for the use of daratumumab (Darzalex) in combination with lenalidomide/dexamethasone or bortezomib/dexamethasone as a treatment for patients with multiple myeloma following at least 1 prior therapy.

The application to expand daratumumab’s approval was primarily based on 2 phase III trials. The phase III POLLUX trial demonstrated that combining daratumumab with lenalidomide and dexamethasone reduced the risk of disease progression by 63% versus lenalidomide and dexamethasone alone in patients with relapsed/refractory multiple myeloma. In the phase III CASTOR trial, adding daratumumab to bortezomib and dexamethasone reduced the risk of progression or death by 61% in patients with recurrent or refractory multiple myeloma.