“Daratumumab infusion is well tolerated in patients with relapsed AL amyloidosis, when administered with appropriate pre- and post-[infusion] medications.”

— Vaishali Sanchorawala, MD

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DARATUMUMAB (DARZALEX) may be an effective treatment for systemic amyloid light-chain (AL) amyloidosis, according to phase II studies reported at the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition.^1,2 While the cohorts were small and the arms uncontrolled, the findings were encouraging in terms of rapid and deep hematologic responses and effects on organ disease in these previously treated patients. 

“Daratumumab, a monoclonal antibody targeting the CD38 surface antigen on plasma cells, has proven to be highly effective in multiple myeloma. While the biology of the clonal plasma cells in AL amyloidosis is distinct from that of myeloma, clonal plasma cells in AL amyloidosis do express surface CD38, providing a rationale for the use of daratumumab in AL amyloidosis,” said Vaishali Sanchorawala, MD, Director of the Amyloidosis Center at Boston University School of Medicine and Boston Medical Center, who presented one of the studies. 

European Phase II Study of Daratumumab 

MURIELLE ROUSSEL, MD, of the Institut Universitaire du Cancer de Toulouse-Oncopole in Toulouse, France, reported findings from a prospective phase II trial of daratumumab in 40 cases of previously treated AL amyloidosis from 22 centers in France and Italy.¹ The median age of patients was 69 years, median number of prior regimens was 3, median number of involved organs was 2, and median N-terminal pro b-type natriuretic peptide (NT-proBNP) value was 1,118 ng/L at baseline. 

Patients received daratumumab in a standard schedule and dose for a total of six cycles. At data cutoff, 36 patients had received at least 1 injection, 33 received at least 1 cycle of treatment, and 15 received the 6 planned cycles. Two patients died, one due to cardiac progression (despite a partial hematologic response) and one due to lung cancer. Three patients discontinued treatment due to disease progression. 

Nine patients experienced at least one grade ≥ 3 adverse event, but only one (lymphopenia) was drug-related. Infusion reactions at first injection, all grade 1 or 2, were observed in 11 patients. Adverse events considered related to daratumumab numbered 18. 

High Hematologic Response Rates 

AMONG EVALUABLE patients completing at least four injections, very good partial responses or better were seen in 43.8% and partial responses were seem in 40.6%, yielding an overall response rate of 59.4% at 6 months among previously treated AL amyloidosis patients. Of 14 patients achieving at least very good partial responses, 2 patients had a complete response and 7 patients had normal serum free light chain levels, Dr. Roussel reported. 

“Daratumumab demonstrates encouraging efficacy in previously treated patients with [amyloid light-chain] amyloidosis, producing deep and rapid responses.”

— Murielle Roussel, MD

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Responses were rapid. After only one injection, a very good partial response or better was achieved by 43.8% of patients and partial responses, by 15.6%. For patients with durable responses, the median decrease in the difference between involved and uninvolved free light chains (dFLC) was 70%, and the minimum dFLC decrease was 35% after just one dose. 

No baseline factor was predictive of response, including the number of previous lines, refractory vs previous response, dFLC value (low vs high), bone marrow plasma cells (low vs high), immunoglobulin (Ig)G/IgA light chain alone, or number of lymphocytes (low vs high). 

“Our conclusion is that daratumumab demonstrates encouraging efficacy in previously treated patients with AL amyloidosis, producing deep and rapid responses. The administration of daratumumab in these patients is associated with a good safety profile and nonsevere adverse events, mostly after the first infusion,” Dr. Roussel said. 

“Our results also showed that if patients do not respond after one cycle (4 doses), they are unlikely to respond further, and we need to modify the treatment,” she added. 

Boston Medical Center Study 

DR. SANCHORAWALA presented preliminary results from a phase II study conducted at her center.² The study’s primary objective was to assess the tolerability of daratumumab with respect to infusion reactions in patients with AL amyloidosis, which have been seen in up to half of myeloma patients receiving daratumumab. 

“High-grade infusion reactions may be detrimental to the tolerability of this agent in a patient with AL amyloidosis with multisystem organ involvement,” she said. 

The study enrolled 12 patients with relapsed AL amyloidosis patients with involvement of at least 1 major vital organ. The median number of organ systems involved was two and the median number of prior therapies was three, including stem cell transplantation in 75% of patients. In more than half of patients, the disease was refractory to the last line of treatment. All patients had cardiac biomarker stage II or III disease. Median NT-proBNP level was 1,357 pg/mL, median urine protein excretion was 0.44 g/24 h, and median dFLC was 105 mg/L. 

Patients received daratumumab at 16 mg/kg by intravenous infusion weekly for weeks 1 to 8, followed by every 2 weeks for weeks 9 to 24. Thereafter, they received the drug every 4 weeks until disease progression or unacceptable toxicity, for up to 24 months. 

For premedication, all patients received acetaminophen, diphenhydramine, loratadine, famotidine, montelukast, and methylprednisolone (100 mg for the first two infusions and 60 mg thereafter) 30 to 60 minutes prior to infusion. Ondansetron was added after the first two patients developed grade 1 nausea/vomiting. 

Diphenhydramine, famotidine, and methylprednisolone (40 mg) were also administered 2 hours after the start of infusion during the first 2 infusions, even in the absence of a reaction. Methylprednisolone at 20 mg (or its equivalent) and montelukast were administered 24 and 48 hours after the start of infusion for the first 2 infusions, and then montelukast was optional. All patients received prophylaxis with acyclovir.

At the time of the data cutoff, 11 patients continued on study and a total of 134 infusions had been completed. The median number of infusions received per patient was 11.5. There were no interruptions or delays in infusions during the study. 

One patient was removed from the protocol after developing progression of plasma cell dyscrasia markers after two cycles. “This patient had been refractory to many prior therapies and went on to have a stem cell transplantation after disease progression. At 3 months, she is in complete hematologic remission,” Dr. Sanchorawala noted. 

There were two infusion-related reactions, but none were grade 3 or 4. Two patients experienced grade 1 nausea and vomiting during the first infusion, which resolved after an antiemetic was administered. There were no interruptions or delays of infusion and no hospitalizations. 

“Infusion-related reactions were minimal and not comparable to their reported incidence in myeloma,” Dr. Sanchorawala said. “No other patient had this after we introduced ondansetron in our preinfusion medications. Daratumumab infusion is well tolerated in patients with relapsed AL amyloidosis, when administered with appropriate pre- and post-[infusion] medications.” 

Response Rates 

A RAPID HEMATOLOGIC response occurred after the first dose of daratumumab. A hematologic response rate of 100% was observed in nine patients (two complete responses, six very good partial responses, and one partial response) at 3 months who completed 3 cycles of protocol-directed treatment at the data cutoff. Similarly, hematologic response of 100% again was seen in four patients (two complete responses and two very good partial responses) at 6 months who completed 6 cycles of protocol-directed treatment at the time of data cutoff. Rapid reduction in serum free light chains was also observed, a treatment effect reported by other investigators in posters at the ASH meeting, Dr. Sanchorawala said. 

Hematologic responses with reductions in serum free light-chain levels were seen after one infusion of daratumumab. Greater than 50% reduction in dFLC occurred in 10 of 12 patients (83%), and involved serum free light-chain levels fell below the upper limit of normal in 7 of 12 patients (58%) after only 1 dose of daratumumab. 

Organ responses were also observed. A cardiac biomarker response (> 30% improvement in NT-proBNP) for patients completing therapy was observed in 8% of patients at 1 month, in 33% at 3 months, and in 75% at 6 months. Similarly, a renal response was seen in 17%, 56%, and 80%, respectively, at these time points. 

The median time of infusion was about 7 hours for the first administration and 4.5 hours for the second. Responding to a question from the audience about logistics, Dr. Sanchorawala said, “Our clinic is open from 8 AM to 5 PM. Patients come in the day before to get blood drawn, and we can start the infusions at 9 AM. We give the first infusion over about 7 hours. It’s completely doable.” ■

DISCLOSURE: Dr. Roussel has received honoraria and research funding from Janssen. Dr. Sanchorawala reported no conflicts of interest, although this study was partially supported by Janssen. 

REFERENCES 

1. Roussel M, Stoppa A-M, Perrot A, et al: A prospective phase II study of daratumumab in previously treated systemic light chain amyloidosis. 2017 ASH Annual Meeting. Abstract 508. Presented December 10, 2017. 

2. Sanchorawala V, Sarosiek S, Sloan JM, et al: Safety and tolerability of daratumumab in patients with relapsed light chain amyloidosis: Preliminary results of a phase II study. 2017 ASH Annual Meeting. Abstract 507. Presented December 10, 2017.