ATLANTA (FRONTLINE MEDICAL NEWS) – In patients with previously treated immunoglobulin light chain (AL) amyloidosis, daratumumab monotherapy produced deep, rapid hematologic responses, based on initial results from a phase 2 trial.

So far, the response rate is about twice the rate seen with daratumumab in relapsed/refractory multiple myeloma, Murielle Roussel, MD, of IUCT-Oncopole, Toulouse, France, said at the annual meeting of the American Society of Hematology. “We observed deep and rapid clonal responses, even after the first infusion.”

“Daratumumab also had a good safety profile characterized by nonsevere adverse events after initial infusion. There was only one drug-related serious adverse event, grade 3 lymphopenia,” she said.

In a second study, the risk for daratumumab infusion reactions was low when patients received a prophylactic regimen initiated about an hour before daratumumab infusion.

Daratumumab, a novel, fully humanized IgG1-kappa monoclonal antibody with high affinity for CD38, is approved for treating relapsed/refractory multiple myeloma. In AL amyloidosis, as in myeloma, monoclonal light chains nearly always originate from plasma cells that consistently express CD38.

Data from small studies indicate that daratumumab effectively treats AL amyloidosis. To further evaluate safety and efficacy, 36 adults with previously treated disease received 28-day cycles of daratumumab (16 mg/kg IV) weekly for two cycles and then every other week for four cycles. Most patients had received three prior lines of therapy, about two-thirds had cardiac involvement (median baseline NT-proBNP 1,118 ng/L; range, 60-6,825), and about 60% had renal involvement.

At data cutoff in mid-November 2017, fifteen patients had completed all six treatment cycles. Three stopped treatment because of progression. Two died, one of progressive cardiac amyloidosis and one of unrelated lung cancer.

Eleven patients had grade 1-2 infusion reactions at first injection. Among 17 grade 3 or higher adverse events, only lymphopenia was deemed treatment related.

At 6 months, 15 of 32 evaluable patients (44%) had a very good partial response (VGPR; at least a 40% drop in baseline difference in involved and uninvolved free light chains (dFLC). Another 16% had a partial response, and 41% did not respond.

Patients with durable responses tended to have about a 70% drop in dFLC after the first daratumumab dose. Baseline variables did not seem to predict durability of response, Dr. Roussel said. “Further studies in amyloidosis are warranted in relapsed or refractory patients and also in the frontline setting.”

The second trial focused on preventing infusion reactions to daratumumab. In early trials of daratumumab for relapsed/recalcitrant multiple myeloma, patients developed moderate to severe bronchospasm, laryngeal or pulmonary edema, hypoxia, and hypertension, noted Vaishali Sanchorawala, MD, of Boston Medical Center. Since those trials, prophylactic therapies have been used to reduce the risk of infusion reactions.

Dr. Sanchorawala’s study enrolled 12 patients with previously treated AL amyloidosis and cardiac biomarker stage II or stage III disease. About 60% of patients were refractory to their last treatment. Median NT-proBNP level was 1,357 pg/mL (range, 469-3,962), median urine protein excretion was 0.44 g (0-10.1), and median dFLC was 105 mg/dL (3.8-854).

Patients received 16 mg/kg daratumumab IV weekly for 8 weeks, then every 2 weeks for 16 weeks, and then every 4 weeks for up to 24 months. About an hour before infusion, they received acetaminophen, diphenhydramine, loratadine famotidine, montelukast, and methylprednisolone (100 mg for two infusions; 60 mg thereafter). Ondansetron also was added to control mild nausea and vomiting. Two hours into the infusion, patients received diphenhydramine, famotidine, and methylprednisolone (40 mg). They received methylprednisolone (20 mg) and montelukast 1-2 days after the first two infusions, after which montelukast was optional. All received prophylactic acyclovir.

At the Nov. 15, 2017 data cutoff, 11 patients remained on study and one left after disease progressed. This patient’s disease was refractory to many prior therapies and had a complete response to autologous stem cell transplant, said Dr. Sanchorawala.

There were no grade 3-4 infusion reactions. Nine evaluable patients at 3 months had two complete hematologic responses, six VGPRs (at least a 65% drop in dFLC), and one partial response. One-third had at least a 30% improvement in NT-proBNP at 3 months, as did three of four evaluable patients at 6 months. About half had least a 30% drop in urine protein excretion at 6 months.

First infusions lasted a median of 7 hours, making them doable during a clinic day if bloods are drawn beforehand, Dr. Sanchorawala said. Second and subsequent infusions took about 4 hours.

“Preliminary data suggest a rapid hematologic response after one dose of daratumumab and high rates of response at 3 and 6 months, ” she concluded. “Since the plasma cell clone is so low in amyloidosis, single-agent daratumumab has a very positive, strong effect. We may not need to combine other agents with this therapy.”

Both presentations sparked substantial interest during the discussion period after the presentations, especially because daratumumab was given as monotherapy. “This would be a new indication for daratumumab,” said session moderator Dan Vogl, MD, director of the Abramson Cancer Center Clinical Research Unit, University of Pennsylvania, Philadelphia.

Janssen makes daratumumab and provided partial funding for both studies. Dr. Sanchorawala had no conflicts of interest. Dr. Roussel disclosed honoraria and research funding from Janssen.

SOURCES: Sanchorawala V et al. ASH 2017 Abstract 507 ; Roussel M et al. ASH 2017 Abstract 508 .


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