Lab mouse

An experimental drug called LCL161 stimulates the immune system to fight multiple myeloma (MM), according to research published in Nature Medicine.

Investigators said LCL161 exhibited “robust” activity in a transgenic myeloma mouse model and in patients with relapsed/refractory MM.

Single-agent LCL161 did not produce responses in MM patients, but patients did respond to treatment with LCL161 and cyclophosphamide.

The investigators also found that single-agent LCL161 provided “long-term anti-tumor protection” in mice, and combining LCL161 with an antibody against PD-1 could cure mice of MM.

“The drug, LCL161, was initially developed to promote tumor death,” said study author Marta Chesi, PhD, of Mayo Clinic Arizona in Scottsdale.

“However, we found that the drug does not kill tumor cells directly. Rather, it makes them more visible to the immune system that recognizes them as foreign invaders and eliminates them.”

Dr Chesi and her colleagues explained that the cellular inhibitors of apoptosis (cIAP) 1 and 2 have been identified as potential therapeutic targets in some cancers.

And LCL161 is a small-molecule IAP antagonist that induces tumor necrosis factor-mediated apoptosis in cancer cells. However, the investigators found that LCL161 was not directly cytotoxic to MM cells.

Instead, the drug upregulated tumor-cell-autonomous type I interferon signaling and induced an acute inflammatory response. This led to the activation of macrophages and dendritic cells, which prompted phagocytosis in MM cells.

Results in mice

The investigators first tested LCL161 alone (at a dose previously shown to be well-tolerated) in Vk*MYC transgenic mice with established MM.

The team said they observed a reduction in tumor burden that was comparable to that observed in response to drugs currently used to treat MM—carfilzomib, bortezomib, melphalan, cyclophosphamide, panobinostat, dexamethasone, and pomalidomide.

The investigators then tested the combination of LCL161 and a PD1 antibody in Vk12598-tumor-bearing mice.

The team said the combination was curative in all mice that completed 2 weeks of treatment. In fact, it was more effective than combination treatment with LCL161 and cyclophosphamide.

Results in patients

Dr Chesi and her colleagues conducted a phase 2 trial of LCL161 in 25 patients with relapsed/refractory MM. Patients could receive cyclophosphamide if they failed to respond or progressed after 8 weeks of treatment with LCL161 alone.

The patients’ median age was 68 (range, 47-90), and they had a median of 3 prior therapies (range, 1-6). Forty-four percent of patients had high-risk features, 28% had relapsed disease, and 72% had relapsed and refractory disease.

Four patients experienced grade 2 cytokine release syndrome when they received LCL161 at a dose of 1800 mg weekly, so the dose was lowered to 1200 mg.

None of the patients responded to single-agent LCL161. So 23 of the patients received 500 mg of weekly cyclophosphamide as well.

There was 1 complete response to the combination therapy, 1 very good partial response, 2 partial responses, and 1 minimal response. The median progression-free survival in these patients was 10 months.

Grade 3 adverse events included decrease in neutrophil count (28%), decrease in lymphocyte count (28%), anemia (24%), fatigue (16%), hyperglycemia (12%), syncope (12%), decrease in white blood cell count (12%), decrease in platelet count (8%), increase in lymphocyte count (8%), nausea (4%), vomiting (4%), diarrhea (4%), maculo-papular rash (4%), hypotension (4%), lung infection (4%), pain in extremity (4%), and urticaria (4%).

Grade 4 events included decrease in lymphocyte count (24%), decrease in neutrophil count (8%), decrease in white blood cell count (8%), hyperuricemia (4%), decrease in platelet count (4%), and sepsis (4%).

Based on these results, the investigators said the combination of LCL161 and cyclophosphamide is “an attractive platform for future trials,” and the same is true for LCL161 in combination with anti-PD1 therapy.

The phase 2 trial was sponsored by Mayo Clinic and the National Cancer Institute. Novartis provided LCL161 for this research and supported the trial.

Drug exhibits anti-myeloma activity in mice, humans