Within the oncology drug development pipeline, “multiple myeloma is one of the more intriguing spaces,” according to R. Donald Harvey, PharmD, who said one reason for his excitement is the emergence of monoclonal antibodies.
Harvey, associate professor of hematology/oncology at Emory University, Atlanta, GA, and director of the Phase I Clinical Trials Program, described investigational agents for myeloma and other cancers at the Hematology/Oncology Pharmacy Association 2014 Annual Conference.
Among the drugs for myeloma are not only better versions of current conventional classes of drugs but entirely new classes of agents for this malignancy. Early-phase trials suggest their impact will be huge, he said.
“It is odd to treat a disease of antibodies with antibodies,” Harvey said, “but improvements in our understanding of molecular biology and cell surface receptors has led to a number of impressive drug development stories.”
Monoclonal antibody inhibition is still in its early phases with respect to myeloma, but already a number of targets are in focus, including CS1, CD38, CD40, CD138, CD200, CD56, interleukin-6, and BAFF.
Harvey said that besides monoclonal antibodies, he is also encouraged by early-phase data on histone deacetylase inhibitors (panobinostat, ricolinostat), a kinesin spindle protein inhibitor (filanesib), and an Akt inhibitor (afuresertib).
Targeting CS1
Elotuzumab targets CS1, a cell surface glycoprotein that is highly expressed on more than 95% of myeloma cells. In a myeloma xenograft mouse model, the combination of elotuzumab plus lenalidomide significantly reduced tumor volume compared with either agent alone, suggesting this drug will work best in combination regimens. In a study of 73 patients, the objective response rate was 82% for the combination, including 12% complete or stringent complete responses (Lonial S, et al. 2011 ASH Annual Meeting. Abstract 303).
Interestingly, elotuzumab displays “saturable receptor occupancy,” likely meaning that with this compound “the more drug you have, the more it knocks itself off the receptor”; therefore, 10 mg/kg is more active than 20 mg/kg.
Infusion reactions are not uncommon with elotuzumab, which has led to the recommendation for aggressive premedication.
Targeting CD38
Daratumumab targets CD38, a transmembrane glycoprotein and ectoenzyme with high receptor density on myeloma cells. The effects of CD38 inhibition include apoptosis after cross-linking, modulation of enzymatic activation, induction of cell-dependent cytotoxicity, and induction of antibody-dependent cell cytotoxicity.
“These things are generally good with respect to cancer but concerning with respect to infusion reactions, and adverse events do occur, including bronchospasm, but it is typically well managed,” Harvey indicated.
As a single agent, daratumumab showed strong activity in a phase 1/2 study in which 47% of patients derived benefit; at doses of 4 mg/kg, 66% had a minor response or better (Plesner T, et al. 2012 ASH Annual Meeting. Abstract 73).
Due to encouraging results from phase 1 trials, a phase 2 trial has enrolled “at record numbers,” he noted, and the FDA has granted this agent breakthrough status.
SAR650984 is also an anti-CD38 antibody. In a phase 1 dose-escalation trial of patients who had received a median of 5 prior lines of therapy, 13 patients received the maximum dose (?10 mg/kg every 2 weeks). The overall response rate was 30.8%, with half of these a complete response (Martin TG III, et al. 2013 ASH Annual Meeting. Abstract 284).
Targeting CD138
Another interesting new drug is a potent antibody-drug conjugate that targets CD138, an antigen highly expressed on myeloma cells. Indatuximab ravtansine (BT062) is designed to deliver the maytansinoid cytotoxic agent DM4 specifically to these CD138-expressing cells. In a phase 1 trial of 21 relapsed/refractory patients, stable disease or better was observed in 100% of 15 evaluable patients, and 73% responded to BT062 plus lenalidomide/dexamethasone (Kelly KR, et al. 2013 ASH Annual Meeting. Abstract 758).
“I think not only in hematology but in solid tumors as well, we are going to see an explosion in antibody-drug conjugates,” he said.
Harvey predicted that based on the activity of these monoclonal antibodies, myeloma may someday be treated more as lymphoma is treated, by adding an antibody. “We might someday be giving 5 or 6 drugs for induction, because we will get deep responses this way. And we might be measuring myeloma like we do CLL [chronic lymphocytic leukemia], where we can say that we eradicated all measurable disease in the patient,”
he said.
Oral Proteasome Inhibitors
In addition to new classes of drugs, conventional classes of agents are becoming even more effective and less toxic.
The oral proteasome inhibitor ixazomib (MLN9708) produced a highly impressive 94% response rate (after 4 cycles) when combined with lenalidomide and dexamethasone in treatment-naive patients (Kumar SK, et al. 2012 ASH Annual Meeting. Abstract 332). Sixty-five patients received ixazomib weekly in combination with lenalidomide (25 mg/day) and dexamethasone (40 mg weekly), then continued on ixazomib as maintenance therapy for up to 12 cycles. Only 2 cases of grade 3 peripheral neuropathy occurred at the recommended phase 2 dose of 2.97 mg/m2.
“This is an exciting 3-drug regimen that is fairly well tolerated. Ixazomib is not an ‘oral bortezomib.’ It is different in terms of activity and also toxicity,” he indicated.
Another oral proteasome inhibitor in development, oprozomib, is a structural analog of carfilzomib that comes in 2 formulations: powder-in-capsule split dose and once-daily modified-release formulation. The drug’s efficacy seems dependent on proteasome inhibition; more than 80% inhibition is achieved with 210 mg/day of oprozomib.
With oral proteasome inhibitors now becoming available, Harvey suggested that induction approaches will eventually look very different than they look now. “I think that ultimately,” he predicted, “we will have an all-oral regimen.”