Based on findings from recent randomized controlled trials next-generation proteasome inhibitors (carfilzomib and ixazomib), a next-generation immunomodulatory agent (pomalidomide), and monoclonal antibodies (elotuzumab and daratumumab) have been approved for relapsed/refractory multiple myeloma (Leukemia 2018; doi:10.1038/leu.2017.329).
However, despite advances, management of the disease still proves challenging.
During the 2018 ASCO Annual Meeting, Rachid Baz, MD, Senior Member, Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Fla., led a discussion on novel antibody strategies in this patient population.
Elotuzumab in Combination
Elotuzumab is an approved monoclonal antibody that enhances the activity of lenalidomide and bortezomib in multiple myeloma. Researchers recently studied the agent in combination with pomalidomide, bortezomib, and dexamethasone (elo-PVD) in relapsed/refractory multiple myeloma (J Clin Oncol 2018;36(suppl; abstr 8012)).
“Elotuzumab is a monoclonal antibody targeting SLAMF7 and it doesn't have robust single-agent activity in relapsed/refractory disease,” noted Baz during the presentation at ASCO. “However, in combination with lenalidomide and dexamethasone, it increases the response rate compared to lenalidomide and dexamethasone alone, and to some extent, with bortezomib and dexamethasone, based on a smaller randomized phase II [study].”
The primary objective of this study was to determine overall response rate (ORR). Eligible patients included those with refractory disease who underwent at least 1 prior line of treatment and disease progression within 60 days of completion of last line of treatment, according to study authors. Other eligibility criteria included prior treatment with at least 2 cycles of lenalidomide and 2 cycles of a proteasome inhibitor in the same or separate regimens, as well as adequate organ function. Patients who had been previously treated with pomalidomide were permitted to participate.
Elotuzumab was administered weekly for the first 2 cycles and then every other week. Pomalidomide was given on days 1-21; bortezomib on days 1, 8, 15; and dexamethasone was weekly. Each cycle was 28 days.
“This initial analysis of elo-PVD shows encouraging responses with ORR 52 percent in patients with a median of 3 prior lines of treatment, all with refractory multiple myeloma and all with prior exposure to lenalidomide and a proteasome inhibitor,” study authors stated. Median progression-free survival was 9.7 months.
Grade 3/4 hematologic adverse events (AEs) included anemia (7%), neutropenia (34%), and thrombocytopenia (17%). Common non-hematologic AEs (all grades) included fatigue (38%), upper respiratory infection (38%), constipation (38%), hyperglycemia (38%), and neuropathy (38%, grade 1/2 only), with two possibly related deaths (sepsis, pneumonia), according to researchers.
“So the question that comes to mind: Is the addition of elotuzumab to PVD safe? And it certainly appears to be the case. Does the addition of elotuzumab to PVD increase the efficacy of the regimen? This is hard to know,” Baz said. “This is not a randomized study and comparing across trials can be very difficult. So I think, while it doesn't quite change the standard of care today, it may be an option for patients who are increasingly receiving daratumumab-based therapy earlier in the disease.”
Baz noted that there are questions that still need answers. “Is PVD the right backbone? We have data that carfilzomib may be the more efficacious proteasome inhibitor compared to bortezomib. Ixazomib is more convenient. So is bortezomib the right proteasome inhibitor in the combination?
“I think the really important question is, is there a role for elotuzumab in patients with advanced myeloma?” Baz continued. “And this study doesn't quite answer that, but I think the ideal way would be to identify the patients who most benefit from this added agent because of the fact that the clinical activity of elotuzumab may be modest.”
Recent studies took a closer look at subcutaneous (SC) daratumumab, a human CD38-targeted monoclonal antibody, among patients with relapsed/refractory disease.
“The phase Ib PAVO study (NCT02519452) demonstrated that delivery of daratumumab with recombinant human hyaluronidase enzyme (rHuPH20) by subcutaneous infusion through a syringe pump (Part 1) or by manual SC injection (Part 2) was well-tolerated with an efficacy profile consistent with IV daratumumab (ASH 2017; Abstract 838),” according to study authors.
Updated data from Part 2 of the study, including safety, pharmacokinetic, and efficacy findings of SC daratumumab, was recently presented (J Clin Oncol 2018;36(suppl; abstr 8013)).
IV daratumumab has been approved for over 2 years in the U.S. “[It is] recognized that infusion reactions occur in about 40-50 percent of patients, and that the first infusion lasts an average of about 7 hours,” Baz explained.
Eligible patients received at least 2 prior lines of therapy including a proteasome inhibitor and an immunomodulatory drug. In Part 2, patients received a concentrated co-formulation of daratumumab (daratumumab SC; 1,800 mg in 15 mL) and rHuPH20 (30,000 U) dose in a single, pre-mixed vial, which was administered in 3-5 minutes by manual SC injection, investigators explained. Primary endpoints included, Ctrough of daratumumab at the end of weekly dosing on cycle 3 day 1 (C3D1) and safety. ORR, rate of complete response, time to response, and duration of response were secondary endpoints.
Patients included in Part 2 (n=25) of the study had a median age of 68 years and received a median of 3 prior lines of therapy. At a median follow-up of 4.6 months, none discontinued due to treatment-emergent adverse events (TEAEs). Lymphopenia (16%), thrombocytopenia (8%), and neutropenia (8%) were the most common grade 3/4 TEAEs.
Infusion-related reactions (IRRs) were reported in four (16%) patients, the majority of which occurred on the first day. No grade 4 IRRs or discontinuations due to IRRs occurred. “Daratumumab SC injections in the periumbilical area were well-tolerated with reversible erythema observed in 20 percent of patients,” study authors observed. Daratumumab SC achieved an ORR of 44 percent.
According to pharmacokinetic analyses, daratumumab SC had a Tmax of approximately 72 hours and achieved similar or greater Ctrough on C3D1 compared to what has been observed with daratumumab IV.
“Daratumumab SC, which enables dosing in 3-5 minutes, was well-tolerated with low IRR rates, had an acceptable pharmacokinetic profile, and demonstrated clinical response rates similar to daratumumab-IV,” researchers concluded.
“Does subcutaneous daratumumab have the potential to change the standard of care, compared to administering the drug intravenously?” Baz queried. While noting that the data is limited in terms of the number of patients treated, he believes the data is very intriguing.
“If you're able to give the same drug with less reactions in a shorter period of time, that's certainly very appealing to patients and doctors.”
Isatuximab + Carfilzomib
Isatuximab (ISA) is an anti-CD38 monoclonal antibody with potent anti-myeloma effects as a monotherapy or together with lenalidomide plus dexamethasone in relapsed/refractory multiple myeloma. Carfilzomib, a proteasome inhibitor, is approved for use in patient population as a single agent or in combination.
A recent phase Ib study analyzed the combination of isatuximab and carfilzomib among patients with relapsed/refractory multiple myeloma (J Clin Oncol 2018;36(suppl; abstr 8014)). The primary objective was to assess the maximum tolerated dose (MTD) of ISA + carfilzomib in relapsed/refractory multiple myeloma. Safety, immunogenicity, and efficacy were secondary objectives.
“[Researchers] combined isatuximab with carfilzomib and looked at patients who received at least two prior therapies,” Baz said. “Carfilzomib refractory patients were allowed, but prior CD-38 monoclonal antibodies were not allowed.”
Researchers utilized a 3+3 dose escalation design. Three dosing levels were tested: 1) ISA 10 mg/kg Q2W; 2) ISA 10 mg/kg QW x 4 then Q2W; and 3) ISA 20 mg/kg QW x 4 then Q2W, all in combination with carfilzomib standard dose (27 mg/m2) and schedule. Additionally, an expansion cohort of 18 patients were enrolled at dose level 2.
Fifteen patients were treated in the dose escalation group and 18 in the expansion cohort. The median age (n=33) was 61 years and included patients who received a median of 3 prior lines of therapy. Researchers reported that the majority of patients (79%) were double refractory to IMids and PIs; additionally, 81 percent had undergone prior autologous transplantation.
Researchers reported an ORR of 60.6 percent and a clinical benefit response of 84.6 percent. Among patients who were carfilzomib refractory, the ORR was 50 percent.
In terms of safety, there were no dose-limiting toxicities or grade 4/5 adverse events. Common adverse events (any grade) included thrombocytopenia (61%), pain (60%), diarrhea (36%), fatigue (39%), anemia (33%), nausea (33%), neutropenia (27%), and headache (24%).
“Infusion-related reactions were in line with what we saw was daratumumab-based therapies and with isatuximab-based therapies,” noted Baz. “Is this combination safe? [It] certainly appears so. There is no toxicity that is particularly unexpected.
“The main question relates to where does isatuximab go and where does it stand in myeloma today?” he continued. “And certainly we know it's an active monoclonal antibody targeting CD-38, but it's not clear how it compares to daratumumab.
“The daratumumab data with subcutaneous use continues to evolve, and it makes the bar [even] higher, when you consider the convenience of subcutaneous use and the [fewer] infusion reactions.”
Catlin Nalley is associate editor.