Researchers highlighted the latest developments in the treatment of multiple myeloma at the 2013 ASCO Annual Meeting. Noteworthy abstracts included updated data on pomalidomide, as well as research involving the novel agents daratumumab and elotuzumab.
Katja C. Weisel, MD
Researchers highlighted the latest developments in the treatment of multiple myeloma at the 2013 ASCO Annual Meeting. Noteworthy abstracts included updated data on pomalidomide (Pomalyst), which the FDA recently approved, as well as research involving the promising novel agents daratumumab and elotuzumab.Pomalidomide plus low-dose dexamethasone “should become the standard of care for patients with relapsed/refractory multiple myeloma (MM) after treatment with lenalidomide and bortezomib,” said Katja C. Weisel, MD, associate professor at University Hospital Tuebingen in Germany, reflecting the views of an international group of investigators taking part in the large MM-003 trial.1
The phase III MM-003 study enrolled 455 patients with relapsed or refractory MM. Eligible patients were refractory to their last prior therapy, had progressive disease during therapy or within 60 days, and had failed lenalidomide and bortezomib after two or more cycles of each therapy alone or in combination.
Patients were randomized 2:1 to a combination of pomalidomide plus low-dose dexamethasone (n = 302) or to high-dose dexamethasone (n = 153). At a median follow-up of 4 months, when the primary analysis was performed, patients receiving the combination of pomalidomide plus low-dose dexamethasone had significantly longer median progression-free survival (PFS), at 3.6 versus 1.8 months (hazard ratio [HR] = 0.45; P <.001) and overall survival (OS; not reached vs 7.8 months; HR = 0.53; P <.001) compared with patients receiving high-dose dexamethasone. The observed OS benefit included 29% of patients who received pomalidomide after experiencing progressive disease on high-dose dexamethasone. Weisel reported data from an updated analysis after a median follow-up of 10 months. At this time, PFS and OS continued to favor treatment with pomalidomide plus low-dose dexamethasone, with median PFS of 4 versus 1.9 months (HR = 0.48; P <.001) and median OS of 12.7 versus 8.1 months (HR = 0.74; P =.028).
The investigator-assessed overall response rate for patients in the pomalidomide arm was 31% versus 10% in the high-dose dexamethasone arm (P <.001), and 24% versus 3% for patients who were randomized 6 months or more after enrollment (P <.001).
The most frequent grade 3/4 adverse event for the pomalidomide combination was neutropenia (48%). Commenting on this rate of neutropenia, Weisel noted that there were only a few febrile complications.
On February 8, 2013, the FDA approved oral pomalidomide for the treatment of patients with MM who have received at least two prior therapies, including lenalidomide and bortezomib, and who have had disease progression on or within 60 days of completion of the last therapy.The investigational monoclonal antibody (mAb) daratumumab targets the CD38 molecule, which is highly expressed on the surface of multiple myeloma (MM) cells. Daratumumab has been shown to have broad-spectrum cytotoxic activity; it acts by mediating killing of CD38-expressing tumor cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis.
In a phase I/II dose-escalation study reported by Henk Lokhorst, MD, PhD, from UMC Utrecht, The Netherlands, for an international group of researchers at ASCO 2013, the performance of daratumumab in patients with relapsed/refractory MM was described as “unprecedented for a single-agent mAb treatment of multiple myeloma.”2
Sagar Lonial, MD
In early May, the FDA granted Breakthrough Therapy Designation for daratumumab for the treatment of patients with MM who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or for patients who are double-refractory to both classes of drugs.
Following on previously published safety and efficacy data, an international group of researchers reported finalized part 1 and preliminary safety data from an ongoing part 2 of the study, which enrolled patients aged 18 years and older with MM that was relapsed or refractory to at least two prior lines of therapy. Patients must also have been ineligible for transplant.
At the ≥4-mg/kg dosage (n = 12), daratumumab induced a marked reduction in paraprotein and bone marrow plasma cells in the group of heavily pretreated patients. In addition, in patients receiving the ≥4-mg/kg dosage, five partial responses and three minor responses were observed; seven of these patients had a 50% to 100% concomitant reduction in bone marrow plasma cells. Median PFS in the ≥4-mg/kg dosage group was not reached by a data cutoff of 3.8 months.
No antidrug antibodies were detected among enrolled patients. The most common reported adverse events were infusion-related and occurred predominantly during the first full infusion. A total of 44% of patients across all dosage groups had infusion-related events of grade 1-3. Other adverse events were anemia (n = 1), thrombocytopenia (n = 1), bronchospasm (n = 2), cytokine release (n = 1), and AST increase (n = 1).The combination of the humanized anti-CS1 monoclonal antibody (mAb) elotuzumab plus lenalidomide/dexamethasone was generally well tolerated and resulted in a high objective response rate and encouraging PFS in patients with relapsed/refractory multiple myeloma (MM), according to Sagar Lonial, MD, Winship Cancer Institute of Emory University, Atlanta, Georgia, in an update of phase II and phase I/II long-term safety results.3 Lonial reported these findings for a large international group of investigators at ASCO 2013.
Elotuzumab is a humanized anti-CS1 mAb that enhances natural killer-cell mediated, antibody-dependent cellular toxicity of CS1-expressing MM cells.
The study included a dose-finding phase I cohort (N = 28) and a phase II cohort (N = 73), with patients treated until disease progression, unacceptable toxicity, or death. (Data for patients treated with one or more [phase I] or one to three [phase II] prior therapies who received elotuzumab plus lenalidomide/dexamethasone were previously published [J Clin Oncol. 2012;30(16):1953-1959; Blood. 2012;120(21):Abstr 202].
The objective response rate in the phase II cohort (median age, 63 years) was 84%: 92% with 10 mg/kg (n = 36) and 76% with 20 mg/kg (n = 37). At a median follow-up of 20.8 months, median PFS was not reached for the 10-mg/kg group and was 18.6 months for the 20-mg/kg group.
The most common treatment-emergent grade ≥3 adverse events were lymphopenia (19%), neutropenia (18%), thrombocytopenia (16%), and anemia (14%). In general, grade 3/4 adverse events that were emergent after 18 months were consistent with those reported during the initial 18 months.