New Agents Vie for Role in Multiple Myeloma

Robert Z. Orlowski, MD, PhD

Despite multiple therapeutic advances in recent years, proteasome inhibitors remain a cornerstone of therapy for multiple myeloma, both newly diagnosed and relapsed and refractory disease, Robert Z. Orlowski, MD, PhD, said in a presentation at the 2016 Society of Hematologic Oncology annual meeting.

“Their good tolerability, and both efficacy and flexibility in combination regimens with almost all other therapeutics, have made them a mainstay of our standard of care,” said Orlowski, MD, PhD, chair ad interim of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center.

A variety of other small-molecule inhibitors have demonstrated promise, he continued, and multiple immunotherapeutic agents have emerged to create more options than ever for either newly diagnosed or relapsed/refractory disease.

“Looking ahead, we need to improve our understanding of biomarkers that predict sensitivity,” said Orlowski. “We need to elucidate mechanisms of resistance that can be subverted to extend the utility of our current drug classes. Finally, we need more studies to understand optimal combinations and sequences of drugs to achieve molecular minimal residual disease negativity and possibly find cures for myeloma.”

In reviewing some of the promising candidate therapies for myeloma, Orlowski started with the BCL2 protein family and the prototype agent venetoclax (Venclexta). In a phase I dose finding/safety study involving patients with relapsed or refractory myeloma, treatment with venetoclax monotherapy led to an overall response rate of 21% in 66 patients, including a 40% response rate in 30 patients with t(11;14) chromosomal translocation.

In the t(11;14) subgroup, responses were observed in patients who had responded to previous lines of therapy, as well as those who had not responded. Six responses were observed in 16 patients who previously had not responded to therapy, including 12 patients refractory to bortezomib (Velcade), 13 refractory to lenalidomide Revlimid), and 10 patients with double-refractory disease.

The most common adverse events (all grades) were nausea (49%); diarrhea (38%); fatigue (26%); anemia, decreased neutrophil count, and back pain, (23% each); vomiting (21%); and decreased platelet count and decreased white blood cell count (20% each). The only grade 3/4 adverse events occurring in as many as 10% of patients were anemia (15%), decreased platelet count (15%), decreased neutrophil count (12%), and decreased white blood cell count (12%).

A recent study evaluated the combination of venetoclax and bortezomib. In 66 patients with relapsed/refractory myeloma, the combination resulted in an overall response rate of 58%, including 84% in patients not refractory to bortezomib.

A new member of the anti-CD38 class, isatuximab also has immunomodulatory properties, said Orlowski. Among 74 patients treated with 3 different dosages of isatuximab, the best response rate was 29% in 24 patients who received 10 mg every 2 weeks. A majority of patients achieved some degree of tumor shrinkage across all 3 dosing schedules.

The most common nonhematologic toxicities (all grades) were nausea (36%), fatigue (34%), cough (34%), and pneumonia (9%). Grade 3/4 toxicity consisted of the 7 cases of pneumonia.

Almost all patients developed anemia, and a majority developed thrombocytopenia. Grade 3/4 hematologic toxicity was 24% for anemia, 17% for thrombocytopenia, and 15% for neutropenia.

The anti—PD-1 immune checkpoint inhibitor pembrolizumab (Keytruda) was evaluated in combination with lenalidomide and dexamethasone in 51 patients with relapsed/refractory myeloma. Three-fourths of the patients had disease refractory to lenalidomide, and almost two-thirds were refractory to bortezomib.

Adverse events (≥20%, all grades) included neutropenia (37%), thrombocytopenia (41%), diarrhea (28%), fatigue (26%), and anemia (22%). Grade 3 to 5 adverse events consisted of neutropenia (33%), thrombocytopenia (18%), anemia (12%), hyperglycemia (8%), and fatigue (2%). Immune events consisted of 2 cases of grade 1 hypothyroidism, 1 case each of grade 1 hyperthyroidism and thyroiditis, 1 case of grade 3 elevated transaminase levels, and 1 case of grade 3 renal failure.

CAR T-cell therapy, evaluated most extensively in leukemia and lymphoma, also has been studied as potential therapy for multiple myeloma. In 1 recent study, 20 patients received CAR T-cells expressing a receptor that recognizes a peptide shared by NY-ESO-1 (expressed in as many as 60% of myelomas) and LAGE-1, administered 2 days after stem cell transplant. Five of the patients had already received a stem cell transplant, and 7 had high-risk cytogenetics.

Three-fourths of patients had some magnitude of response to the CAR T-cell therapy, said Orlowski. The cohort had a median progression-free survival of 19.1 months, defining progression as T-cell loss or antigen escape.

CAR T-cells expressing BCMA were evaluated in 12 patients with relapsed-refractory myeloma and a treatment history of at least 3 prior lines of therapy. The therapy resulted in 2 partial responses, 1 very good partial response, and 1 complete response. The remaining patients all had stable disease. Some patients had dramatic responses, as illustrated in pre- and posttreatment PET scans, showing regression or disappearance of extensive bony disease. The longest duration of response, including stable disease, was 16 weeks, although the patient who attained a complete response had an ongoing response beyond 12 weeks.

As an illustration of the potential toxicities associated with CAR T-cell therapy, Orlowski described 2 patients’ treatment experience. One developed cytokine release syndrome that required 2 weeks to resolve. The patient was platelet-transfusion dependent for 9 weeks after treatment. Another patient developed a wide range of toxicities that included fever, delirium, dyspnea, hypotension, tachycardia, acute kidney injury, and prolonged thrombocytopenia.

“I think it will be a matter of time before we understand why some patients responded and others didn’t,” said Orlowski. “Whether it relates to the level of BCNA expression or other factors remains to be seen.”

The three-drug combination resulted in an overall response rate of 39% (20/51). In the efficacy population treated with the maximum tolerated dose, pembrolizumab-lenalidomide-dexamethasone achieved objective responses in 20 of 40 patients.