A handful of immunotherapies and small molecules are emerging for the treatment of multiple myeloma. Many different treatment strategies are currently in clinical trials to treat multiple myeloma that are designed to attack molecular targets, enhance immune response, and inhibit transport of critical proteins out of the nucleus, including chimeric antigen receptor (CAR) T-cell therapy and other therapies, said Suzanne Lentzsch, MD, PhD, Professor of Medicine, and Director, Multiple Myeloma and Amyloidosis Service at Columbia University Medical Center in New York, speaking at the Great Debates & Updates in Hematologic Malignancies.
Selinexor is a first-in-class, novel, small molecule selective inhibitor of exportin 1. This oral drug is given 1-2 times per week and has potent anti-myeloma effects in vitro and in vivo in multiple myeloma models, explained Lentzsch.
The phase II STORM trial found that selinexor plus low-dose dexamethasone was active in patients with heavily pretreated refractory multiple myeloma. Among 78 patients, the overall response rate (ORR) was 21 percent. The eight patients with 17p deletion did even better, with a 38 percent ORR.
The median duration of response was 5.5 months, median overall survival was 9.3 months, and median progression-free survival (PFS) was 2.3 months.
“Response rates were similar in the overall population and in patients with high-risk cytogenetic abnormalities,” she noted. “Adverse events were manageable with dose interruptions and reductions and supportive care.”
Venetoclax as monotherapy for relapsed/refractory multiple myeloma is under investigation in a phase I study to evaluate safety and tolerability in previously treated patients. The ORR rate is 21 percent and patients with high BCL2 expression have an 88 percent response rate and a longer time to progression. “We may be able to use BCL2 as a selective marker,” said Lentzsch.
Venetoclax plus bortezomib/dexamethasone is “a promising combination based on laboratory data,” she added. Early studies show this combination demonstrated an acceptable safety profile with encouraging response rates, with 56 percent ORR and higher ORRs in patients who are not refractory to bortezomib and those who received only 1-3 prior lines of therapy. Higher BCL2 expression is also associated with improved response. Phase III trials of this regimen are planned in relapsed/refractory multiple myeloma patients.
Another promising combination is pembrolizumab plus pomalidomide plus dexamethasone. In a study of 45 patients with relapsed/refractory multiple myeloma, the ORR was 65 percent. Those with high-risk cytogenetics had a slightly lower response rate of 56 percent.
“Median PFS of 17.4 months was significantly longer than in a pomalidomide plus dexamethasone phase III trial with a PFS of 4 months,” reported Lentzsch.
In this small study, this combination appears active, with adverse events occurring in about half of the study population. Discontinuations occurred in 10 percent of patients. Most adverse events were manageable. “Based on the data, pembrolizumab is not added in to debulk tumors but to enhance T cells and the immune system to achieve and keep remissions,” she explained.
CAR T Cells
A potential new therapy in multiple myeloma is CAR T cells, especially those that target BCMA, which is a protein in the tumor necrosis factor superfamily expressed by normal and malignant plasma cells and B cells. “Autologous T cells can be genetically modified to express CARs targeted to malignancy-associated antigens. BCMA is a potent target for myeloma CAR T-cell therapy,” noted Lentzsch.
A first in-human phase I trial of 12 multiple myeloma patients evaluated CAR T-cell infusion. Autologous T cells were stimulated, transduced with CAR-BCMA retroviruses, and cultured for 9 days before infusion. So far, one patient with a high disease burden who was chemotherapy-resistant experienced a strict complete response (sCR) for more than 12 weeks. One patient had a very good partial response (VGPR) for 8 weeks, one patient a partial response (PR) for 6 weeks, and another patient a PR for 2 weeks.
CAR-BCMA T cells eliminated plasma cells without causing direct organ damage. Substantial, but reversible, toxicity was comparable to that observed in previous CAR T-cell studies.
“This is a promising new strategy in multiple myeloma to eradicate high tumor burden. The experience with CAR T-cell therapy in multiple myeloma is still limited. Certain patients may be beyond a cure. This is proof of principle, and future trials will show how best to select patients,” Lentzsch said.
Yet another new strategy is to administer daratumumab as subcutaneous therapy. The phase Ib PAVO study included 53 patients with relapsed/refractory multiple myeloma who received subcutaneous daratumumab. For those who received the 1,800 mg dose, the ORR was 38 percent, including two sCRs, seven VGPRs, and 29 PRs. In this group, only 24 percent with subcutaneous administration had infusion-related reaction whereas IV administration of daratumumab would have led to an expected 50 percent infusion-related reaction rate, according to Lentzsch.
There were no grade 4 infusion-related reactions. All infusion-related reactions occurred during the first infusion and within 4 hours.
Radium-223 dichloride is an alpha particle-emitting radiopharmaceutical that has strong synergistic effects when combined with bortezomib. A phase 1b/2 trial is evaluating the safety and efficacy of radium-223 dichloride in combination with bortezomib and dexamethasone in early relapsed multiple myeloma.
“Many exciting drugs are emerging in myeloma. This brings us in the direction of targeted therapy or precision medicine,” concluded Lentzsch.
Mark L. Fuerst is a contributing writer.