Pioneering Multiple Myeloma Trials Evaluate Novel Immunologic Approaches for Long-term Disease Control

Hemato-oncologists at the Jerome Lipper Multiple Myeloma Center at Dana-Farber/Brigham and Women’s Cancer Center are leading studies of innovative immunologic approaches for patients with multiple myeloma that are designed to achieve long-term control of the disease.

Phase 2 CAR T-Cell Study

Nikhil C. Munshi, MD, director of Basic and Correlative Science in the Jerome Lipper Multiple Myeloma Center, is the principal investigator of a current Phase 1 study and an upcoming Phase 2 trial of bb2121, an anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed or refractory BCMA-expressing multiple myeloma. Updated results from the Phase 1 study, which were presented at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting in Chicago in June, showed that 100 percent of patients enrolled in the Phase 1 study have responded to active doses of the treatment, with 73 percent achieving a very good partial response or better. No dose-limiting toxicities and limited grade cytokine release syndrome (CRS) were observed. Patients enrolled in the Phase 1 study had been heavily pretreated, with at least three prior treatments and a median of seven prior therapies. Recruitment of a separate Phase 2 study, which will also be led by Dr. Munshi, is expected to begin in the coming months.

“Because CAR T-cell therapy uses a very different mechanism to target cancer cells than traditional treatments, it has the ability to destroy cancer cells that have become resistant to multiple other therapies,” says Dr. Munshi. “In the current studies, we are treating many multiple myeloma patients who have exhausted other options and would otherwise likely succumb to the disease.”

For more information regarding these CAR T-cell trials, please contact Dr. Munshi at (617) 632-5607.

Daratumumab with RVd

Jacob Laubach, MD, MPP, clinical director of the Jerome Lipper Multiple Myeloma Center, is the site principal investigator of a new Phase 2 randomized study evaluating the addition of daratumumab, a human monoclonal antibody targeting CD38, to lenalidomide-bortezomib-dexamethasone (RVd) in patients with newly-diagnosed multiple myeloma prior to high-dose chemotherapy and autologous stem cell transplantation (ASCT). The primary outcome measure for this trial is a stringent complete response (sCR) rate – as defined by the International Myeloma Working Group criteria – by the end of post-ASCT consolidation treatment.

The current daratumumab plus RVd (D-RVd) study builds on years of research at Dana-Farber/Brigham and Women’s Cancer Center related to both RVd and daratumumab. Dr. Laubach and Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center, along with European colleagues, previously led the clinical development of the drug. In 2015, a Phase 1/2 study of daratumumab demonstrated remarkable single-agent activity, including complete responses, in patients with heavily pretreated and refractory myeloma. Since that time, daratumumab has been shown to significantly lengthen progression-free survival in relapsed myeloma when added to lenalidomide and dexamethasone and when added to bortezomib and dexamethasone. Dr. Richardson and Dr. Laubach were both instrumental in the development of the design of the new D-RVd study.

“Our team has extensive experience with both daratumumab and RVd, including managing toxicities related to these therapies,” says Dr. Laubach. “In this trial, we are hoping to elicit deep responses in patients with newly-diagnosed disease by combining a standard regimen with a transformative drug in the treatment of multiple myeloma and comparing outcomes to those who receive the standard regimen.” For more information regarding this Phase 2 trial, please contact Dr. Laubach at (617) 632-3823.

Other Immunologic Studies and Vaccines

Dr. Richardson is the site principal investigator of an international Phase I/2 study to determine the recommended dose and regimen of durvalumab, a PD-L1 inhibitor, and pomalidomide (POM) with or without low-dose dexamethasone (dex) in patients with advanced multiple myeloma.

“Researchers at Dana-Farber/Brigham and Women’s Cancer Center led the discovery and development of PD-L1 inhibition, as well as PD-1 inhibition,” says Dr. Richardson. “This study and others like it should play an important role in determining this immunologic approach in myeloma patients in a variety of settings, and so hopefully provide a broader application to this approach.”

A separate and important Clinical Trials Network (CTN) Phase 2 study is evaluating single autologous hematopoietic cell transplant followed by LEN maintenance therapy for multiple myeloma with or without vaccination with dendritic cell (DC)/myeloma fusions with granulocyte macrophage colonystimulation factor (GM-CSF). Dr. Munshi is the site principal investigator of this study whose primary objective is to compare survival and response at one year post-transplant between patients receiving DC/myeloma vaccine/GM-CSF with LEN maintenance therapy to those receiving LEN maintenance therapy with or without GM-CSF.

For more information regarding these trials, please contact Dr. Richardson at (617) 632-4893.

Allogeneic HSCT with Ixazomib Maintenance Therapy

John Koreth, MBBS, DPhil, is the site principal investigator of this national CTN Phase 2 study examining the role of allogeneic hematopoietic stem cell transplant (alloHSCT) earlier in the treatment of patients with standard and high-risk multiple myeloma, as well as plasma cell leukemia.

“While autologous stem cell transplantation (autoSCT) is an established upfront modality for multiple myeloma, patients almost invariably relapse with refractory disease,” says Dr. Koreth.

“Recent alloHSCT advances, including reduced-intensity conditioning regimens, improved recipient matching, and supportive care after transplant, have improved our ability to manage treatment-related toxicities and allow us to offer alloHSCT as an option for myeloma patients early in the course of their disease.”

All patients in this trial will receive alloHSCT and be randomized thereafter to receive ixazomib as a novel maintenance anti-myeloma therapy or placebo. The aim is to utilize maintenance ixazomib for myeloma control, allowing the graft versus myeloma effect to develop, to reduce relapse and to improve patient survival rates.

For this study, high-risk disease is defined by the presence of any one of the following characteristics detected at any time prior to enrollment: deletion of chromosome 13 by conventional cytogenetics, hypodiploidy, abnormality in chromosome 1(1q amplification or 1p deletion), t(4;14), t(14;16), t(14;20) or deletion of 17p by fluorescence in situ hybridization (FISH) or conventional karyotyping; high risk criteria based on commercially available gene expression profiling (GEP)1.

Consultation for evaluation for alloHSCT is encouraged early in the treatment planning process (within 18 months from initiation of anti-myeloma therapy, including autoHSCT). For more information regarding this trial, please contact Dr. Koreth at (617) 632-3470.