Advances in Hematologic Malignancies
Issue 14, Spring 2021
— Omar Nadeem, MD and Adam Sperling, MD, PhD
Multiple myeloma (MM) therapy has improved significantly over the past several decades due to discovery of many novel agents, including proteasome inhibitors (PI), immunomodulatory agents (IMiD), and monoclonal antibodies (MoAB). Not only have these therapies
led to an unprecedented improvement in patient outcomes; they are also generally well-tolerated, allowing for patients to remain on treatment for many years. However, MM remains incurable, and patients usually experience several disease relapses over
the course of their myeloma journey.
Immunotherapy has shown incredible promise and is used across a wide range of cancer subtypes. Chimeric antigen receptor T-cell (CAR T-cell) therapy is a novel form of immunotherapy, in which
a patient's own T-cells are collected and then genetically modified to recognize specific antigens on cancer cells. These engineered T-cells are then re-infused back into the patients, allowing one's own immune system to effectively kill cancer cells.
CAR T-cell therapy has been approved for non-Hodgkin lymphoma and pediatric leukemia for the past several years.
Abecma (idecabtagene vicleucel, ide-cel) is a novel CAR T-cell therapy that targets B-Cell Maturation Antigen (BCMA), which is highly expressed on multiple myeloma cells.
Abecma was recently granted FDA approval for treatment of relapsed and/or refractory MM (RRMM) in patients who have had 4 prior lines of therapy and have received treatment with a PI, IMiD and MoAB (triple-class refractory).
Abecma's approval is based on promising results from studies led by researchers at Dana-Farber Cancer Institute, including a recent study published in the New England Journal of Medicine by Nikhil Munshi, MD, of the Jerome Lipper Multiple Myeloma Center. In this trial, a total of 128 heavily pre-treated MM patients were infused with Abecma, of which 94 experienced a response (73%) and 42 had
a complete response (33%), with 26% achieving minimal residual disease negative status (a marker of highly effective treatment effect and improved prognosis). The median progression-free survival was 8.8 months, and up to 20.2 months in patients that
experienced a complete response or better.
One of the challenges of CAR T-cell therapy is the specific toxicity profile, including cytokine release syndrome (CRS), in which patients can experience transient fevers/chills, low blood pressure and low blood oxygen levels. CRS occurred in 84% of patients
with a median time to onset of one day after infusion but was generally mild, with severe (grade ≥3) CRS occurring in only 5% of patients. Immune effector cell-associated neurotoxicity syndrome (ICANS), which can include altered mental status and
encephalopathy, was seen in 18% of patients, with severe neurological toxicity (grade ≥3) reported in only 4% of patients. Our team at Dana-Farber is highly experienced in delivering CAR T-cell therapy
and managing related toxicity, with various tools available for early intervention to prevent a more significant adverse event.
Work is ongoing at Dana-Farber to develop the next generation of cellular therapies. This includes approaches to speed up the manufacturing of CAR T-cells and improve their persistence and function, as well as the use of "off-the-shelf" allogeneic products
and different immune cell types such as NK (natural killer) T-cells and γδ T-cells. Finally, we are also working to identify new antigens in MM cells that can be targeted alone or in combination with BCMA. One of these novel targets, GPRC5D, was discovered
by Dana-Farber researcher Eric Smith, MD, PhD, and is now in early phase clinical trials.
Patients with relapsed or refractory MM can be referred for further evaluation and to discuss the individual cellular therapy that may be best for them.