Advances in Hematologic Malignancies
Issue 15, Winter 2022
— Adam Sperling, MD, PhD
Therapy for multiple myeloma (MM) has improved dramatically over the past two decades with the addition of proteasome inhibitors (PI), thalidomide analogs, and monoclonal antibodies. However, MM remains an incurable
disease, and most patients eventually exhaust all available options and eventually succumb to their disease.
Therapies that harness or reprogram a patient's own immune system to attack the MM cells have shown incredible promise across a wide array of cancers. Immune effector cell (IEC) therapies such as chimeric antigen
receptor (CAR) T-cells are a novel approach in which a patient's own T-cells are harvested and genetically modified to recognize specific antigens on the surface of MM cells. These engineered cells are then infused back into patients, where they can
attack the MM cells. Idecabtagene vicleucel (Abecma®, ide-cel, bb2121), a BCMA-targeting CAR T-cell, was recently FDA-approved for patients
with relapsed or refractory (r/r) MM who have received four prior lines of therapy.
Despite high response (>70%) and complete remission (>30%) rates, patients uniformly relapsed, and the median progression-free survival (PFS) was approximately 10 months in the pivotal KarMMa trial that led to Ide-cel's approval. In addition,
the process of CAR T-cell manufacturing typically takes up to six weeks, a length of time that many patients with aggressive disease cannot wait. Finally, the standard of care for patients receiving CAR T-cells has been close observation following
their infusion, and it remains unknown whether other standard MM therapies can be safely combined with CAR T-cells to improve outcomes.
To address these issues, clinical trials are ongoing at Dana-Farber Cancer Institute to test both ide-cel and another anti-BCMA CAR T-cell product, ciltacabtagene autoleucel (cilta-cel), in newly
diagnosed patients and in the r/r setting directly compared to other standard anti-myeloma agents. Additional studies are combining CAR T-cells with other anti-myeloma drugs. These studies promise to inform how to best sequence and combine anti-BCMA
CAR T-cells with other standard agents in patients with MM in the future.
New antigenic targets are also being evaluated in MM, such as the receptor protein GPRC5D. This is a novel target that is highly expressed on the surface of most MM cells but not on normal cells. GPRC5D was discovered by Dana-Farber researcher Eric Smith, MD, PhD,
and pre-clinical models suggest that it may be an effective target even after anti-BCMA targeted therapies have already been used. A phase 1 study is exploring this as a target of a novel CAR T-cell product.
Additional promising approaches include harnessing the activity of other components of the immune system, including γδT-cells and natural killer (NK) cells. A phase 1 study is exploring the activity of a novel γδT-cell receptor (TCR) that targets MM cells,
while another study is exploring the role of NK cells, which have the ability to naturally recognize and destroy MM cells, in newly diagnosed patients in combination with autologous transplant. Yet another phase 1 study is evaluating allogeneic iNKT
cells, rare T-cells with NK-like qualities that are involved in both innate and adaptive immune responses, in patients with relapsed/refractory MM.
Finally, in an effort to improve the speed with which patients can be treated, novel approaches, including rapid manufacturing of autologous anti-BCMA CAR T-cells and allogeneic "off-the-shelf" CAR T-cells, are being tried. These new production approaches
may shorten the time it takes to get CAR T-cells to patients, allowing those with aggressive disease to be treated in a timely fashion.
These ongoing studies have the promise to inform how we use IEC therapies going forward, to develop new targets and identify additional immune cell types that may have activity in patients with MM, and to identify novel combinations that may improve outcomes
for our patients.