Experimental Treatments for Myeloma
Aplidin (plitidepsin) is an investigational anti-cancer agent isolated from the sea squirt (Aplidium albicans). Aplidin binds specifically to the protein product of the eEF1A2 gene that exists on the surface of tumor cells, inhibiting their development and viability by changing their shape and function. These changes lead to tumor cell death through a natural process called apoptosis, or programmed cell death. A Phase 3 trial in patients with relapsed/refractory multiple myeloma was recently completed.
CAR T-cell Therapy
Chimeric antigen receptor (CAR) T-cell therapy is an immunotherapy in which the body’s own T-cells are engineered to produce synthetic receptors that recognize and attack cancer cells. Researchers are studying CAR T-cells engineered to produce a protein called B-cell maturation antigen (BCMA) in myeloma patients. They are also investigating the use of a dual-CAR T-cell combination that expresses both BCMA and anti-CD19 for higher specificity and better targeting efficiency to prevent cancer relapse.
CLR 131 is a combination of Cellectar Bioscience‘s proprietary phospholipid drug conjugate (PDC) and the radioisotope Iodine-131 (I-131), which is commonly used to kill thyroid cancer cells. The PDC contains a phospholipid ether molecule that targets cancer cells. Researchers hope that in the case of CLR 131, I-131 will accumulate and deliver radiation to the cancer cells and destroy them. The treatment is currently being tested in Phase 1 and Phase 2 trials in several cancers, including myeloma.
DTP3 is designed to inhibit two proteins in the NF-kB pathway called GADD45b and MKK7. Normally, the interaction between GADD45b and MKK7 results in cells evading programmed cell death. DTP3 blocks this mechanism and prevents these two proteins from interacting, thus promoting cell death. A small Phase 1/2a pilot study in relapsed or refractory multiple myeloma patients has been completed in the U.K.
GBR 1342 is an investigational antibody therapy being developed to to treat multiple myeloma patients who failed to respond to prior therapies. It is able to simultaneously bind to a T-cell surface protein called CD3 and to a B-cell surface protein called CD38. This process triggers the T-cell to mount an immune response against the cancerous B-cell. GBR1342 is being tested in an open-label Phase 1 trial, which is recruiting up to 125 previously treated multiple myeloma patients.
GMI-1271 is an E-selectin antagonist that is being investigated as a possible way to restore sensitivity to a commonly used chemotherapy in patients with multiple myeloma and acute myeloid leukemia. It blocks the site of E-selectin, a cell adhesion molecule that allows cancer cells to bind to one another. This moves cancer cells out of the protective function of the bone marrow, making them vulnerable to chemotherapy and proteasome inhibition therapy. A Phase 1/2 trial has been completed.
Marizomib is a small molecule proteasome inhibitor being investigated for the treatment of relapsed or refractory multiple myeloma. Marizomib is a small molecule that inhibits a large protein complex called the proteasome whose role is to degrade abnormally folded or damaged proteins. Myeloma cells are highly dependent on proteasomes for their growth and survival. Marizomib is currently being tested in Phase 1 and Phase 2 trials for the treatment of myeloma.
MOR202 is an experimental bispecific antibody for the treatment of relapsed and refractory multiple myeloma in combination with Revlimid (lenalidomide) and dexamethasone. MOR202 binds to CD38 on myeloma cells and also to natural killer (NK) cells. This brings NK cells in close proximity to, and helps in the destruction of, the myeloma cells. MOR202 is being tested in Phase 1, 2, and 3 trials for the treatment of myeloma.
Oprozomib is a next-generation proteasome inhibitor analog of Kyprolis (carfilzomib). Oprozomib had demonstrated good anti-tumor activity comparable to Kyprolis and can be administered orally. It is a smaller molecule than Kyprolis and can be easily absorbed by the small intestine. However, Phase 2 trials have been halted to investigate the current formulation.
Romidepsin is a histone deacetylase (HDAC) inhibitor approved to treat cutaneous T-cell lymphoma and peripheral T-cell lymphoma. Romidepsin alone was not found to be effective in treating relapsed and refractory multiple myeloma, although patients showed improvement in bone pain and hypercalcemia (excess calcium in the blood). A Phase 1/2 trial is underway to evaluate the efficacy of the therapy in combination with Revlimid in relapsed and refractory myeloma patients.
TAK-079 is an experimental CD38 inhibitor that has high affinity for the CD38 protein found on myeloma cells. Binding of TAK-079 to CD38 triggers the programmed death of myeloma cells. TAK-079-bound myeloma cells also can be killed by other antibodies or complement proteins by phagocytosis. An open-label Phase 1/2a trial is testing TAK-079 administered subcutaneously as a single agent in patients with relapsed and refractory multiple myeloma.
TAK-169 is an engineered toxin body that functions as a CD38 inhibitor for the treatment of relapsed and refractory multiple myeloma. TAK-169 is engineered to evade any immune response. Once bound to CD38, it gets internalized into the myeloma cells and targets the ribosome, blocking protein synthesis — leading to the death of the myeloma cell. TAK-169 is being tested in an open-label Phase 1 trial, which is currently recruiting.
Zolinza (vorinostat) is an HDAC inhibitor approved for the treatment of T-cell lymphomas. Results from a Phase 2 trial showed that a combination of Zolinza and Velcade (bortezomib) ay also benefit patients with relapsed and refractory multiple myeloma. A Phase 1 trial showed that adding Zolinza to Revlimid maintenance therapy after an autologous hematopoietic stem cell transplant improved transplant response and prolonged survival outcomes.