Although myeloma is not curable, several treatments exist to control the disease and improve life expectancy. Experimental therapies, summarized below, are also being developed.
Aplidin (plitidepsin) is an investigative anti-cancer agent isolated from the sea squirt (Aplidium albicans) and developed by PharmaMar. Aplidin binds to the product of the EEF1A2 gene present on the surface of tumor cells. This leads to apoptotic, or programmed, cell death by a series of downstream cellular events.
Aplidin is being tested in clinical trials in combination with other medicines in patients with myeloma.
CAR T-cell therapy
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.
DTP3 is an experimental treatment that inhibits 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 pilot study showed that DTP3 is well-tolerated with no adverse effects. Its effectiveness depends on whether or not myeloma cells express the GADD45b protein.
GBR 1342 is an investigational antibody therapy developed by Glenmark Pharmaceuticals. GBR 1342 is based on Glenmark’s bispecific engagement by antibodies based on the T-cell receptor (BEAT) platform that uses a type of immune cells called T-cells to target and destroy myeloma cells. The GBR 1342 antibody can 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.
GMI-1271 is an E-selectin antagonist being developed by GlycoMimetics. GMI-1271 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.
GMI-1271 is being tested in Phase 1/2 trials for the treatment of myeloma.
Isatuximab is a CD38 inhibitor developed by Sanofi that is being investigated for the treatment of myeloma. Isatuximab triggers cell death via several mechanisms including programmed cell death, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP). The mechanism of cell death is dependent on the concentration of CD38 found on the surface of myeloma cells.
Isatuximab is being tested in Phase 3 trials as a potential treatment for myeloma.
Marizomib is a small molecule proteasome inhibitor developed by Triphase and later acquired by Celgene, being investigated for the treatment of relapsed or refractory multiple myeloma RRMM. Proteasomes in the cell help break down and recycle proteins. Proteasomes are highly active in cancer cells, as these cells rapidly divide and produce a lot of waste protein. By blocking the functioning of the proteasome machinery, marizomib could prevent protein breakdown and recycling so the cells would then die from the toxic accumulated waste proteins.
Marizomib is being investigated in Phase 1 and Phase 2 trials for the treatment of myeloma.
MOR202 is an experimental bispecific antibody developed by MorphoSys for the treatment of RRMM in combination with Revlimid 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 investigated in Phase 1, 2, and 3 trials for the treatment of myeloma.
Oprozomib is a next-generation proteasome inhibitor analog of Kyprolis (carfilzomib) developed by Amgen for myeloma treatment. Oprozomib has demonstrated good anti-tumor activity comparable to Kyprolis and can be administered orally for patient convenience. Oprozomib is a smaller molecule than Kyprolis and can be easily absorbed by the small intestine.
Oprozomib is currently in Phase 1/2 trial.
Romidepsin is a histone deacetylase (HDAC) inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). HDAC inhibitors work by inhibiting the activity of the HDAC enzyme, which is required to remove acetyl groups from DNA-associated proteins called histones. This turns on tumor suppressor genes and controls cell division.
Romidepsin alone was not found to be effective in treating RRMM, although patients showed improvement in bone pain and hypercalcemia (excess calcium in the blood). A Phase 1/2 trial (NCT01755975) is underway to evaluate the efficacy of a combination of romidepsin and Revlimid (lenalidomide) in patients with RRMM.
TAK-079 is an experimental CD38 inhibitor developed by Takeda Oncology. and 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 can also be killed by other antibodies or complement proteins by phagocytosis.
The safety and tolerability of TAK-079 were tested in healthy volunteers, and the treatment is now being tested in myeloma patients.
TAK-169 is an engineered toxin body (ETB) developed Molecular Templates in collaboration with Takeda that functions as a CD38 inhibitor for the treatment of RRMM. 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.
Results from a Phase 2 trial (NCT00773838) showed that a combination of Zolinza and Velcade (bortezomib) can also benefit patients with RRMM. A Phase 1 trial (NCT00729118) showed that adding Zolinza to Revlimid maintenance therapy during AHSCT can improve transplant response and prolong survival outcomes.
Last updated: Jan. 24, 2020
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