BLOOD CANCER: MULTIPLE MYELOMA
Plasma cells are the antibody-producing cells of our immune system that play a critical role in our defense against infections. In multiple myeloma, plasma cells begin to grow and divide uncontrolled, forming a cancerous mass known as plasmacytoma. Marrow—which produces plasma—no longer functions in our defense; it simply takes up space inside the bone.
What does biotech have in store to fight multiple myeloma? Let’s find out the treatments on the market and the up-and-comers in development.
EASILY CONFUSED: PLASMA CELLS VS BLOOD PLASMA
Plasma cells are specialized white blood cells that produce infection-fighting antibody proteins. Most plasma cells are found bone marrow.
Blood plasma is the straw-colored liquid component of blood that holds blood cells in suspension, made up of water (95%), proteins, glucose, clotting factors, electrolytes, hormones, carbon dioxide, and oxygen.
PICKING APART PLASMACYTOMA
Plasmacytoma formation can lead to a host of problems with recognizable clinical symptoms. Instead of producing normal disease-fighting antibodies, plasmacytoma cells produce abnormal antibodies called M proteins, which don’t provide any benefit to the body and crowd out normally functioning antibodies. And because all blood cells are formed in the bone marrow, overproduction of plasma cells can also crowd out normal blood-forming cells. This can lead to anemia, caused by a shortage of oxygen-carrying red blood cells; increased bruising and bleeding due to a reduction in clot-promoting platelets; and an increased risk of infection due to lower levels of healthy infection-fighting white blood cells.
Although multiple myeloma is classified as a blood cancer, it significantly impacts bone health. As the plasmacytoma grows, bone-forming cells called osteoblasts are suppressed. At the same time, the production of a substance that activates bone-reabsorbing cells, osteoclasts, is increased. The resultant damage to the bone structure creates soft spots or lesions which may extend from the inner bone marrow to the outside surface of the bone. Bone lesions result in significant pain and increase the risk of fracture. Bone destruction also releases excessive calcium into the bloodstream, leading to a range of symptoms, including confusion, nausea, and loss of appetite. Excess blood calcium, combined with high levels of M protein, also contributes to impaired kidney function seen in multiple myeloma patients.
UNMASKING MULTIPLE MYELOMA
There is no diagnostic test for multiple myeloma. Blood and urine tests to detect some of the symptoms listed above, such as low blood cell counts, elevated blood calcium levels, and impaired kidney function, may suggest multiple myeloma. A bone marrow biopsy follows these tests for confirmation.
Most cases of multiple myeloma have no known cause. However, some research suggests that regular exposure to herbicides, insecticides, petroleum products, heavy metals, and asbestos increases the risk of developing the disease. And although there is not a specific gene yet associated with multiple myeloma, abnormalities in chromosome structure or number are associated with the disease.
ON THE MARKET
Once considered incurable, there are now a number of effective treatments for multiple myeloma, and several more are in the pipeline.
Darzalex (Johnson & Johnson; New Brunswick, NJ) and Empliciti (Bristol Myers Squibb; Princeton, NJ) are both monoclonal antibody therapeutics approved to treat multiple myeloma. They work by recognizing and binding to proteins on the surface of multiple myeloma cells, activating the patient’s immune system to destroy those cells.
Ninlaro (Takeda; Osaka, Japan) is a small molecule proteasome inhibitor therapy. A proteasome is a specialized compartment within the cell that gets rid of damaged proteins by digesting them. If the proteasome is inhibited, damaged proteins build up within the cell. This triggers a process called apoptosis — essentially, cell suicide. In other words, the cancer cell kills itself.
Farydak (Novartis; Basel, Switzerland) is a small molecule “histone deacetylase (HDAC) inhibitor.” HDACs are enzymes that modify chromosomes (DNA strands containing our genes) and influence how often specific genes are activated. Some cases of multiple myeloma are associated with changes in gene activation. By inhibiting HDACs, Farydak can correct this changed gene expression.
Selinexor (Karyopharm Therapeutics; Newton, MA) helps to increase the number of tumor suppressor proteins present in the nucleus of cancer cells. These proteins help to protect against cancer by detecting DNA damage and promoting apoptosis in cells with high levels of DNA damage. In many types of cancer cells, tumor suppressor proteins are transported out of the nucleus, where they can no longer do their job of detecting DNA damage. By blocking this transport, Selinexor enables tumor suppressor proteins to do their job of triggering apoptosis in cancer cells. FDA approved Selinexor in July 2019 for myeloma.
Chimeric Antigen Receptor T-cell (CAR-T) therapy is a promising new type of immunotherapy approved by the FDA in 2017. In this therapy, a patient’s T cells are collected, genetically modified to recognize and attack myeloma cells, and then reinfused into the patient. While it’s a rapidly advancing area of research, its availability is currently limited to specialized centers.
IN THE PIPELINE
The novel drug in the multiple myeloma pipeline is Mivebresib (Abbvie; North Chicago, IL). It inhibits BET proteins and is in Phase I clinical testing for multiple myeloma.
Similar to Farydak, Mivebresib influences the activation of specific genes by inhibiting a group of proteins called Bromodomain and Extra Terminal motif (BET) proteins. In some types of cancer, genes are activated or deactivated inappropriately due to BET activity. By inhibiting BET, Mivebresib may restore normal gene activity to these cells. Mivebresib is currently in Phase I clinical testing for multiple myeloma.
CAR-T therapies are also in development for multiple myeloma. Bluebird Bio (Cambridge, MA), in partnership with Celgene (Summit, NJ) and Nanjing Legend Biotech (Nanjing, China), has announced promising results in early-phase CAR-T trials for multiple myeloma. Abecma (Bristol Myers Squibb; New York) was the first CAR-T therapy to treat multiple myeloma that FDA approved in March 2021. Carvykti is another CAR-T therapy to treat adults with multiple myeloma that FDA approved in February 2022.
Multiple myeloma is complex cancer. In recent years, a better understanding of the disease has led to the approval of several new therapeutics. We can look forward to additional approvals as novel therapeutics move through the pipeline in the coming years.
In summary, blood cancer, known as multiple myeloma, is a disease that affects our body’s defense system. Plasma cells, which are special white blood cells that fight infections, start growing uncontrollably in this condition, forming a cancerous mass called plasmacytoma. This disrupts the bone marrow’s ability to make normal blood cells, causing problems like anemia, bruising, and infections. Luckily, there are treatments available. Some drugs like Darzalex and Empliciti help our immune system fight cancer cells. Others, like Ninlaro and Farydak, target the cancer cells directly, causing them to die. Excitingly, there are more treatments being developed. Mivebresib and other CAR-T therapies are in testing and might offer hope to people with multiple myeloma.