The Multiple Myeloma Landscape

In Biologics, Cancer, Clinical Trials, Drug Development, Drug Targets, Easily Confused, Genetics, Mechanism of Action, Monoclonal Antibodies, Small Molecule Drugs by Emily Burke

BLOOD CANCER: MULTIPLE MYELOMA

Plasma cells are the antibody-producing cells of our immune system which happen to play a critical role in our defense against infections. In multiple myeloma, plasma cells begin to grow and divide in an uncontrolled manner, forming a cancerous mass known as a 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 in the 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 has a significant impact on bone health. As the plasmacytoma grows, bone-forming cells called osteoblasts are suppressed. At the same time, 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 one 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. These tests are followed by a bone marrow biopsy for confirmation.

Most cases of multiple myeloma have no known cause, although 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 (strands of DNA that contain 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.

IN THE PIPELINE

Two novel drugs in the multiple myeloma pipeline are Mivebresib (AbbVie; North Chicago, IL) and Selinexor (Karyopharm Therapeutics; Newton, MA).

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.

Selinexor 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 those cells that have 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 is cancer cells. Selinexor began Phase III clinical testing for myeloma in June 2017.

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) have announced promising results in early phase CAR-T trials for multiple myeloma.

Multiple myeloma is a complex cancer. In recent years, a better understanding of the disease has led to the approval of several new therapeutics. In the coming years, we can look forward to additional approvals as novel therapeutics move through the pipeline.