What is Extramedullary Disease in Multiple Myeloma?

Multiple myeloma is a type of cancer that affects plasma cells, which are found in the bone marrow. Normal plasma cells are anchored to the bone marrow with surface proteins. When a person has multiple myeloma, their plasma cells can mutate and lose their attachment to the bone marrow. This allows them to grow outside of their normal environment. These cancerous myeloma cells detach and escape the bone marrow to form tumors in soft tissues and organs. This is called extramedullary disease (EMD). 

EMD is hard to treat and is considered an aggressive form of cancer. This is because myeloma cells that have left the bone marrow can create their own microenvironment that protects them from standard treatment. Often, treatment will treat the myeloma itself, but the extramedullary disease remains.

EMD can be found when myeloma is first diagnosed, or it can happen later. EMD occurs in about 6% to 20% of relapsed patients. It is usually found in the liver, lymph nodes, and central nervous system. Treatment generally involves a combination of therapies used for high-risk multiple myeloma. 

What are the signs and symptoms of extramedullary disease?

The signs and symptoms of EMD can vary depending on where the tumors are located. But general symptoms are unexplained weight loss, fatigue, night sweats, and fever. 

Some patients are at a higher risk of developing EMD. Hypercalcemia, which is when you have too much calcium that can weaken the bones, and osteolytic lesions, which is an area where the bone tissue has been destroyed, are risk factors for EMD. 

Because EMD can affect many different parts of the body, the signs and symptoms can vary from person to person. It is important to remember that many of the signs and symptoms listed below have other causes. If you are concerned about any sign or symptom that you are experiencing, contact your healthcare team right away. 

Head and neck symptoms of EMD

• Nasal and sinus symptoms: Nasal blockage, nosebleeds, or continuous discharge.
• Throat: Sore throat, hoarseness, or difficulty swallowing.
• Respiratory: Coughing up blood or shortness of breath.
• Neurological: Headaches, or vision and hearing changes if the tumors are pressing on the cranial nerve.

Abdominal and gastrointestinal symptoms of EMD

• Liver and spleen: Jaundice (yellowing of skin and eyes), stomach pain or swelling, and feeling full after eating only a small amount of food. 
• Gastrointestinal: Nausea, vomiting, indigestion, or stomach discomfort. 

Skin and muscular symptoms of EMD

• Skin: The appearance of reddish-purple bumps or small, raised nodules.
• Musculoskeletal: Localized masses that you can feel and general muscle weakness. 

Nervous system and spine symptoms of EMD

• Central nervous system: Any changes in mental status, confusion, or seizures.
• Spinal coordination: Back pain, weakness, or a 'pins and needles' tingling sensation in the lower body.

Thoracic and lymphatic symptoms of EMD

• Chest and lungs: Chest pain or fluid build-up around the lungs (pleural effusion) leading to difficulty breathing.
• Lymph nodes: Visible or noticeable swelling in the neck, armpits, or groin.

How is extramedullary disease diagnosed?

Diagnosing EMD typically involves the following steps: 

Imaging. You may get a PET/CT scan or MRI to find masses in the soft tissue or organs outside of the bone marrow.

Biopsy. If a mass is found during imaging, a tissue biopsy or fine needle aspiration is done to confirm the results.

Pathological analysis. The tissue samples will be analyzed by a pathologist, a doctor who specializes in diagnosing disease from cell samples. They will confirm if there are cancerous (malignant) cells. 

Because EMD can appear during myeloma treatment, the International Myeloma Working Group (IMWG) guidelines recommend getting advanced imaging throughout the course of the disease to monitor for EMD.

How is extramedullary disease treated?

Because EMD is aggressive and harder to treat, treatment typically focuses on an intensive approach with multiple medications. Therapy strategies are based on the patient's history and the location of the tumors. 

Systemic therapies. The general approach to treating EMD involves powerful drug combinations. Typically, people with EMD are treated with quadruplet therapies, which are four medications together, instead of triplet therapies. This involves a proteasome inhibitor, an immunomodulatory drug, a monoclonal antibody, and a steroid. 

Novel agents: New medications like bortezomib (Velcade), lenalidomide (Revlimid), pomalidomide (Pomalyst), isatuximab (Sarclisa), and selinexor (Xpovio) have been effective at treating EMD. 

Stem cell transplant: For eligible patients, EMD can be treated with a stem cell transplant. Patients are usually given high-dose chemotherapy followed by an autologous stem cell transplant. Autologous means the patient's own healthy stem cells are transplanted back into their body. 

Radiation and surgery: For isolated and defined soft tissue tumors or single-organ tumors, high-dose radiation is often recommended. Surgery combined with radiation may also be used for localized tumors. 

Immunotherapy: For relapsed or refractory EMD, CAR-T therapy and bispecific antibodies, such as teclistamab (Tecvayli) or talquetamab (Talvey), are treatment options.

Living with extramedullary disease

Living with EMD means navigating a challenging and aggressive illness. Patients often face complex treatments depending on where tumors are located and their size. But doctors are always trying to find new ways to treat EMD. Medical advancements are significantly changing the outlook for people with EMD. For many people with isolated tumors, treatment can successfully work to control the cancer. For widespread disease, new therapies are being tested in clinical trials that could help. And targeted therapy, immunomodulatory drugs, and advanced proteasome inhibitors can help people live for many years with EMD. 

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Sources: 

Advances in the treatment of extramedullary disease in multiple myeloma

Extramedullary disease in multiple myeloma: a systematic literature review

UAMS Health: Extramedullary disease