Multiple myeloma is a cancer that begins in the plasma cells, a type of white blood cell found in the bone marrow. These abnormal plasma cells, called myeloma cells, can multiply uncontrollably, crowding out healthy blood cells and producing abnormal proteins. While initial treatments can often lead to periods of remission or stable disease, multiple myeloma is currently considered incurable. The disease can return or stop responding to therapy over time, leading to what is known as relapsed or refractory multiple myeloma.
Understanding Relapsed and Refractory Disease
Relapsed multiple myeloma occurs when the disease returns after a period of remission or stable disease following initial treatment. Myeloma activity, which had previously decreased or disappeared, shows a clear increase based on specific measurements in the blood, urine, or bone marrow. The International Myeloma Working Group (IMWG) sets criteria for this return of disease activity.
Refractory multiple myeloma refers to the disease progressing during treatment or within 60 days of the last treatment. Patients who fail to achieve a minimal response to initial therapy and progress while undergoing treatment are also considered to have primary refractory myeloma.
The disease becomes relapsed or refractory due to drug resistance, where myeloma cells adapt and develop mechanisms to evade previously effective drugs. This can involve changes in their genetic makeup or alterations in cellular pathways that render them less susceptible to specific treatments.
When a patient’s myeloma progresses during or after treatment with both a proteasome inhibitor and an immunomodulatory agent, it is referred to as “double refractory” disease. If resistance extends to an anti-CD38 monoclonal antibody as well, it becomes “triple-class” refractory, which can indicate a more challenging prognosis.
Recognizing Symptoms and Diagnosis
The return or progression of multiple myeloma can manifest through various symptoms. Patients may experience increased bone pain, often in the back or ribs, due to myeloma cells affecting bone tissue. Persistent fatigue is another common symptom, linked to anemia caused by the crowding out of healthy red blood cells in the bone marrow.
Kidney problems, such as a rise in serum creatinine levels, can indicate disease progression as abnormal proteins produced by myeloma cells can damage the kidneys. Recurrent infections may occur because the immune system is compromised by abnormal plasma cells and reduced healthy white blood cells. New soft tissue plasmacytomas or bone lesions, or an increase in the size of existing ones, are also signs of potential relapse.
Diagnosis of relapsed or refractory multiple myeloma involves specific tests to confirm disease progression and assess its extent. Blood tests measure M-protein, an abnormal protein produced by myeloma cells, and check for hypercalcemia, an elevated calcium level. Urine tests detect abnormal proteins, providing further insight into disease activity.
A bone marrow biopsy evaluates the percentage of plasma cells. Imaging studies, such as MRI and PET/CT scans, identify new bone lesions or evaluate the size of existing ones, helping to determine the disease’s spread and activity. These diagnostic tools collectively provide a comprehensive picture of the disease state and guide subsequent treatment decisions.
Treatment Strategies
When multiple myeloma becomes relapsed or refractory, treatment strategies often involve a combination of different therapeutic approaches, building upon prior treatments and considering the disease’s specific characteristics.
Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, affect the immune system and directly target myeloma cells. Proteasome inhibitors (PIs), like bortezomib and carfilzomib, block proteasome activity, leading to the buildup of proteins that cause myeloma cells to die.
Monoclonal antibodies, such as daratumumab and isatuximab, recognize and attach to proteins on the surface of myeloma cells, marking them for destruction by the immune system. Histone deacetylase (HDAC) inhibitors, like panobinostat, alter gene expression in cancer cells, making them more vulnerable to other therapies. Antibody-drug conjugates, like belantamab mafodotin, combine a monoclonal antibody with a chemotherapy drug, delivering the toxic agent directly to myeloma cells.
Cellular therapies represent a significant advancement. Chimeric antigen receptor (CAR) T-cell therapy involves collecting a patient’s own T-cells, engineering them to recognize a specific target on myeloma cells (e.g., B-cell maturation antigen or BCMA), and then reinfusing them. Bispecific T-cell engagers (BiTEs) are another type of immunotherapy that can bridge myeloma cells and T-cells, activating T-cells to kill the cancer cells.
Newer agents, such as selinexor, block a protein involved in regulating cell growth. The selection of a treatment regimen is highly individualized, taking into account previous therapies, disease response, patient’s overall health, and genetic abnormalities. Clinical trials offer access to novel therapies and combinations that are not yet widely available, providing additional avenues for patients whose disease has become resistant to standard treatments.
Living with Relapsed Refractory Multiple Myeloma
Managing life with relapsed refractory multiple myeloma involves comprehensive supportive care to enhance quality of life. Pain management is a significant aspect, often requiring medications and other interventions to alleviate bone pain. Strategies to manage infections are also paramount, as patients are at a higher risk due to compromised immune function, necessitating prompt treatment.
Maintaining bone health is another important consideration, involving medications to strengthen bones and prevent fractures. Nutritional support ensures patients receive adequate nutrients, which can be challenging due to treatment side effects or the disease. Addressing mental health, such as anxiety and depression, is also part of holistic care, with support groups or counseling often recommended.
Patients with relapsed refractory multiple myeloma benefit from a multidisciplinary care team, including oncologists, nurses, pain specialists, nutritionists, and social workers. This team provides comprehensive care and addresses various challenges. Patient advocacy groups also offer valuable resources and support. While complete remission may not always be achievable, the goal is often to achieve a good partial response or stable disease, with ongoing monitoring of disease markers.