Multiple myeloma is a blood cancer originating in plasma cells, a type of white blood cell in the bone marrow. Abnormal plasma cells multiply uncontrollably, crowding out healthy blood cells and damaging organs. While initial treatments often lead to remission, the disease frequently returns. This reappearance of cancer after remission is called a relapse. Understanding this progression is important for managing the condition, including its characteristics, detection, causes, and treatment.
Defining Relapse and Refractory Disease
When multiple myeloma returns after a period of remission, it is termed relapsed myeloma. This means the cancer had previously responded to treatment, leading to a reduction in disease signs and symptoms, but has now become active again. This reappearance indicates that initial treatment was effective for a time, but some cancer cells survived and began to grow.
In contrast, refractory myeloma refers to cancer no longer responding to treatment. This occurs in two main scenarios. Primary refractory myeloma means the cancer never achieved a satisfactory response to initial treatment, or it progressed within 60 days of completing therapy. Alternatively, relapsed and refractory myeloma means the disease returned after remission and then stopped responding to subsequent treatment. Differentiating between relapsed and refractory disease is important, as treatment decisions are often based on this distinction.
Signs and Diagnostic Process of a Relapse
Recognizing a multiple myeloma relapse involves observing new or returning symptoms and changes in laboratory test results. Many relapse symptoms are similar to those at initial diagnosis, often relating to the disease’s impact on bones, kidneys, and blood counts.
Healthcare providers use the “CRAB” criteria for active myeloma:
Calcium elevation in the blood, causing nausea, confusion, increased thirst, and muscle weakness.
Renal (kidney) problems, where abnormal proteins impair kidney function, leading to fatigue, swelling, or foamy urine.
Anemia (low red blood cell count), resulting from cancerous plasma cells crowding out healthy blood-forming cells. This causes persistent fatigue, weakness, and shortness of breath.
Bone lesions, areas of bone damage causing pain, fractures, or spinal cord compression.
Other signs of relapse may include frequent infections due to a weakened immune system.
To confirm a relapse, doctors rely on a combination of tests. Blood and urine tests measure M-protein and free light chain levels; an increase often indicates progression. A bone marrow biopsy examines plasma cell percentage and characteristics. Imaging studies (X-rays, MRI, PET scans) identify new or worsening bone damage or tumors outside the bone marrow.
Biological Mechanisms Behind Relapse
Multiple myeloma relapse occurs due to complex biological processes within cancer cells. One significant factor is clonal evolution. Myeloma is not uniform; it consists of different “clones” of cancer cells, each with distinct genetic characteristics. Initial treatments may eliminate dominant or sensitive clones, leading to remission. However, a small number of resistant clones can survive.
These surviving cells multiply, becoming the dominant population and causing the disease to return. The relapsed disease can be more aggressive or challenging to treat, as these new dominant clones have already demonstrated resistance. This genetic instability contributes to the cancer’s ability to adapt and evade treatment.
Another factor is the development of drug resistance by cancer cells. Similar to bacteria becoming resistant to antibiotics, myeloma cells can acquire mechanisms to evade chemotherapy or targeted drugs. This involves changes like mutations that alter drug binding sites or pathways that help them survive. Interactions between myeloma cells and their bone marrow environment can also promote drug resistance, shielding cancer cells from treatment.
Treatment Strategies for Relapsed Multiple Myeloma
The approach to treating relapsed multiple myeloma is highly individualized, depending on various factors. These include the patient’s overall health, previous treatments, remission length, and the characteristics of the relapsed disease. The goal is to select therapies that offer the best chance of controlling the disease while managing potential side effects.
If the remission period was long (typically more than 6 to 12 months), a previous treatment regimen that proved effective might be reused if cancer cells are still sensitive. However, if remission was short or the disease is more aggressive, different approaches are usually pursued.
Newer generation drugs represent an important category of treatment. These include next-generation proteasome inhibitors (such as carfilzomib or ixazomib) or immunomodulatory drugs (like pomalidomide), which may be more potent or have different resistance profiles than earlier versions. Combining these agents with other drugs, such as the steroid dexamethasone, is a common practice to enhance their effectiveness. Monoclonal antibodies also play an important role.
Monoclonal antibodies (like daratumumab or elotuzumab) work by targeting specific proteins on the surface of myeloma cells, marking them for destruction by the immune system. These can be used alone or in combination with other anti-myeloma agents. Another innovative approach involves cellular therapies, which harness the body’s own immune system to fight the cancer.
CAR T-cell Therapy
Chimeric Antigen Receptor (CAR) T-cell therapy involves collecting a patient’s own T-cells, genetically modifying them in a lab to recognize and attack myeloma cells, and then infusing them back into the patient. These modified T-cells, often targeting a protein called BCMA on myeloma cells, can provide durable responses.
Bi-specific T-cell Engagers (BiTEs)
Bi-specific T-cell Engagers (BiTEs), such as teclistamab or elranatamab, are another type of immunotherapy that can bridge myeloma cells and T-cells, activating the T-cells to kill the cancer. These therapies are generally considered for patients who have received multiple prior treatments.
A second stem cell transplant might be an option for some patients, especially if they had a good response to their first transplant and a long period of remission. This intensive treatment involves high-dose chemotherapy followed by the infusion of healthy blood-forming stem cells. Clinical trials are also an important consideration for patients with relapsed myeloma, offering access to investigational therapies and novel combinations.
Managing Multiple Myeloma as a Chronic Condition
Advances have transformed multiple myeloma into a condition often managed over many years, similar to a chronic disease. This involves sequential therapy, using different treatments as the disease progresses or resistance develops. The goal is to control cancer, manage symptoms, and maintain quality of life.
Long-term management includes targeting cancer cells and providing comprehensive palliative and supportive care. Palliative care focuses on relieving symptoms, pain, and stress associated with the disease and its treatments, beneficial at any illness stage. This includes managing pain, common due to bone involvement, through medications or radiation therapy.
Supportive care addresses other challenges like fatigue and peripheral neuropathy (nerve damage from disease or therapies). Nutritional support, physical therapy, and psychosocial care (emotional and spiritual support) are also components of holistic care. Integrating these aspects helps individuals live more comfortably and maintain well-being while navigating multiple myeloma.