Multiple Myeloma (MM) is a cancer affecting plasma cells, a type of white blood cell located in the bone marrow that normally produces infection-fighting antibodies. Relapsed/refractory multiple myeloma (RRMM) describes a complex situation where the cancer either returns after a period of remission or stops responding to ongoing treatment. This condition presents unique challenges for patients due to its persistent nature and the need for adapted therapeutic strategies.
Understanding Relapsed and Refractory Myeloma
Multiple myeloma originates from an uncontrolled proliferation of abnormal plasma cells within the bone marrow. These cancerous cells can crowd out healthy blood cells and produce dysfunctional proteins, leading to various complications.
When multiple myeloma returns after a period of improvement or remission, it is termed “relapsed” myeloma. “Refractory” myeloma refers to cancer that does not respond to treatment or progresses while a patient is undergoing therapy. RRMM signifies that the disease has both returned and is resistant to standard therapies.
The development of drug resistance is a reason why multiple myeloma can become relapsed or refractory. This resistance can stem from various mechanisms, including genetic and epigenetic changes within the myeloma cells, alterations in drug transport and metabolism, and the activation of survival pathways that prevent programmed cell death. Interactions between myeloma cells and the bone marrow microenvironment, such as cell adhesion and the release of soluble factors like interleukin-6, can also contribute to drug resistance.
Recognizing the Signs
The return or progression of multiple myeloma can manifest through various symptoms, often similar to those experienced during the initial diagnosis. Bone pain is a common indicator, resulting from the accumulation of myeloma cells within the bone marrow, which can weaken bones and lead to fractures. This pain can be persistent and progressive, often affecting areas like the back.
Fatigue is another frequently reported symptom, often due to anemia where the cancerous plasma cells crowd out healthy red blood cell production in the bone marrow. Kidney problems may also arise as abnormal proteins produced by myeloma cells can accumulate and impair kidney function, leading to symptoms like swollen legs, hands, weakness, shortness of breath, or itchiness. Additionally, patients may experience frequent infections because the myeloma cells interfere with the production of healthy white blood cells and antibodies, compromising the immune system’s ability to fight off pathogens.
Diagnostic Approaches
Diagnosing relapsed or refractory multiple myeloma involves a combination of tests designed to detect and assess the extent of the disease. Blood tests are a standard component, including serum protein electrophoresis (SPEP) and serum immunofixation electrophoresis (SIFE) to identify and quantify monoclonal proteins (M-proteins) produced by the cancerous plasma cells. A serum free light chain (FLC) assay is particularly useful for monitoring light chain myeloma and detecting smaller amounts of M-protein. A complete blood count (CBC) helps assess for anemia, low white blood cell counts, or low platelet counts, while a comprehensive metabolic panel evaluates kidney function and electrolyte balance, including serum calcium levels for hypercalcemia.
Urine tests, such as a 24-hour urine collection for protein electrophoresis (UPEP) and immunofixation electrophoresis (UIFE), are performed to detect Bence Jones proteins, which are abnormal light chains in the urine. A bone marrow biopsy is also performed to examine the bone marrow for plasma cell infiltration and to identify genetic abnormalities in myeloma cells through fluorescence in situ hybridization (FISH) and cytogenetics, which inform risk stratification and treatment planning. Imaging studies, including X-rays, MRI, and PET/CT scans, are used to evaluate for bone lesions and assess bone marrow involvement or soft tissue disease.
Treatment Strategies
Treatment for relapsed/refractory multiple myeloma (RRMM) has evolved significantly, offering a range of options often used in combination to target cancer cells through different mechanisms. The selection of therapy depends on factors such as prior treatments, the rate of relapse, patient health, and genetic abnormalities.
Immunomodulatory drugs (IMiDs), such as lenalidomide, pomalidomide, and thalidomide, are frequently used. These drugs work by suppressing myeloma cell growth, inducing cell death, improving immune cell function, and inhibiting the formation of new blood vessels that support tumor growth. IMiDs also disrupt the interaction between myeloma cells and the bone marrow microenvironment, which can contribute to drug resistance.
Proteasome inhibitors (PIs), including bortezomib, carfilzomib, and ixazomib, are another class of drugs that have improved outcomes. These agents block the proteasome, a cellular “garbage disposal” system, leading to an accumulation of misfolded proteins within myeloma cells. This buildup triggers cellular stress and programmed cell death, effectively killing the cancer cells. Proteasome inhibitors also inhibit pathways that promote myeloma cell survival and adhesion.
Monoclonal antibodies, which are human-made proteins designed to target specific proteins on the surface of myeloma cells, represent a significant advancement. Examples include daratumumab and isatuximab, which target the CD38 protein, and elotuzumab, which targets SLAMF7. These antibodies work by targeting specific proteins on myeloma cells, leading to their destruction through various immune mechanisms.
Newer immunotherapies, such as CAR T-cell therapy and bispecific antibodies, offer options, particularly for heavily pretreated patients. CAR T-cell therapy involves collecting a patient’s own T cells, genetically modifying them in a lab to express a chimeric antigen receptor (CAR) that recognizes a specific protein on myeloma cells (like BCMA), multiplying these modified cells, and then infusing them back into the patient. These engineered T cells then seek out and destroy cancer cells.
Bispecific antibodies, such as teclistamab, elranatamab, and talquetamab, have two “arms.” One arm binds to a specific target on the myeloma cell (e.g., BCMA, GPRC5D), and the other arm binds to an immune cell, typically a T cell, bringing them into close proximity. This dual binding activates the immune cell to directly engage and destroy the myeloma cell. These therapies can be administered directly, unlike the multi-week manufacturing process for CAR T-cells. Often, combination therapies, involving multiple classes of drugs, are used to achieve a more comprehensive and durable response.
Living with Relapsed and Refractory Myeloma
Managing life with relapsed and refractory multiple myeloma extends beyond direct medical treatments to encompass comprehensive supportive care. Pain management is a significant aspect, often involving a supportive care team to establish an optimal regimen, which may include procedures like kyphoplasty for bone pain. Addressing side effects from treatments, such as fatigue, peripheral neuropathy, and gastrointestinal issues, is also important to improve daily functioning.
Infection prevention is a continuous concern due to the compromised immune system in myeloma patients. This involves maintaining good hygiene, protecting skin integrity, and sometimes receiving prophylactic medications like antivirals or antibiotics. Nutritional considerations are also important, as proper diet can help manage fatigue and support overall well-being. Emotional and psychological support is also important, as a diagnosis of RRMM can be overwhelming. Counseling and support groups can provide valuable resources for patients and their families, helping them cope with the challenges of the disease. While multiple myeloma remains incurable, modern treatments have improved quality of life and extended survival.