Multiple myeloma is a cancer affecting plasma cells, a type of white blood cell found primarily in the bone marrow. These cells are part of the immune system and produce antibodies to fight infections. In multiple myeloma, abnormal plasma cells multiply uncontrollably, leading to various health complications. When this condition becomes refractory, it means the disease no longer responds to standard therapies.
Understanding Refractory Disease
Refractory multiple myeloma signifies that the cancer has either progressed while a patient was receiving treatment, or it has not responded to treatment at all. This condition is distinct from relapsed multiple myeloma, where the disease returns after a period of initial remission. While relapsed myeloma implies the cancer had previously responded and then recurred, refractory myeloma indicates a lack of effectiveness from ongoing or recent treatment.
The International Myeloma Working Group (IMWG) defines refractory disease as progression during therapy or within 60 days after completing the most recent treatment. A patient may be classified as “primary refractory” if they never achieve at least a minimal response to initial therapy. Refractory multiple myeloma can also develop after a patient has experienced a relapse, meaning the disease initially responded to treatment but then became resistant to subsequent therapies.
The term “double refractory” is used when the disease progresses despite treatment with both a proteasome inhibitor and an immunomodulatory agent. If the cancer also becomes resistant to monoclonal antibodies, it is then termed “triple-class refractory.”
How Myeloma Becomes Refractory
Multiple myeloma can develop resistance to treatment through several biological mechanisms. One factor is clonal evolution, where myeloma cells acquire additional genetic mutations over time. These mutations can lead to the emergence of new subclones less susceptible to previously effective drugs. Treatment pressure can inadvertently select for these resistant cell populations, allowing them to proliferate and dominate the disease.
Specific drug resistance mechanisms within the cancer cells contribute to this refractoriness. Myeloma cells may alter their drug targets, such as mutations in the proteasome that reduce the effectiveness of proteasome inhibitors. They can also decrease the expression of proteins necessary for drug action, like Cereblon, crucial for immunomodulatory drugs. Some cells develop the ability to pump drugs out of themselves more efficiently through mechanisms involving proteins like P-glycoprotein, reducing the drug’s intracellular concentration.
The bone marrow microenvironment also plays a role in fostering drug resistance. Interactions between myeloma cells and surrounding bone marrow stromal cells can lead to cell adhesion-mediated drug resistance (CAM-DR). The release of soluble factors and cytokines by these stromal cells can induce soluble factor-mediated drug resistance (SFM-DR). These environmental factors provide signals that promote the survival and proliferation of myeloma cells, protecting them from therapeutic agents and contributing to treatment failure.
Current Treatment Strategies
Managing refractory multiple myeloma often involves a personalized approach, utilizing combinations of different therapeutic agents to overcome resistance. Treatment strategies aim to target multiple pathways within cancer cells or engage the immune system to fight the disease.
Immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs) remain foundational components of combination therapies. For example, combinations like daratumumab with pomalidomide and dexamethasone, or carfilzomib with pomalidomide and dexamethasone, are frequently employed. These regimens combine agents that act through different mechanisms to enhance their anti-myeloma effects.
Newer therapeutic options have expanded the treatment landscape for refractory disease. Chimeric antigen receptor (CAR) T-cell therapy, such as ciltacabtagene autoleucel and idecabtagene vicleucel, genetically modifies a patient’s own T-cells to recognize and attack myeloma cells. Bispecific antibodies, including teclistamab, elranatamab, and talquetamab, are another advancement. These antibodies can simultaneously bind to a protein on myeloma cells, such as BCMA, and to CD3 on T-cells, bringing immune cells close to cancer cells to trigger their destruction. Nuclear export inhibitors, like selinexor, also offer an alternative mechanism to induce myeloma cell death. Clinical trials continue to investigate novel agents and combinations, providing access to promising new options for patients with refractory disease.
Navigating Life with Refractory Multiple Myeloma
Confirming refractory multiple myeloma involves careful monitoring and specific diagnostic tests. These tests help confirm disease progression, often indicated by a 25% increase in M-protein levels or the development of new symptoms.
Healthcare providers routinely use:
- Blood tests, such as complete blood counts, M-protein measurements, and free light chain assays, to track disease activity.
- Urine tests, including urine protein electrophoresis, to assess the disease’s impact.
- Imaging studies like X-rays, CT scans, MRI, and PET scans to visualize bone lesions or other areas of disease.
- A bone marrow biopsy to provide a direct sample for detailed analysis of plasma cells.
Advancements in treatment are continually improving outcomes for refractory multiple myeloma. The prognosis, though historically poor, has seen improvements due to novel therapies. For example, a 2021 study indicated a median survival time of 32.4 months for relapsed or refractory multiple myeloma patients after starting second-line treatment.
Supportive care plays an important role in managing life with refractory multiple myeloma. This includes addressing symptoms such as bone pain, fatigue, and kidney issues, which are common manifestations of the disease. Managing treatment side effects is also a key aspect of care, aiming to maintain a patient’s quality of life. Access to clinical trials is important, as these studies offer opportunities to receive cutting-edge therapies that may not yet be widely available. These trials represent a pathway to new and potentially more effective treatments, contributing to the evolving landscape of myeloma care.