Multiple myeloma is a cancer that originates in the plasma cells, a type of white blood cell found in the bone marrow. These abnormal plasma cells, also known as myeloma cells, can multiply uncontrollably and form tumors in various bones throughout the body. The term “refractory” describes a challenging state where the disease no longer responds to treatment or recurs after initial therapies. Understanding the available treatment options for this persistent form of multiple myeloma is important for individuals facing this diagnosis.
Understanding Refractory Multiple Myeloma
Refractory multiple myeloma refers to the condition where the cancer either does not respond to initial treatment or stops responding to a therapy that was previously effective. This differs from “relapsed” disease, which means the cancer returned after a period of remission. While often used together as “relapsed/refractory,” refractory specifically indicates a lack of response or progression despite ongoing treatment.
The development of refractory disease presents a significant challenge because the cancer cells have become resistant to current therapies. This resistance can stem from various factors, including genetic mutations that allow cancer cells to evade drug effects or even pump drugs out of the cells. Myeloma cells can also alter their microenvironment within the bone marrow, creating conditions that help them survive and hide from treatments.
When multiple myeloma becomes refractory, it often signifies a more aggressive form of the cancer. “Primary refractory multiple myeloma” indicates that the cancer did not achieve at least a partial response to the very first treatment. If the disease progresses despite treatment with a proteasome inhibitor and an immunomodulatory agent, it may be termed “double refractory,” and with the addition of monoclonal antibodies, “triple-class refractory” if these also fail to control the disease.
Established Treatment Strategies
Several established treatment approaches are utilized for refractory multiple myeloma, often in combination to enhance their effectiveness and overcome resistance.
Immunomodulatory drugs (IMiDs) like pomalidomide (Pomalyst) and lenalidomide (Revlimid) modify the immune system’s response and directly affect myeloma cells. They alter the cellular environment, leading to myeloma cell death and enhancing anti-tumor immunity.
Proteasome inhibitors (PIs) interfere with the proteasome, a cellular complex that breaks down proteins. This leads to the accumulation of toxic proteins within myeloma cells, ultimately causing their death. Carfilzomib (Kyprolis), ixazomib (Ninlaro), and bortezomib (Velcade) are commonly used PIs.
Monoclonal antibodies specifically target proteins on the surface of myeloma cells, leading to their destruction. Daratumumab (Darzalex) and isatuximab (Sarclisa) target the CD38 protein, while elotuzumab (Emplicia) targets the SLAMF7 receptor. These antibodies can directly induce cell death or flag cancer cells for destruction by the immune system.
Corticosteroids, such as dexamethasone, are frequently used in combination with other anti-myeloma drugs. They have direct anti-tumor effects and can also help manage symptoms and side effects. Corticosteroids often enhance the effectiveness of other agents.
Conventional chemotherapy, though less commonly used as a primary treatment, may still play a role in specific situations or as part of combination regimens. Autologous stem cell transplant (ASCT) involves collecting a patient’s own healthy stem cells, administering high-dose chemotherapy to eliminate cancer cells, and then reinfusing the stem cells to restore bone marrow function. This approach may be considered for select patients with relapsed or refractory disease who are eligible for transplant and have responded to salvage therapy.
Novel and Targeted Therapies
The landscape of refractory multiple myeloma treatment has expanded significantly with novel and highly targeted therapies. These newer agents often focus on specific markers on cancer cells or harness the patient’s own immune system. Many target B-cell maturation antigen (BCMA), a protein highly expressed on myeloma cells.
Chimeric Antigen Receptor (CAR) T-cell therapy is an advanced immunotherapy. A patient’s T-cells are collected and genetically engineered to produce CARs, specialized receptors that recognize and attach to specific proteins, like BCMA, on myeloma cells. These modified T-cells are expanded and re-infused, seeking out and destroying cancer cells. Idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti) are two BCMA-directed CAR T-cell therapies approved for heavily pretreated relapsed/refractory multiple myeloma.
Bispecific antibodies are an innovative class of drugs that bring immune cells and cancer cells into close proximity. These antibodies have two “arms”: one binds to a specific target on the myeloma cell (like BCMA or GPRC5D), and the other binds to a T-cell. This dual binding activates the T-cell to attack the myeloma cell. Examples include teclistamab (Tecvayli), elranatamab (Elrexfio), and talquetamab (Talvey).
Antibody-drug conjugates (ADCs) are often described as “guided missiles” because they combine a monoclonal antibody with a potent chemotherapy drug. The antibody component specifically targets a protein on the cancer cell, delivering the chemotherapy directly to the malignant cell while minimizing damage to healthy tissues. Belantamab mafodotin (Blenrep) was an example of a BCMA-directed ADC.
Other targeted agents are also available. Selinexor (Xpovio), a nuclear export inhibitor, blocks a protein that helps myeloma cells survive and is approved for use in combination regimens. Venetoclax, a BCL-2 inhibitor, targets a protein involved in cell survival and is used for patients with specific genetic abnormalities, such as the t(11;14) translocation.
Navigating Treatment Decisions
Deciding on the most suitable treatment for refractory multiple myeloma involves a careful assessment of various patient-specific and disease-specific factors. This personalized approach aims to optimize efficacy while considering quality of life.
Patient-Specific Factors
These include the patient’s age, overall health status, kidney function, and the presence of other medical conditions (comorbidities). The types of prior treatments received, how long the patient responded to them, and any lingering side effects also guide future choices. Patient preferences regarding administration route, frequency of treatment, and potential impact on daily activities are also considered.
Disease-Specific Factors
Factors such as the presence of high-risk genetic mutations (e.g., high-risk cytogenetics), found in about 25% of patients, can influence the aggressiveness of the disease and dictate the need for more intensive therapies. The overall burden of the disease and the specific symptoms experienced, such as bone pain or kidney issues, also inform treatment urgency and selection. The rate at which the disease has relapsed or progressed is another important consideration.
Managing Side Effects
Managing treatment-related side effects is an ongoing aspect of care, as toxicities can significantly impact a patient’s quality of life and adherence to therapy. For example, peripheral neuropathy can be associated with bortezomib, while cardiac side effects may occur with carfilzomib. Open communication with the healthcare team about side effects is important to adjust treatment plans and provide supportive care.
Clinical Trials and Multidisciplinary Care
Clinical trials offer access to investigational therapies not yet widely available and represent a crucial option for patients with refractory disease, particularly when standard treatments have been exhausted. These trials contribute to advancing the understanding and treatment of multiple myeloma. A multidisciplinary team approach, involving hematologist-oncologists, nurses, pharmacists, and other specialists, is also important to coordinate care and provide comprehensive support throughout the treatment journey.