Multiple myeloma is a cancer of plasma cells, a type of white blood cell found in the bone marrow. Initial treatments often lead to a period of remission, where the signs and symptoms of the cancer decrease or disappear. However, for many, the disease will eventually return or stop responding to therapy. This stage is broadly known as relapsed or refractory multiple myeloma, a common phase in the disease’s course that prompts a change in treatment strategy.
Defining Relapsed and Refractory Disease
The terms “relapsed” and “refractory” describe two distinct situations in the multiple myeloma journey, though they can overlap. Relapsed myeloma refers to the disease returning after a patient has gone through a period of improvement or remission following initial treatment. In this case, the initial therapy was effective for a time, but the cancer has become active again. Many people experience several cycles of remission and relapse.
Refractory myeloma, on the other hand, describes a situation where the cancer is no longer responding to the current treatment. This can occur if the disease does not respond to a first-line therapy from the outset, known as primary refractory myeloma, or it may stop responding to a treatment that was previously working. A cancer is also considered refractory if it progresses within 60 days of the last treatment dose.
Clinicians confirm a relapsed or refractory status through specific diagnostic markers. This includes a rise in monoclonal protein (M protein) levels in the blood or urine, an increase in the number of plasma cells in the bone marrow, or the development of new bone lesions or plasmacytomas.
Causes of Disease Progression
The progression of multiple myeloma to a relapsed or refractory state is driven by clonal evolution. A patient’s body contains various subgroups of myeloma cells, known as clones, with different genetic characteristics. In response to treatment, these clones can mutate and change, similar to how bacteria develop resistance to antibiotics.
Initial treatments may eliminate the dominant cancer cell clones, leading to remission. However, a small number of resistant clones can survive the therapy. These surviving cells then multiply, and a new, more aggressive or treatment-resistant clone can become the dominant type, driven by new genetic mutations in the cancer cells.
The bone marrow microenvironment—the ecosystem of cells surrounding the myeloma cells—also contributes to disease progression. This environment can provide signals that protect the cancer cells from treatment and encourage their growth. This allows the disease to adapt and overcome a given therapy, leading to relapse or a refractory state.
Current Treatment Strategies
When multiple myeloma becomes relapsed or refractory, a new treatment plan is developed based on prior therapies, the patient’s health, and disease characteristics. The therapeutic landscape has expanded, offering advanced options that often involve novel drug combinations or advanced cellular therapies.
Immunotherapies harness the patient’s immune system to fight cancer. Chimeric antigen receptor (CAR) T-cell therapy is a treatment where a patient’s T-cells are collected, genetically modified to recognize and attack myeloma cells, and then infused back into the patient. Approved CAR T-cell therapies for relapsed/refractory myeloma target a protein on myeloma cells called B-cell maturation antigen (BCMA).
Bispecific antibodies represent another powerful immunotherapy. These are engineered proteins that act as a bridge, connecting a patient’s T-cells to a myeloma cell. This connection activates the T-cell to destroy the cancer cell. There are approved bispecific antibodies that target BCMA and others that target a different protein called GPRC5D, providing options for patients.
Beyond immunotherapies, there are next-generation versions of established drug classes. Newer proteasome inhibitors and immunomodulatory drugs (IMiDs) may work even if the myeloma has become resistant to earlier drugs in the same class. These agents are often used in new combination regimens. For some patients with a long-lasting remission after their first transplant, a second autologous stem cell transplant may be considered. Clinical trials also offer access to therapies under investigation.
Monitoring and Managing RR Multiple Myeloma
Once a new treatment for relapsed or refractory (RR) multiple myeloma begins, ongoing monitoring is a central part of the management plan. This allows the healthcare team to track the disease’s response to the new therapy, manage any side effects, and make timely adjustments.
The monitoring process involves a regular schedule of tests similar to those used for initial diagnosis. Frequent blood and urine tests are performed to measure M-protein and serum-free light chain levels, providing a direct indication of whether the number of myeloma cells is decreasing. These biochemical markers are sensitive indicators of treatment effectiveness.
In addition to laboratory tests, imaging scans such as PET scans, CT scans, or MRIs may be used periodically. These scans help visualize the extent of the disease, checking for changes in bone lesions or plasmacytomas. In some cases, a follow-up bone marrow biopsy may be performed to directly assess the percentage of plasma cells in the marrow and look for genetic changes in the myeloma cells.
The results of these monitoring tests guide the ongoing management of RR multiple myeloma. If the disease is responding well, the current treatment will likely continue. If the response is not adequate or if significant side effects occur, the healthcare team may adjust dosages or switch to a different therapeutic approach.