Navigating Treatment Options for Relapsed and Refractory Multiple Myeloma

When multiple myeloma returns after a period of remission (relapsed) or stops responding to treatment (refractory), it presents new challenges for both patients and healthcare providers. Fortunately, the field of oncology has made significant strides, leading to a growing number of effective therapies for what is known as relapsed/refractory multiple myeloma (RRMM). The goal of treatment shifts to controlling the disease, managing symptoms, and maintaining the best possible quality of life. The choice of therapy depends on many factors, including previous treatments, the patient's overall health, and the specific characteristics of the cancer.

Below is a comprehensive overview of the primary treatment categories available for managing RRMM. It's important to remember that treatment plans are highly individualized and are often developed by a specialized medical team.

Key Treatment Classes for RRMM

Proteasome Inhibitors (PIs)

Proteasome inhibitors are a cornerstone of multiple myeloma treatment. They work by blocking the action of proteasomes, which are cellular complexes that break down unneeded proteins. Cancer cells, including myeloma cells, produce large amounts of abnormal proteins and rely heavily on proteasomes to survive. By inhibiting these proteasomes, PIs cause a buildup of these proteins, leading to cell stress and ultimately triggering apoptosis, or programmed cell death. This mechanism is particularly effective against myeloma cells.

For patients with RRMM, doctors may use a different PI than the one used in initial therapy or may reintroduce a previously used one, sometimes in a new combination. Common proteasome inhibitors include bortezomib (Velcade®), carfilzomib (Kyprolis®), and ixazomib (Ninlaro®), which is the first oral PI, offering more convenience for patients.

Immunomodulatory Drugs (IMiDs)

Immunomodulatory drugs are another foundational class of therapy for multiple myeloma. These agents work in several ways: they directly kill myeloma cells, inhibit the growth of new blood vessels that feed tumors (anti-angiogenesis), and, most importantly, they stimulate the patient's own immune system to recognize and attack cancer cells. This multi-pronged approach makes them highly effective.

The main IMiDs used in RRMM are lenalidomide (Revlimid®), pomalidomide (Pomalyst®), and thalidomide (Thalomid®). Pomalidomide is often reserved for patients whose disease has become resistant to other therapies, including lenalidomide. These drugs are typically used in combination with other agents, such as proteasome inhibitors or corticosteroids like dexamethasone, to enhance their effectiveness.

Monoclonal Antibodies

Monoclonal antibodies represent a significant advancement in targeted therapy. These are lab-engineered proteins designed to recognize and attach to specific targets on the surface of myeloma cells. Once attached, they can work in various ways: some "mark" the cancer cells so the immune system can find and destroy them, while others may block signals that help the cancer cells grow and survive. Two key targets in multiple myeloma are CD38 and SLAMF7.

Daratumumab (Darzalex®) and isatuximab (Sarclisa®) are examples of anti-CD38 monoclonal antibodies. Elotuzumab (Empliciti®) is an antibody that targets SLAMF7. These drugs have shown impressive results in patients with RRMM, especially when combined with other standard therapies like IMiDs or PIs, often leading to deeper and more durable responses.

CAR T-Cell Therapy

Chimeric Antigen Receptor (CAR) T-cell therapy is a revolutionary form of immunotherapy that supercharges a patient's own immune cells to fight cancer. The process involves collecting T-cells (a type of white blood cell) from the patient's blood. These cells are then genetically engineered in a lab to produce special receptors (CARs) on their surface. These receptors are designed to recognize a specific protein on myeloma cells called B-cell maturation antigen (BCMA). The engineered cells are multiplied into the millions and then infused back into the patient, where they act as a "living drug," seeking out and destroying myeloma cells.

Two BCMA-directed CAR T-cell therapies approved for RRMM are idecabtagene vicleucel (Abecma®) and ciltacabtagene autoleucel (Carvykti®). This is a one-time treatment that has produced deep and lasting remissions in patients who have exhausted many other options. However, it is a complex and intensive procedure available only at specialized medical centers.

Bispecific Antibodies

Bispecific antibodies are another exciting immunotherapy innovation. These are engineered proteins that can bind to two different targets simultaneously. In the context of RRMM, they are designed to attach to a myeloma cell (often targeting BCMA or another protein called GPRC5D) with one arm, and to a T-cell with the other arm. By bringing the cancer cell and the immune cell into close proximity, the antibody activates the T-cell to kill the myeloma cell directly. This approach effectively redirects the patient’s existing immune system to fight the cancer.

Teclistamab (Tecvayli®), which targets BCMA, and talquetamab (Talvey®), which targets GPRC5D, are examples of bispecific antibodies approved for heavily pretreated RRMM. They are administered as regular injections and offer an "off-the-shelf" alternative to the personalized manufacturing process of CAR T-cell therapy.

Other Targeted Therapies

As our understanding of myeloma cell biology deepens, more targeted drugs are being developed. Selinexor (Xpovio®) is a first-in-class nuclear export inhibitor. It works by blocking a protein called XPO1, which is responsible for moving cancer-suppressing proteins out of the cell's nucleus. By trapping these proteins inside the nucleus, selinexor forces the myeloma cells to die. Venetoclax (Venclexta®) is another targeted drug that has shown significant efficacy in a specific subset of myeloma patients who have a genetic change called translocation t(11;14).

Understanding Relapsed and Refractory Multiple Myeloma

To fully appreciate the treatment landscape, it's essential to understand the terms "relapsed" and "refractory." Multiple myeloma is considered a chronic disease, and for most patients, the cancer will eventually return after initial treatment. Relapsed myeloma refers to the reappearance of the disease after a patient has achieved a partial or complete remission. The cancer becomes detectable again through blood tests, urine tests, or imaging, and may or may not be causing symptoms.

Refractory myeloma is a more challenging situation. This term is used when the myeloma does not respond to a particular treatment in the first place (primary refractory) or when it begins to progress while the patient is still on active therapy. A patient can also be refractory to a specific drug or class of drugs they have received in the past. For example, a patient whose disease progresses despite being treated with lenalidomide would be considered "lenalidomide-refractory." This distinction is critical because it helps doctors select the next line of therapy, often choosing drugs with different mechanisms of action.

Navigating Treatment Decisions and Future Outlook

How Are Treatment Decisions Made for RRMM?

Choosing the right therapy for RRMM is a complex, multi-faceted decision. Oncologists consider several key factors to create a personalized plan. First and foremost is the patient's treatment history. Which drugs have they received before, how well did they work, and for how long? The side effects experienced with prior treatments also play a major role. A patient who had severe neuropathy with one drug might be better suited for a therapy with a different side effect profile.

The patient's overall health, age, and fitness level are also crucial. More intensive therapies like CAR T-cell therapy or a stem cell transplant have strict eligibility criteria. Finally, the specific characteristics of the myeloma itself, including its genetic markers and the pace of the relapse, guide the decision-making process. The ultimate goal is to select a regimen that offers the best chance of controlling the disease while preserving the patient's quality of life.

What Are Clinical Trials and Should I Consider One?

Clinical trials are research studies that test new treatments or new ways of using existing treatments in people. For patients with RRMM, clinical trials are a vital and often excellent treatment option. The pace of drug development in multiple myeloma is incredibly fast, and trials provide access to the most cutting-edge therapies—including new CAR T-cells, bispecific antibodies, and other targeted agents—long before they become widely available.

Participating in a clinical trial can offer hope when standard options have been exhausted or are no longer effective. It also contributes to the scientific knowledge that helps future patients. Patients considering a clinical trial should discuss the possibility with their healthcare team. They can explain the potential benefits and risks, the logistics of participation, and help identify trials that might be a good fit based on the patient's specific medical situation.

Conclusion

The treatment landscape for relapsed and refractory multiple myeloma has been transformed over the past decade. The development of powerful immunotherapies like CAR T-cell therapy and bispecific antibodies, alongside a growing arsenal of targeted drugs, has provided new hope and extended survival for many patients. While a cure remains elusive, the goal of managing multiple myeloma as a chronic disease is becoming more of a reality. Treatment decisions are highly personalized, taking into account prior therapies, patient health, and the specifics of the disease. Continuous communication with a specialized oncology team is the best way to navigate the available options and find the most effective path forward.

For more information and patient support, you can visit these resources:

• Multiple Myeloma Research Foundation (MMRF)
• The Leukemia & Lymphoma Society (LLS)