Doctors and researchers have made huge steps in treating this blood cancer lately. Yet, most people face a time when the cancer returns or stops responding to the drugs. This is known as relapsed-refractory multiple myeloma (RRMM). 

It marks a turning point in the disease journey, but it does not signal the end of options. In fact, treatment for RRMM has advanced rapidly over the past decade.

Here, we’ll walk you through what relapsed-refractory multiple myeloma means and treatment options that are helping patients live longer and better lives.

Understanding Relapsed/Refractory Multiple Myeloma

Multiple myeloma is an incurable condition marked by a repeating pattern of clinical responses followed by eventual progression. 

When the disease returns or becomes resistant to treatment, it enters the Relapsed-Refractory Multiple Myeloma (RRMM) stage. 

Specifically, the International Myeloma Working Group (IMWG) defines refractory myeloma as a disease that is non-responsive to therapy, achieving less than a minimal response. It also includes cases where the disease progresses within 60 days of the last line of therapy.

Primary refractory disease occurs when a patient never achieves a significant response to initial induction, whereas secondary refractory disease involves an initial response followed by resistance to subsequent treatments.

Resistance in myeloma typically arises through clonal evolution, as treatment-resistant sub-populations expand over time. This resistance can stem from various mechanisms, including changes in the bone marrow microenvironment. These changes may promote myeloma cell growth or help the cells evade the immune system.

Treatment Options for Relapsed/Refractory Multiple Myeloma

Here, we’ll explore some of the most important and promising options available today:

Immunomodulatory Drugs (IMiDs)

Immunomodulatory drugs remain a cornerstone of RRMM therapy. This class, including thalidomide, lenalidomide, and pomalidomide, has evolved from the early 2000s to provide increasingly potent options for patients who have failed prior lines of treatment. 

IMiDs are pleiotropic agents, meaning they exert several different anti-cancer effects simultaneously. They are directly cytotoxic, anti-angiogenic, and immunomodulatory.

The primary molecular target for IMiDs is Cereblon (CRBN), a substrate receptor for the Cullin-RING E3 ubiquitin ligase 4, or CRL4-CRBN E3 ubiquitin ligase complex.   

When an IMiD binds to CRBN, it alters the substrate specificity of the ligase. This leads to the ubiquitination and subsequent proteasomal degradation of the transcription factors Aiolos (IKZF3) and Ikaros (IKZF1). 

These transcription factors are important for the survival of plasma cells. Their depletion results in the downregulation of interferon regulatory factor 4 (IRF4), triggering cell cycle arrest and apoptosis in the myeloma cells.

IMiDs also enhance the immune response by co-stimulating T-cells and natural killer (NK) cells. This increases the production of IL-2 and interferon-gamma (IFNγ), which augments the body's native anti-tumor surveillance.

Bispecific Antibodies

Bispecific antibodies (BsAbs) represent a breakthrough in RRMM treatment, particularly for patients who are triple-class refractory. 

Built on an advanced bispecific antibody platform, these are engineered with two distinct binding domains. One targets an antigen on the myeloma cell (such as BCMA, GPRC5D, or FcRH5) and another that targets the cluster of differentiation 3 (CD3) receptor on the surface of T-cells.

BCMA stands for B-cell maturation antigen, GPRC5D stands for G protein-coupled receptor class C group 5 member D, and FcRH5 stands for Fc Receptor-Like 5. 

Bispecific antibodies create a direct physical link between T-cells and cancer cells, removing the need for the body's usual, complex antigen-recognition process. Once linked, the T-cells are triggered to release destructive proteins that puncture the cancer cell's surface, leading to its immediate destruction.

In many ways, bispecific antibodies function as a T-cell receptor (TCR) mimic. Alloy Therapeutics explains that these agents replicate T-cell receptor functionality by recognizing peptide-HLA (pHLA) complexes, which are unique signatures on the cell surface originating from intracellular proteins. 

Targeting these complexes lets TCRm antibodies effectively 'unmask' internal cancer drivers that were previously inaccessible to standard antibody treatments.

CAR T-Cell Therapy

Chimeric Antigen Receptor (CAR) T-cell therapy involves the genetic modification of a patient’s own T-cells to express a receptor that recognizes myeloma-specific antigens, primarily BCMA. 

The process begins with leukapheresis, where T-cells are harvested from the patient's blood. These cells are then transported to a laboratory and engineered via viral vectors to produce CARs. They are synthetic proteins that combine an extracellular antigen-binding domain with intracellular signaling domains such as CD3-zeta. 

The two primary CAR T products for RRMM are idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti). 

Carvykti is notable for its unique structure, featuring 2 BCMA-binding domains that increase its affinity for the target. In the CARTITUDE-1 trial, Carvykti achieved an overall response rate of 98%. 

The treatment journey for CAR T is extensive. The manufacturing process for the cells generally takes 4 to 6 weeks to complete. Once the cells are ready, the patient receives "lymphodepleting" chemotherapy to prepare their body, ensuring the CAR T-cells can grow and thrive after infusion. 

After infusion, these cells function as living drugs, multiplying within the body and providing long-term surveillance against the cancer. 

Hope Continues to Grow

Relapsed-refractory multiple myeloma can be a challenging phase of the disease, but it is far from hopeless. These advancements have transformed RRMM into a manageable chronic condition for many patients. 

Most importantly, treatment decisions are no longer one-size-fits-all. They are tailored to each individual, focusing not only on controlling the disease but also on maintaining quality of life.

So, if you or your loved one is navigating RRMM, remember that you are not alone and the future of myeloma care continues to look brighter every day.