Relapsed Refractory Multiple Myeloma: Key Insights
Explore key insights into relapsed refractory multiple myeloma, including the cellular and molecular factors influencing treatment resistance and disease progression.
Explore key insights into relapsed refractory multiple myeloma, including the cellular and molecular factors influencing treatment resistance and disease progression.
Multiple myeloma is a persistent cancer of plasma cells, with some patients experiencing relapse or resistance to treatment. Relapsed refractory multiple myeloma (RRMM) no longer responds to standard therapies, requiring advanced treatment strategies. Understanding the mechanisms behind relapse and resistance is crucial for improving outcomes.
Researchers are investigating why some cases become refractory while others respond longer. Identifying these factors is key to developing better interventions.
Multiple myeloma recurs due to cellular adaptations that allow malignant plasma cells to survive despite treatment. A key factor is minimal residual disease (MRD), where a small population of myeloma cells evades eradication and later expands. These cells exhibit altered metabolism, enhanced DNA repair, and resistance to apoptosis, allowing them to persist in the bone marrow until conditions favor their resurgence.
Myeloma cells exploit the bone marrow niche for survival. The stroma provides protection through direct interactions and cytokines like interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1), which promote proliferation and drug resistance. Adhesion to stromal cells further shields them from chemotherapy, reducing susceptibility to treatment. This effect is particularly evident in patients who initially respond well but later relapse aggressively due to reactivation of dormant tumor cells.
Clonal evolution also drives relapse, with myeloma cells acquiring new genetic and epigenetic alterations over time. Longitudinal genomic studies show relapsed myeloma often harbors subclones with mutations in genes like TP53, KRAS, and NRAS, which enhance proliferation and resistance. Treatment pressure fosters the expansion of these aggressive clones, leading to disease progression and reduced efficacy of standard therapies.
Multiple myeloma resists treatment through molecular adaptations that help malignant plasma cells evade therapy. A major factor is dysregulation of apoptotic pathways, particularly involving the BCL-2 family of proteins. Overexpression of anti-apoptotic proteins like BCL-2, BCL-XL, and MCL-1 prevents programmed cell death, allowing survival despite cytotoxic agents. High MCL-1 expression correlates with poor response to proteasome inhibitors like bortezomib. Targeting this pathway with BCL-2 inhibitors such as venetoclax has shown promise, particularly in patients with t(11;14) translocations.
Aberrant PI3K/AKT/mTOR signaling also sustains myeloma cell survival. Persistent activation of this pathway enhances resistance by promoting protein synthesis, metabolic adaptation, and inhibition of autophagic cell death. Increased AKT phosphorylation is common in refractory cases, contributing to treatment failure. Inhibitors like everolimus and temsirolimus have been explored in clinical trials, though their efficacy varies based on patient-specific molecular factors. Additionally, KRAS and NRAS mutations activate MAPK signaling, reinforcing survival mechanisms and complicating treatment.
Genomic instability further contributes to refractoriness, with high-risk cytogenetic abnormalities linked to poor response. Deletions of chromosome 17p, affecting the TP53 tumor suppressor gene, are associated with aggressive disease and resistance to proteasome inhibitors and immunomodulatory drugs. Whole-genome sequencing reveals refractory myeloma often exhibits structural variations like chromothripsis and copy number alterations, driving rapid disease progression and treatment resistance.
Epigenetic modifications also play a role by altering gene expression without changing DNA sequence. Hypermethylation of tumor suppressor genes like CDKN2A silences regulatory pathways controlling cell cycle progression and apoptosis. Histone modifications, including increased acetylation of oncogenic loci, contribute to resistance. Histone deacetylase (HDAC) inhibitors like panobinostat have shown potential in overcoming some of these barriers, though their benefit is often limited to specific patient subsets. Combination strategies incorporating HDAC inhibitors with proteasome inhibitors or immunomodulatory agents are under investigation.
The clinical presentation of RRMM varies based on disease burden, prior treatment, and patient-specific factors. Some experience gradual biochemical relapse, with rising monoclonal protein levels before symptoms appear. Others present with rapid bone pain, worsening anemia, or renal dysfunction, indicating a more aggressive and treatment-resistant state. Relapse patterns can be localized or widespread, affecting multiple systems.
Bone-related complications are common, as myeloma cells disrupt normal bone remodeling by increasing osteoclast activity and suppressing osteoblast function. This leads to osteolytic lesions, fractures, and spinal cord compression, significantly impacting mobility and quality of life. In some cases, skeletal involvement dominates, while in others, extramedullary disease emerges, with myeloma cells proliferating outside the bone marrow. Soft tissue plasmacytomas in the liver, lungs, or central nervous system indicate a more aggressive course and poorer outcomes. Extramedullary involvement is a hallmark of high-risk RRMM, often requiring alternative therapeutic strategies.
Renal impairment is another significant manifestation. Light chain deposition, hypercalcemia, and recurrent infections contribute to kidney dysfunction. Some patients develop cast nephropathy, where filtered light chains precipitate in the renal tubules, causing acute kidney injury. Others experience gradual decline in renal function, necessitating dose adjustments or alternative drug choices. Severe renal dysfunction limits treatment options and is associated with reduced overall survival.