Multiple Myeloma Not Having Achieved Remission: What’s Next?

Multiple myeloma treatment aims to reduce cancerous plasma cells, but not all patients achieve full remission. For some, the disease persists despite aggressive therapy, requiring ongoing management and treatment adjustments. Understanding why remission is not achieved can help guide next steps.

Several biological and clinical factors contribute to residual disease, influencing treatment response and long-term outcomes. Exploring these mechanisms provides insight into potential therapeutic approaches for those who have not reached remission.

Common Response Patterns In Myeloma

Treatment responses in multiple myeloma vary, influencing disease progression and therapeutic decisions. Some patients achieve a complete response (CR), where no detectable myeloma cells remain, while others experience a partial response (PR) or stable disease (SD), indicating residual tumor burden. The depth and durability of these responses correlate with prognosis, with deeper responses generally leading to longer survival. However, relapse remains a concern, even among those who initially respond well.

Minimal residual disease (MRD) negativity has emerged as a more precise measure of treatment success. MRD testing, using next-generation sequencing (NGS) or flow cytometry, detects myeloma cells at a sensitivity of one in a million bone marrow cells. Patients achieving MRD negativity generally experience longer progression-free survival (PFS) and overall survival (OS). However, some still relapse, emphasizing the need for ongoing monitoring and potential maintenance therapies.

For those who do not achieve deep responses, biochemical progression often precedes clinical relapse. Rising monoclonal protein (M-protein) levels or increasing free light chains can signal disease activity months before symptoms appear. The rate of progression varies, complicating treatment decisions. Slow increases may not require immediate intervention, while rapid progression often necessitates early therapeutic adjustments.

Cellular Mechanisms Of Residual Disease

Residual myeloma cells persist due to intrinsic survival mechanisms. One key factor is their ability to enter a quiescent state, reducing metabolic activity and avoiding therapies targeting actively dividing cells. These dormant cells can later re-enter the cell cycle, contributing to relapse. Single-cell RNA sequencing has identified transcriptional profiles associated with cell cycle arrest and stress resistance, reinforcing their ability to withstand treatment.

Another mechanism involves upregulated anti-apoptotic pathways. Overexpression of proteins like BCL-2, MCL-1, and BCL-XL inhibits programmed cell death, giving residual cells a survival advantage. Targeted therapies, such as BCL-2 inhibitors like venetoclax, have shown promise, particularly in patients with t(11;14) translocations, where BCL-2 dependency is higher. However, not all patients benefit equally from these approaches.

Residual cells also adapt metabolically, shifting toward oxidative phosphorylation (OXPHOS) rather than glycolysis to generate energy efficiently under stress. This metabolic plasticity contributes to resistance against proteasome inhibitors. Investigational therapies targeting mitochondrial metabolism, such as IACS-010759, aim to disrupt this adaptive advantage. Additionally, autophagy enables myeloma cells to recycle intracellular components for survival. Pharmacological autophagy inhibitors are being explored as potential treatment strategies.

Bone Marrow Microenvironment

The bone marrow microenvironment plays a crucial role in sustaining myeloma cells and influencing treatment resistance. Stromal cells, extracellular matrix components, and soluble factors provide structural and biochemical support, shielding malignant cells from therapy.

Bone marrow stromal cells (BMSCs) promote myeloma cell survival through direct contact and secretion of growth factors. Adhesion molecules like VLA-4 and LFA-1 facilitate binding between myeloma and stromal cells, triggering intracellular signaling that enhances resistance. This adhesion-mediated resistance reduces sensitivity to multiple drug classes, including proteasome inhibitors. Additionally, BMSCs secrete cytokines such as interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1), both of which support myeloma cell growth. Elevated IL-6 levels in the marrow correlate with poor treatment response.

Beyond cellular interactions, the extracellular matrix (ECM) reinforces disease persistence. Components like fibronectin and collagen provide structural support while actively influencing myeloma cell behavior. Studies show that myeloma cells embedded in ECM-rich regions exhibit increased chemotherapy resistance. Targeting ECM interactions, including integrin inhibitors and matrix-modifying agents, is under investigation, though clinical translation remains challenging.

Role Of Specific Biomarkers

Assessing treatment response and predicting outcomes relies on specific biomarkers. Traditional markers like monoclonal (M-) protein levels in serum and urine measure tumor activity but lack the sensitivity to detect minimal residual disease (MRD). Advanced techniques, including mass spectrometry-based assays, provide greater precision, identifying trace amounts of M-protein that conventional methods might miss. This sensitivity is particularly valuable for patients who do not achieve complete remission, allowing for earlier detection of persistent disease.

Circulating free light chains (FLCs) serve as additional indicators, especially in cases where myeloma cells produce excess light chains rather than intact immunoglobulins. Abnormal kappa/lambda FLC ratios are associated with poor prognosis, and persistent elevation after treatment suggests ongoing malignant activity. Next-generation sequencing (NGS) further refines biomarker detection by identifying patient-specific clonotypic rearrangements in immunoglobulin genes, enabling highly sensitive MRD monitoring.

Genetic Mutations In Persistent Plasma Cells

Genetic evolution of malignant plasma cells contributes to persistent myeloma. As therapy exerts selective pressure, resistant subclones emerge. Whole-genome and exome sequencing studies show that residual myeloma cells frequently harbor mutations in genes linked to cell survival, DNA repair, and drug resistance.

Alterations in TP53, a tumor suppressor gene, are strongly associated with poor prognosis, as they impair apoptosis. Patients with TP53 mutations often exhibit resistance to proteasome inhibitors and immunomodulatory drugs, necessitating alternative therapies like venetoclax or antibody-based treatments.

Mutations affecting the MAPK and NF-κB pathways also contribute to resistance. KRAS and NRAS mutations, found in approximately 40% of refractory cases, drive continuous proliferative signaling, reducing treatment efficacy. Similarly, mutations in TRAF3 and CYLD, which regulate NF-κB signaling, promote uncontrolled cell growth and apoptosis resistance. These genetic alterations highlight the need for molecular profiling to guide treatment decisions. Precision oncology is increasingly integrating genomic data into clinical practice, allowing for tailored therapeutic approaches.

Immunological Factors Influencing Remission Status

The immune system plays a crucial role in determining whether multiple myeloma is eradicated or persists. Immune dysfunction allows malignant plasma cells to survive by evading immune responses.

Cytotoxic T cell impairment is a primary factor in treatment resistance. Many patients with refractory disease exhibit T cell exhaustion markers such as PD-1 and TIM-3, which suppress function and enable immune evasion. Checkpoint inhibitors targeting these pathways have been explored to restore T cell activity, though results in myeloma have been inconsistent due to additional immunosuppressive factors.

Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) further suppress anti-tumor responses. Elevated Tregs in the bone marrow correlate with poor treatment outcomes by inhibiting cytotoxic lymphocytes. Similarly, MDSCs secrete immunosuppressive cytokines like TGF-β and IL-10, creating an environment favorable for myeloma cell persistence. Strategies to modulate these suppressive populations are under investigation, with early-phase trials evaluating agents that deplete Tregs or block their function. Addressing these immune barriers may improve the likelihood of sustained remission in patients with persistent disease.