From May 13–19, 2026, the 12th World Congress on Multiple Myeloma (COMy 2026) was held in Paris, France. As one of the most influential global meetings in the field of multiple myeloma (MM), the congress brought together leading investigators to discuss the latest advances in translational research, innovative therapies, and patient care.Among the most thought-provoking presentations was a keynote lecture by Professor Nizar Bahlis of the University of Calgary entitled “Overcoming Resistance.” Drawing on emerging biological insights and translational research, Professor Bahlis systematically examined the mechanisms underlying primary and acquired resistance to bispecific antibodies (BsAbs) in multiple myeloma. He further outlined a series of therapeutic strategies—including debulking approaches, immune modulation, dual-target therapies, and precision monitoring—that may help extend the clinical benefit of T-cell–redirecting therapies.
Immune Synapse Formation and T-Cell Activation: The Central Role of Effector Memory T Cells
Bispecific antibodies function as artificial T-cell engagers, redirecting cytotoxic T cells toward malignant plasma cells by simultaneously binding CD3 on T cells and tumor-associated antigens on myeloma cells.
Professor Bahlis began by revisiting the molecular basis of this process. Through engagement of the CD3ε complex, BsAbs recruit the kinase LCK, triggering phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) within the CD3ζ chain. This subsequently activates ZAP-70–dependent downstream signaling cascades and initiates T-cell–mediated cytotoxicity.
Importantly, successful activation depends not only on antibody design but also on the intrinsic functional state of the T-cell population.
Emerging evidence suggests that the cytotoxic response induced by BsAbs is driven predominantly by CD8-positive CX3CR1-positive effector memory T cells. In contrast, naïve T cells exhibit insufficient CD45 phosphatase activity and impaired LCK activation, limiting their ability to generate effective signaling responses.
Ex vivo studies have also revealed a fascinating biological phenomenon: a single T cell is often insufficient to eliminate a tumor cell independently. Instead, effective killing frequently requires multiple sequential attacks from several T cells within a short period, ultimately inducing irreversible membrane and nuclear damage.
These findings highlight that the efficacy of BsAbs depends not only on T-cell fitness but also on the frequency and spatial distribution of T-cell–tumor interactions within the tumor microenvironment. This concept provides the biological rationale for strategies aimed at improving the effector-to-target (E:T) ratio through tumor debulking.
Defining Resistance: Antigen Loss Emerges as the Dominant Mechanism of Acquired Resistance
Professor Bahlis proposed a practical framework that distinguishes primary resistance from acquired resistance, emphasizing that each category arises through distinct biological pathways and therefore requires different therapeutic interventions.
Primary resistance occurs early during treatment and is typically driven by factors such as:
- High tumor burden resulting in an unfavorable E:T ratio
- Elevated levels of soluble target antigens (e.g., soluble BCMA)
- Increased regulatory T-cell populations
- Intrinsic deficiencies in T-cell adaptability and function
Collectively, these mechanisms impair the initiation of a productive immune response.
Acquired resistance, however, appears to be largely driven by tumor evolution under selective therapeutic pressure.
Professor Bahlis presented genomic analyses involving more than 100 relapsed patients that identified functional antigen loss as the dominant mechanism of resistance.
For BCMA-directed therapies, approximately 80% of relapse events were associated with BCMA loss or dysfunction. For GPRC5D-targeted therapies, the corresponding figure approached 70%.
Mechanisms of antigen escape included:
- Allelic deletions
- Single nucleotide variants affecting binding epitopes
- Complex structural genomic alterations
These observations strongly support the concept that long-term antigen-directed pressure promotes clonal selection and evolution, ultimately leading to treatment failure.
Perhaps most importantly, they provide compelling biological justification for the development of dual-target therapeutic strategies.
Improving the Effector-to-Target Ratio Through Debulking Strategies
For patients with high tumor burden and primary resistance—or those who experience early progression—Professor Bahlis advocated a pragmatic clinical strategy: reducing disease burden before or during BsAb treatment to restore immune responsiveness.
He described a representative case involving a high-risk patient who progressed on elranatamab therapy.
The patient subsequently received a debulking regimen consisting of:
- Daratumumab
- Pomalidomide
- Talquetamab
This approach resulted in a dramatic reduction in disease burden, with serum free light chains decreasing from approximately 12,000 mg/L to 250 mg/L.
Remarkably, when elranatamab was reintroduced, the patient achieved renewed disease control that has now been maintained for nearly two years.
This case illustrates an important principle: resistance to a bispecific antibody may not always be permanent. By reducing tumor burden, lowering soluble antigen levels, and reshaping the immune microenvironment, it may be possible to restore sensitivity to previously ineffective therapies.
According to Professor Bahlis, the goal of debulking is not necessarily maximal cytoreduction but rather the creation of an “immune window” in which T-cell–tumor interactions become more efficient.
Reversing T-Cell Exhaustion: CELMoDs as Immune Reinvigoration Partners
T-cell exhaustion represents another major barrier to sustained BsAb activity.
Professor Bahlis highlighted research demonstrating that the transcription factor Ikaros is significantly upregulated in exhausted T cells. Increased Ikaros expression is associated with elevated levels of inhibitory receptors such as:
- TIGIT
- TIM-3
- CTLA-4
This observation has led to growing interest in combining BsAbs with cereblon E3 ligase modulators (CELMoDs).
By promoting degradation of Ikaros, CELMoDs can reduce inhibitory receptor expression and restore T-cell proliferation and cytotoxic function.
Clinical evidence supporting this approach continues to accumulate.
In the TRIMM-2 study, combinations incorporating mezigdomide resulted in significant expansion of both CD8-positive and CD4-positive effector memory T-cell populations.
Notably, some patients who had progressed on BsAb monotherapy regained clinical responses after the addition of pomalidomide-based immune modulation.
Professor Bahlis emphasized that this strategy offers a unique advantage: rather than altering tumor biology, it directly improves T-cell adaptability and function, making it broadly applicable across multiple bispecific platforms.
Dual-Target Strategies and Epigenetic Modulation: Preventing Antigen Escape
To address antigen escape, Professor Bahlis proposed two complementary therapeutic avenues.
Epigenetic Restoration of Antigen Expression
Emerging evidence suggests that downregulation of GPRC5D may, in some cases, result from epigenetic silencing.
Preclinical studies indicate that hypomethylating agents can partially restore antigen expression, potentially enabling successful rechallenge with targeted therapies.
Dual-Target Therapeutic Approaches
Perhaps the most promising strategy involves simultaneous targeting of multiple antigens.
Professor Bahlis highlighted the combination of:
- Teclistamab (BCMA-directed)
- Talquetamab (GPRC5D-directed)
Data from the Red Maple analysis demonstrated highly durable responses among high-risk patients with extramedullary disease.
Most notably, the 12-month progression-free survival rate approached 90%, substantially exceeding historical outcomes observed with single-agent BCMA-directed therapy.
Dual-target approaches offer two major advantages:
- They address tumor heterogeneity by targeting multiple cellular populations.
- They prevent the emergence and expansion of antigen-negative resistant clones from the outset of therapy.
For these reasons, Professor Bahlis views dual-target immunotherapy as a key future direction for BsAb development.
Looking Ahead: Fixed-Duration Therapy and Precision Monitoring
In the final section of his presentation, Professor Bahlis explored the relationship between treatment duration and resistance evolution.
Continuous antigen exposure creates strong selective pressure favoring resistant clones.
Single-cell sequencing studies have demonstrated that resistant populations—such as BCMA-mutated clones—may become detectable four to six months before clinical relapse becomes apparent.
These findings raise the possibility of earlier intervention based on molecular monitoring.
However, the concept of fixed-duration therapy remains complex.
In the MajesTEC-3 study, patients who achieved deep responses discontinued teclistamab after reaching complete response or very good partial response. Early analyses suggest that patients who later relapsed rarely responded to BsAb rechallenge, with only a small minority regaining meaningful clinical benefit.
These observations indicate that the long-term immunologic consequences of discontinuing therapy remain poorly understood.
Professor Bahlis therefore advocated for future strategies based on dynamic monitoring of:
- Peripheral blood immune status
- Bone marrow microenvironment changes
- Emerging resistant clones detected through liquid biopsy and genomic profiling
Such approaches may ultimately enable individualized treatment duration and more precise resistance prevention.
Conclusion
Professor Nizar Bahlis delivered one of the most comprehensive analyses to date of resistance mechanisms associated with bispecific antibody therapy in multiple myeloma.
From the molecular biology of immune synapse formation and the pivotal role of effector memory T cells, to antigen loss, T-cell exhaustion, and tumor evolution under selective pressure, his presentation provided a detailed roadmap of how resistance emerges and how it may be overcome.
Equally important, he outlined a broad range of practical solutions—including tumor debulking, CELMoD-based immune reinvigoration, dual-target therapies, and epigenetic interventions—that are already beginning to influence clinical practice.
Perhaps the most important message of the lecture was conceptual rather than technical: resistance should not be viewed as a problem to address only after it develops. Instead, resistance prevention must become an integral component of treatment planning from the very beginning, guided by biological risk assessment, rational combination strategies, and continuous molecular monitoring.
As single-cell technologies, liquid biopsy platforms, and next-generation immunotherapies continue to advance, the field moves closer to a future in which resistant clones can be detected early, intercepted proactively, and ultimately prevented from undermining long-term disease control—bringing the goal of durable remission, and perhaps cure, within reach.
