Hematologic Oncology Preview Content | ESMO 2026

Introduction: The Next Phase of Treatment Innovation in Blood Cancers 

Hematologic oncology is entering a phase in which therapeutic progress is increasingly measured not simply by the availability of new drugs, but by their ability to deepen responses, delay resistance, improve treatment tolerability and preserve long-term disease control. Across multiple myeloma, B-cell lymphoma and Acute Myeloid Leukemia (AML), advances in antibody-based therapies, targeted agents, Antibody–drug Conjugates (ADCs) and cellular immunotherapy are reshaping the treatment landscape. Yet the growing number of options is creating a new clinical challenge: determining which treatment should be used, at what point in the disease course, and for which patients.

ESMO 2026, scheduled to take place in Madrid from October 23–27, will bring several of these questions into focus. The announced hematologic malignancy programme includes studies of belantamab mafodotin-based combinations in newly diagnosed multiple myeloma, a GPRC5D/CD3 bispecific antibody in relapsed or refractory myeloma, novel approaches to B-cell lymphoma, and an anti-Galectin-9 antibody in high-risk Myelodysplastic syndromes (MDS) and AML. These programmes represent different stages of therapeutic development, but collectively illustrate a broader shift towards more selective targeting of malignant cells and more deliberate treatment design.

The central question is no longer whether a new mechanism can produce a response. It is whether that response can be translated into a clinically meaningful advantage over existing therapies, without introducing a burden of toxicity, complexity or resistance that diminishes its value.

Multiple Myeloma: Moving Beyond the Search for the Next Active Agent

Multiple myeloma remains one of the most dynamic areas of hematologic drug development. The expansion of proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies, BCMA-directed therapies, and bispecific antibodies has transformed the options available across treatment lines. However, repeated relapse remains a defining feature of the disease, and the challenge is shifting from establishing activity in heavily pretreated patients towards identifying the most effective sequence and combination of therapies throughout the disease course.

A key theme at ESMO 2026 will be the development of belantamab mafodotin in combination regimens. Belantamab mafodotin is a BCMA-directed ADC that uses an antibody to deliver a cytotoxic payload to myeloma cells. Its development illustrates the growing importance of targeting a validated plasma-cell antigen through multiple therapeutic modalities rather than relying on a single mechanism of action.

The programme includes the Bela-DRd study, evaluating belantamab mafodotin with daratumumab, lenalidomide and dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma. The scheduled presentation focuses on Minimal Residual Disease (MRD) negativity and Progression-free Survival (PFS). A separate presentation will report longer-term results from the Phase I/II BelaRd trial of belantamab mafodotin with lenalidomide and dexamethasone in a similar treatment setting. Both are scheduled for presentation during the haematological malignancies session on October 24.

These studies are important because they examine the potential role of a BCMA-directed ADC earlier in the treatment pathway, rather than exclusively after multiple previous regimens. The clinical rationale is straightforward: if a treatment can produce deeper responses when tumor burden is more manageable, and patients have received fewer previous therapies, it may alter the subsequent course of disease. However, earlier deployment also raises important questions. The benefit of introducing a novel agent must be weighed against cumulative toxicity, treatment duration, quality of life and the availability of effective therapies at relapse. In particular, MRD negativity is a valuable measure of response depth, but it should be interpreted alongside the duration of that response and longer-term outcomes.

Why MRD Is Becoming a More Important Development Endpoint

MRD assessment has become increasingly influential in myeloma because conventional response criteria may not fully capture the depth of disease suppression achieved by modern combinations. Detecting no residual disease at the sensitivity of a validated assay can provide evidence of a deep response and may help distinguish treatment regimens that otherwise produce similar conventional response rates. Nevertheless, MRD negativity is not interchangeable with cure. Its clinical value depends on the durability of the response, the population studied, the assay used and the relationship between MRD status and subsequent progression or survival.

For the belantamab-based programmes, the most informative question is therefore not simply whether high MRD-negative rates can be achieved. It is whether deeper responses are accompanied by durable PFS improvement and whether the benefit justifies the additional treatment burden. The strategic implication is that myeloma development is increasingly focused on the quality and durability of response, rather than response rate alone. The implication is significant. The next generation of cancer-vaccine innovation may be determined less by the number of antigens encoded and more by the accuracy with which tumor biology is translated into an immune target.

G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D): Expanding the Targeting Landscape beyond BCMA

Another important development is the first-in-human Phase I study of LBL-034, a GPRC5D/CD3 bispecific antibody, in relapsed or refractory multiple myeloma. Unlike BCMA-directed therapies, LBL-034 targets GPRC5D on myeloma cells while engaging CD3 on T cells, bringing immune effector cells into proximity with the malignant population. The programme will provide early clinical evidence regarding the safety and antitumor activity of this approach.

The rationale for exploring GPRC5D is closely linked to the limitations of repeated BCMA-directed treatment. Although BCMA has become a major therapeutic target, resistance, antigen-related escape, and the consequences of successive immune-directed therapies can complicate treatment sequencing. A different target may provide another route to disease control, particularly for patients whose disease has progressed after previous BCMA-directed treatment. However, an alternative target does not automatically establish a superior treatment option. Early-phase results will need to be assessed for response depth, duration, safety and the characteristics of patients who derive benefit. For bispecific antibodies, the treatment burden associated with immune-mediated toxicities, infection risk and ongoing administration is also relevant to their eventual positioning.

The wider development trend is clear: myeloma treatment is moving towards a multi-target environment in which the availability of different mechanisms may allow therapy to be adapted to disease biology and prior treatment exposure.

 

The myeloma story at ESMO 2026 is therefore not simply about adding another drug to an increasingly crowded market. It is about determining whether new combinations and targets can improve the sequencing of therapy, extend disease control and preserve future treatment options.

B-Cell Lymphoma: Precision Targeting Meets Established Treatment Backbones

B-cell lymphomas present a different therapeutic challenge. Although rituximab-based combinations and newer immune-directed treatments have substantially expanded treatment options, outcomes remain heterogeneous across disease subtypes and treatment lines. Patients with aggressive disease, transformed lymphoma or relapse after multiple therapies may require approaches that deliver more selective tumor killing without compromising the ability to receive subsequent treatment. At ESMO 2026, two programmes illustrate how developers are approaching this challenge through different mechanisms: rocburitinib, a fourth-generation Bruton's tyrosine kinase (BTK) inhibitor, in combination with R-CHOP, and TRS005, a novel anti-CD20 ADC.

Rocburitinib: Integrating Targeted Inhibition with Chemoimmunotherapy

The announced Phase Ib study of rocburitinib in previously untreated B-cell lymphoma evaluates the agent in combination with R-CHOP, an established chemoimmunotherapy backbone. BTK is a key component of B-cell receptor signalling, which supports the survival and proliferation of several B-cell malignancies. Inhibiting this pathway can therefore provide a mechanistically targeted approach to disrupting malignant B-cell activity. The combination strategy is notable because it does not replace established treatment outright. Instead, it tests whether pathway inhibition can complement the activity of chemotherapy and antibody-based treatment. This approach may be particularly relevant where malignant cells remain dependent on B-cell signalling despite the use of conventional therapy.

The study is an early Phase Ib investigation, and its first report should be interpreted accordingly. The principal considerations are safety, feasibility of combining the agents, preliminary efficacy and whether the findings justify further clinical development. It would be premature to infer a new standard of care from an early-phase presentation alone. From a development perspective, the key question is whether adding targeted therapy produces enough incremental benefit to justify the additional toxicity, monitoring requirements and treatment complexity. In a setting where established regimens already have substantial activity, demonstrating a clinically meaningful advantage will be essential.

TRS005: Exploring a New ADC Approach in Transformed DLBCL

TRS005, a novel anti-CD20 ADC, will also be featured in a Phase I study in transformed diffuse large B-cell lymphoma (DLBCL). ADCs combine the target specificity of an antibody with the cytotoxic activity of a linked drug payload. In principle, this can enable targeted delivery of a cytotoxic agent to cells expressing the relevant antigen. CD20 is a well-established target in B-cell malignancies, making it an attractive basis for an ADC approach. However, the clinical value of a new CD20-directed construct depends on more than target validity. Antibody properties, payload, linker design, internalisation, pharmacokinetics and the toxicity profile can all influence the therapeutic index.

The relevance of TRS005 is heightened by the complexity of transformed lymphoma, where disease behaviour and previous treatment exposure can limit the effectiveness of conventional strategies. Early clinical data may help establish whether the ADC has sufficient activity and tolerability to warrant broader investigation. For now, the programme should be viewed as an emerging approach rather than a clinically validated alternative to established lymphoma therapies. The most consequential future evidence will come from adequately powered studies that clarify response durability, comparative efficacy and the patients most likely to benefit. Together, rocburitinib and TRS005 reflect two distinct development strategies: reinforcing an established regimen through pathway inhibition, and using an ADC to deliver cytotoxic activity through a defined tumor antigen. Their ultimate value will depend on whether mechanistic differentiation translates into better clinical outcomes.

AML and High-Risk MDS: Targeting Disease beyond Conventional Cytotoxicity

AML and high-risk MDS remain particularly challenging because of their biological heterogeneity, the potential for rapid disease progression and the limitations imposed by patient age, comorbidities and treatment eligibility. Relapse and treatment resistance continue to drive substantial unmet need, reinforcing the importance of approaches that extend beyond conventional cytotoxic therapy. At ESMO 2026, LYT-200 will be presented in a Phase Ib study evaluating an anti-Galectin-9 monoclonal antibody alone and in combination with hypomethylating agents, with or without venetoclax, in relapsed or refractory high-risk MDS and AML. The programme is intended to explore whether Galectin-9-directed treatment can contribute to disease control in populations with limited therapeutic options.

Galectin-9 is an immunoregulatory protein implicated in interactions between malignant cells and the immune microenvironment. Targeting this pathway represents an attempt to modify the biological conditions that can contribute to immune dysfunction and treatment resistance. The rationale is distinct from directly inhibiting a driver mutation or delivering a cytotoxic payload: it focuses on disrupting a component of the tumor-associated immune environment. The combination strategy also reflects the practical realities of AML and high-risk MDS development. Hypomethylating agents and venetoclax are established components of treatment for selected patients, and a novel agent must demonstrate that it can be incorporated into existing regimens without creating prohibitive toxicity or compromising dose intensity.

Because LYT-200 is being evaluated in an early-phase study, the topline findings should primarily be interpreted in terms of safety, feasibility and preliminary antitumor activity. The most important questions include whether the treatment can be administered reliably in a heavily pretreated population, whether responses are observed across clinically relevant subgroups, and whether any activity is durable enough to justify larger trials. A positive early signal would support further investigation, but it would not establish Galectin-9 inhibition as an effective treatment strategy without confirmatory evidence.

The Importance of Combination Design in Myeloid Malignancies

The LYT-200 programme highlights a broader issue in myeloid malignancies: adding a new mechanism to an existing regimen is not inherently beneficial. Combination development must account for overlapping toxicity, infection risk, cytopenias, patient frailty and the possibility that treatment-related complications may limit the ability to deliver therapy. Consequently, future progress will depend on identifying not only which pathways are biologically relevant, but also which combinations are clinically feasible. Biomarker development may become particularly important if it can identify patients whose disease is more likely to respond to immune-microenvironment modulation.

For AML and high-risk MDS, the goal is not simply to increase response rates in isolation. It is to improve the depth and duration of response, preserve eligibility for subsequent treatment where appropriate, and ultimately establish a meaningful benefit in survival or other clinically relevant outcomes.

The Common Thread: From Mechanistic Innovation to Treatment Positioning

Although multiple myeloma, B-cell lymphoma and myeloid malignancies have distinct biology, the studies selected for ESMO 2026 share a common development challenge. Each tests whether a new or refined mechanism can improve treatment beyond what is already achievable with existing therapies.

In myeloma, the central questions concern deeper responses, durability and the selection of targets across treatment lines. In B-cell lymphoma, developers are exploring whether targeted inhibition or ADC technology can improve established treatment strategies. In AML and high-risk MDS, the priority is to find tolerable and effective combinations for patients with substantial unmet need. These are not interchangeable clinical problems, and the evidence required to resolve them differs by disease. Nevertheless, the broader direction of travel is consistent: treatment development is increasingly focused on how therapies fit into a complete treatment pathway rather than on the activity of individual agents in isolation.

The most informative studies will therefore be those that provide evidence relevant to clinical decisions. For myeloma, this includes the relationship between MRD negativity and durable disease control. For lymphoma, it includes whether a new combination or ADC delivers sufficient incremental benefit to justify its additional burden. For AML and high-risk MDS, it includes whether a novel immune-directed approach can be administered safely and produce meaningful activity in a difficult-to-treat population.

 

Beyond Efficacy: Tolerability, Access and the Future Treatment Sequence

As the number of therapeutic options expands, the competitive landscape will increasingly depend on factors beyond response rates. Treatment duration, administration schedule, monitoring requirements, cumulative toxicity and the feasibility of using a therapy in routine practice can all influence its eventual clinical position. This is particularly relevant for therapies that require prolonged administration or intensive monitoring. A treatment that produces deep responses but imposes substantial practical burdens may not be optimal for every patient. Conversely, a treatment with a manageable safety profile and convenient administration could become valuable even if its efficacy is comparable to that of existing options.

The economics of treatment will also matter. Novel biologics, ADCs and immune-directed therapies can add high costs to already complex treatment pathways. Their commercial and clinical value will ultimately depend on whether the benefits they provide are sufficiently meaningful to justify those costs and whether healthcare systems can deliver them equitably.

For developers, this raises the importance of comparative evidence and careful patient selection. For clinicians, it reinforces the need to evaluate treatments according to disease biology, prior therapy, comorbidities, patient preferences and the anticipated benefits and burdens of each option.

Conclusion: A More Deliberate Era of Hematologic Oncology Development

ESMO 2026 is set to showcase a diverse range of therapeutic approaches across multiple myeloma, lymphoma and myeloid malignancies. Belantamab mafodotin-based combinations are exploring the value of deeper responses and earlier BCMA-directed treatment; LBL-034 represents the continued expansion of myeloma targeting beyond BCMA; rocburitinib and TRS005 illustrate different strategies for improving lymphoma treatment; and LYT-200 reflects ongoing efforts to modify the immune environment in AML and high-risk MDS.

These programmes should not be viewed as equivalent in maturity or clinical evidence. Some address established treatment strategies through additional follow-up, while others remain early-phase investigations. Their significance will depend on the strength and maturity of the data presented, rather than the novelty of their mechanisms alone. The broader transformation in hematologic oncology is nonetheless clear. The field is moving from a model centered on the introduction of new active agents towards one in which treatment depth, durability, sequencing, resistance and tolerability must be considered together.

The next phase of progress will be determined not by how many mechanisms can be brought into clinical development, but by how effectively those mechanisms translate into better decisions and better outcomes for patients. ESMO 2026 offers an opportunity to assess that transition across several major blood cancers and to identify which emerging strategies are ready for further clinical validation, and which still require substantial evidence before their place in treatment can be defined.