The therapeutic goal in multiple myeloma (MM) is changing from long-term disease control to a potential cure. While anti-CD38-containing quadruplets have improved outcomes, relapses continue to occur in many patients. In recent years, advancements in immunotherapy have fundamentally changed this paradigm. Bispecific antibodies (BsAbs) and chimeric antigen receptor T-cells (CAR T-cells) have deepened responses and achieved sustained MRD negativity in an unprecedented way, raising the possibility of curing MM in a subset of patients. Recently, the International Myeloma Society (IMS) reached a consensus and discussed a framework to define cure. This review examines how novel immunotherapies are redefining frontline strategies in newly diagnosed MM (NDMM) and attempts to summarize how BsAbs, CAR T-cells, and cereblon E3 ligase modulators (CELMoDs) can be integrated into induction, consolidation, and maintenance phases. It also discusses the evolving role of autologous stem cell transplant (ASCT) in the immunotherapy era and MRD-guided treatment and discontinuation strategies. Together, this review attempts to provide a roadmap to fulfill the criteria for cure.

Multiple myeloma is a plasma cell malignancy associated with heterogeneous clinical outcomes. The majority of patients are diagnosed during their seventh decade and often present with age-related comorbidities and organ dysfunction. Myeloma therapeutic landscape is rapidly evolving with the introduction of immune-based therapies, including monoclonal and bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapies targeting CD38, BCMA, and GPRC5D. These novel therapies have led to deeper and more durable responses and have raised the possibility of functional or definitive cure. However, older and frail patients continue to experience poorer outcomes, higher toxicity rates, and substantial treatment attrition, representing a major unmet clinical challenge. In this review, we discuss current approaches to the assessment and management of frailty in patients with multiple myeloma, with a focus on optimizing frontline therapy and treatment at relapse in the era of the possible achievement of a cure. We highlight emerging data on cellular therapies in this population and the importance of individualized, goal-directed treatment strategies aimed at balancing efficacy, tolerability, and quality of life.

B-cell maturation antigen (BCMA) targeted chimeric antigen receptor T-cell (CAR-T) cell therapy has proven highly efficacious for relapsed multiple myeloma, inducing deep and durable remissions. Recent reporting has bolstered significant enthusiasm, describing upwards of one-third of patients in continued remission, 5 years following BCMA CAR-T without receiving any subsequent therapy, suggesting the possibility that this treatment may offer the hope of a cure. There are many well-characterized side effects from CAR-T, and mitigation strategies have been established to make this therapy safe. However, as the use of CAR-T cells has become more widespread, several novel and unanticipated side effects have emerged. These novel toxicities of CAR-T can be delayed, occurring within the first 3 to 6 months, and can be life-threatening or life-altering. Thus, early detection and timely management are essential. This comprehensive review will cover the diagnosis and management of common and emerging toxicities associated with CAR T-cell therapy for multiple myeloma.

Bispecific antibodies (BsAbs) bind simultaneously to an antigen on the surface of multiple myeloma (MM) cells and to CD3 on the surface of T cells. This engagement leads to T-cell activation and degranulation, releasing perforin and granzymes, followed by the killing of the MM cell. Off-the-shelf available BsAbs targeting BCMA, GPRC5D, and FcRH5 have pronounced antitumor activity in heavily pretreated MM with cytokine-release syndrome, neutropenia, and infections as the most common side effects. To further improve clinical outcomes, BsAb-based combinations are being evaluated in earlier treatment lines, including newly diagnosed MM. Notably, the MajesTEC-3 trial established the combination of teclistamab and daratumumab as a new standard-of-care for relapsed/refractory MM as early as first relapse. The most common mechanism underlying acquired resistance to BsAbs is loss of antigen expression; therefore, dual-targeting strategies (combination of BsAbs targeting different tumor antigens or trispecific antibodies) are being intensively investigated to enhance the depth and duration of response.

Chimeric antigen receptor (CAR) T cells have rapidly reshaped the treatment of relapsed and refractory multiple myeloma (MM), progressing from an experimental salvage option to a therapy with a demonstrated overall survival advantage and durable, potentially curative remissions in a subset of patients. This review surveys the current evidence supporting their use, the biology underlying their successes and failures, established and emerging toxicities, and novel approaches that will define the field in the coming years. Approved products directed against B cell maturation antigen (BCMA) induce rapid and deep responses even in heavily pretreated patients, and long-term follow-up now suggests a meaningful fraction of patients achieve prolonged remission after a single infusion without maintenance therapy. These benefits are accompanied by distinctive toxicities that shape the risk-benefit calculus as therapy moves to earlier lines and even to treatment naïve patients. We discuss the determinants of response and relapse, as well as the mechanisms of antigen-positive and antigen-negative escape that next-generation approaches aim to overcome. These include novel antigen targets, multi-antigen and armored constructs, rapid manufacturing, and in vivo CAR generation, all with the goal of extending durable remissions to every patient.

Multiple myeloma has long been considered incurable; however, advances in therapy have markedly improved outcomes, with a growing proportion of patients achieving sustained remissions suggestive of cure. Minimal (or measurable) residual disease (MRD) has emerged as the most informative biomarker for assessing depth of response and predicting clinical outcomes. Evidence consistently demonstrates that MRD negativity surpasses conventional complete response in prognostic value across disease settings, treatment regimens, and risk groups. Furthermore, MRD has shown potential as a surrogate endpoint for clinical trials and as a tool to guide therapeutic decisions, including treatment intensification, de-escalation, and maintenance strategies. Emerging data also support its relevance in the context of immunotherapy and non-bone marrow-based assessment approaches. Collectively, these findings position MRD as a central component in the evolution toward more precise and individualized management of multiple myeloma.

Monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs) have significantly expanded the therapeutic landscape of multiple myeloma (MM), contributing to deeper and more durable responses and meaningful survival benefits across the continuum of the disease. CD38-targeting mAbs are now integral to frontline regimens, while ADCs introduce a complementary strategy by enabling targeted delivery of cytotoxic payloads, most notably through B-cell maturation antigen (BCMA). However, the clinical integration of these agents has revealed new resistant mechanisms, including antigen loss, immune exhaustion, and the emergence of cross-resistance across BCMA-directed therapies. Furthermore, challenges in the sequencing of treatments have emerged, as novel immunotherapies have also become available in the early relapse setting. This contemporary review examines the evolving role of mAbs and ADCs in MM, addressing both current status and directions for future research in the field.

Multiple myeloma cells are uniquely dependent on proteostasis due to their exceptionally high immunoglobulin synthesis and protein turnover, rendering them hypersensitive to disruptions in protein degradation. Proteasome inhibitors targeting the 20 S catalytic core exploit this vulnerability and remain a therapeutic cornerstone in newly diagnosed and relapsed/refractory settings, anchoring both triplet and quadruplet regimens that incorporate anti-CD38 monoclonal antibodies, immunomodulatory agents, antibody-drug conjugates, and nuclear export inhibitors. Beyond the 20 S core, emerging targets, including the 19 S regulatory particle, deubiquitinating enzymes, and the E1-E2-E3 ubiquitination cascade, offer opportunities to intensify proteotoxic stress and overcome resistance. Targeted protein degradation platforms, including CELMoDs, proteolysis targeting chimeras, molecular glues, and proteasome cap-recruiting chimeras, further expand the therapeutic repertoire. Compensatory stress responses involving autophagy, the unfolded protein response, and the bone marrow microenvironment modulate therapeutic vulnerability. Collectively, these advances position proteostasis not as a single druggable target but as an integrated therapeutic network amenable to rational, biomarker-informed combination strategies in multiple myeloma.

Despite substantial improvements in survival over recent decades, multiple myeloma (MM) remains largely incurable, and most patients ultimately experience relapsed or refractory disease, highlighting the need for novel therapeutic strategies. Immunomodulatory drugs (IMiDs) have transformed MM treatment through direct antitumor and immune-enhancing effects mediated by cereblon modulation, while their ability to stimulate T-cell and NK-cell function has provided a strong rationale for combination with modern immunotherapies, including bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapies. More recently, cereblon E3 ligase modulators (CELMoDs), such as iberdomide and mezigdomide, have emerged as next-generation cereblon-targeting agents with enhanced potency, deeper substrate degradation, and activity in lenalidomide- and pomalidomide-resistant settings. Clinical studies have demonstrated promising efficacy and manageable safety profiles across newly diagnosed and relapsed/refractory MM, including in heavily pretreated patients. In parallel, novel degraders such as cemsidomide have shown encouraging preliminary activity, further expanding the therapeutic potential of cereblon-directed approaches in MM. In this review, we aim to summarize the evolution of oral therapies in MM, focusing on the efficacy and safety of next-generation cereblon modulators and emerging cereblon-directed degraders.

Smoldering multiple myeloma (SMM) is an asymptomatic precursor of multiple myeloma characterized by marked heterogeneity in the risk of progression. Current management relies on clinical risk stratification to identify patients who might benefit from early intervention. Models such as the 20/2/20 score and its International Myeloma Working Group refinement incorporate tumor burden and cytogenetic abnormalities, whereas emerging approaches integrating dynamic biomarkers, circulating tumor cells, genomic alterations, and immune signatures could further improve the prediction of progression if validated in larger cohorts. Randomized trials suggest that early treatment with lenalidomide-based regimens or anti-CD38 monoclonal antibodies delays progression and possibly improves survival in high-risk SMM, and daratumumab has been approved as an early intervention in high-risk SMM. More intensive immunotherapy-based strategies can achieve high rates of sustained measurable residual disease negativity, which might translate into durable disease control or even a cure. Future management will likely depend on biologically informed, risk-adapted strategies to balance early treatment benefits against overtreatment, together with safety profile and patients' preferences.

Multiple myeloma (MM) exhibits marked clinical heterogeneity, with outcomes ranging from long-term disease control to rapid progression. Accurate identification of high-risk patients is therefore essential. Over the past decades, cytogenetic abnormalities have emerged as key prognostic factors, leading to successive staging systems integrating genomic data. However, limitations in existing models and a lack of standardization have hindered optimal risk assessment. The recent Consensus Genomic Staging (CGS) provides a unified definition of high-risk disease, emphasizing TP53 alterations, biallelic 1p32 deletion, and combinations of intermediate-risk lesions. Validation studies confirm its prognostic value, while also highlighting residual heterogeneity and the concept of functional high-risk disease. Advances in next-generation sequencing, particularly whole-genome sequencing, offer deeper insight into genomic complexity and may further refine stratification. Integration of genomic profiling, gene expression, and minimal residual disease assessment is likely to enhance precision medicine. Ultimately, improved risk stratification is critical to guide risk-adapted therapeutic strategies and improve outcomes in multiple myeloma.

Treatments for lung cancer have advanced significantly over the last 2 decades, improving survival and long-term outcomes. However, lung cancer mortality remains high, and cures for metastatic disease have remained elusive. Here, we outline recent advances in our understanding of lung cancer biology and areas of interest for future therapeutic development, with a focus on resistance mechanisms, tumor heterogeneity, plasticity, minimal residual disease, and the tumor microenvironment. A comprehensive understanding of how these areas influence tumor biology will be essential for the development of future lung cancer therapies and to improve the care of lung cancer patients.

Brain metastases are a common complication among patients with non-small cell lung cancer and are historically associated with significant morbidity and limited survival. Although surgery and radiation therapy remain essential pillars in the clinical management of brain metastases, the development of several pharmacologic agents with activity in the central nervous system has broadened the role of systemic therapies for treating brain metastases. There is accumulating evidence that, in the appropriate clinical scenarios, systemic therapies may be used to manage both intracranial and extracranial disease while delaying local therapy and mitigating potential treatment-related morbidity. Determining the optimal treatment approach requires careful consideration of the intracranial tumor burden, location of lesions, pathologic and molecular profile, local and systemic therapy options, and overall prognosis. This review will provide updates on the medical management of non-small cell lung cancer brain metastases, with a focus on recent advances in systemic therapy options.

Unresectable, locally advanced nonsmall cell lung cancer (LA‑NSCLC) accounts for ∼20% to 30% of newly diagnosed cases of NSCLC and remains associated with poor long‑term outcomes. Concurrent chemoradiotherapy (cCRT) has long been the therapeutic backbone for unresectable stage III disease, and the addition of consolidative durvalumab represents a major advance, significantly improving progression‑free and overall survival. Nonetheless, early progression and treatment‑related toxicity limit benefit for many patients, prompting investigation into alternative immunotherapy sequencing and escalation strategies. To date, randomized trials evaluating concurrent immune checkpoint blockade or intensified consolidation have not demonstrated additional survival benefit. In contrast, emerging precision‑medicine approaches-including consolidative targeted therapy for oncogene‑driven tumors-have yielded profound improvements in selected populations. Concurrently, advances in radiation delivery emphasize individualized strategies to optimize local control while minimizing toxicity. This review summarizes evolving systemic and radiation‑based approaches for LA‑NSCLC, highlighting current limitations and future directions to improve outcomes.