Gordon Cook

In MAIA (Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma), daratumumab plus lenalidomide/dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS) versus Rd in transplant-ineligible newly diagnosed multiple myeloma (NDMM). Here, we report an updated subgroup analysis by frailty status. We retrospectively performed frailty assessments using age, Charlson Comorbidity Index, and baseline Eastern Cooperative Oncology Group performance status score; patients were classified as fit, intermediate, non-frail (fit + intermediate), or frail. After a 64.5-month median follow-up, OS benefit of D-Rd versus Rd was maintained in the non-frail subgroup (median, not reached [NR] vs 69.8 months; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.37–0.76; P = 0.0004); the OS HR point estimate favored D-Rd versus Rd in the frail subgroup (NR vs 50.4 months; HR, 0.79; 95% CI, 0.58–1.06; P = 0.1128). Improved PFS and rates of complete response or better and minimal residual disease negativity (10 ^–5 ) were observed with D-Rd versus Rd across frailty subgroups. Duration of therapy was consistently longer with D-Rd versus Rd, highlighting the improved disease control and long-term tolerability of daratumumab in frail patients. These long-term data, although limited by the retrospective assessment of frailty using baseline characteristics, continue to support the therapeutic benefit of D-Rd in terms of improved PFS and higher rates of deep responses in transplant-ineligible NDMM, regardless of frailty status.

As emphasipzed by Xiao-Dan Qian et al, the dual nature of cellular senescence represents a central challenge for cancer immunology. Senescence can restrain tumor growth by preventing proliferation of damaged cells and by generating signals that facilitate immune recognition and clearance. However, persistent senescent tumor cells may acquire properties that favor their survival and immune escape. The SASP can establish a chronic inflammatory and immunosuppressive microenvironment, while senescence-associated immune checkpoints may further compromise immune surveillance. Thus, whether senescence is beneficial or detrimental may depend on its depth, duration, cellular context, and ability to engage effective immune clearance. This conceptual framework provides a common thread linking the diverse contributions included in this Research Topic. This complexity becomes particularly evident when senescence is considered in the context of aging. Marina Gergues et al emphasizes the reciprocal relationship between senescence and natural killer (NK) cells, whose ability to eliminate malignant and senescent cells may decline with age. Immunosenescence and inflammaging can therefore weaken a critical mechanism of senescent cell surveillance precisely when the burden of senescent cells increases. Jia-Wen Wang et al extends this concept to oncolytic virus therapy, highlighting the immune frailty of older patients as a potentially important determinant of both efficacy and tolerability. These observations underscore the need to move beyond chronological age and incorporate functional measures of immune competence and frailty when designing and evaluating cancer immunotherapies for older populations.The therapeutic implications of therapy-induced senescence (TIS) represent another major thread of this Research Topic. Chemotherapy, radiotherapy, and targeted agents can induce a senescent phenotype in tumor cells, potentially creating an immunogenic state that can subsequently be exploited for tumor elimination. The "one-two punch" strategy (i.e., first inducing senescence and subsequently eliminating senescent cells) therefore offers an attractive framework for integrating senescence into precision oncology. However, senescence induction alone is unlikely to be sufficient [4]. The work discussed by Javier A. Menendez et al highlights mitochondrial apoptotic priming as a potentially critical and underappreciated determinant of the response of TIS cells to CAR-T and CAR-NK immunosenolytic therapies. Importantly, the persistence of pre-existing anti-apoptotic dependencies after senescence induction suggests that the therapeutic vulnerability of senescent cells may be, at least in part, predictable. This provides a rationale for companion diagnostics such as BH3 profiling and for rational combinations of cellular immunotherapy with agents targeting apoptotic dependencies.A complementary strategy is to interfere directly with mechanisms that allow senescent cancer cells to evade immune elimination. The review by Bei Zhao et al identifies CD47 as a molecular bridge between TIS and immune tolerance. By engaging the CD47-SIRPα axis, senescent tumor cells may inhibit phagocytic clearance and contribute to their persistence. Targeting this pathway could therefore transform a senescent state from a reservoir of therapy-resistant cells into therapeutically exploitable vulnerability. More broadly, these observations reinforce the concept that the surfaceome of senescent cells may provide a valuable source of targets for immunosenolytic approaches.The potential clinical relevance of senescence-associated molecular programs is further illustrated by the computational and multi-omics studies included in this collection. In bladder cancer, Kaixuan Du et al developed a senescence-related signature associated with immunotherapy response, prognosis, and the immune landscape, identifying PPIL3 as a potential regulatory target. Similarly, the multi-omics analysis of hepatocellular carcinoma by Talaiti Tuergan et al identified an MCM7-associated senescence axis linked to tumor progression, immune dysfunction, and potential resistance to immunotherapy. Although such signatures require prospective and functional validation, they illustrate how senescence-related molecular features may eventually contribute to patient stratification and treatment selection.Importantly, the implications of senescence extend beyond tumor growth and therapeutic response. Fabrizio Antonangeli et al introduce the "innervated niche" as another dimension of the senescent tumor microenvironment, proposing that senescence-associated inflammation may contribute to neuroinflammation and cancer-associated pain. This perspective expands the biological consequences of tumor senescence and raises the intriguing possibility that immune-mediated targeting of senescent cells, including through NK cells, could simultaneously influence tumor control and cancer-associated symptoms.Collectively, the eight contributions in this Research Topic support a shift from viewing senescence as a static tumor-suppressive state toward understanding it as a dynamic component of the tumor ecosystem. Several important questions remain open. How can beneficial, transient senescence be distinguished from persistent, tumor-promoting senescence? Which senescent-cell surface markers are sufficiently selective to permit safe immunosenolysis? How does the aging immune system alter the efficacy of senescence-targeting therapies? And can senescence-associated biomarkers reliably predict which tumors will benefit from senogenicsenolytic combinations? Addressing these questions will require integration of functional senescence assays, single-cell and spatial approaches, immune profiling, and longitudinal clinical studies. Ultimately, the therapeutic opportunity may not lie simply in inducing or eliminating senescence, but in controlling its timing, cellular location, and interaction...

Immunomodulatory drugs (IMiDs) are associated with an increased risk of arterial thromboembolism (ATE) in multiple myeloma (MM), but determinants and mechanisms remain poorly defined. We evaluated incidence, timing, and clinical risk factors in 4287 patients with newly diagnosed MM from the Myeloma-XI-trial; all received IMiD-based induction and 1412 were randomised to Lenalidomide (Len) maintenance. Associations with tumour and inherited genetics, the latter through a genome-wide association study (GWAS), were interrogated in subsets of 1800 patients each. ATE occurred in 92 patients (2.1%), predominantly as ischaemic stroke (>80%). At MM diagnosis, higher leucocyte count, lower serum albumin, and Len-based-induction in elderly were independent risk factors. Older age was the predominant determinant for maintenance-related ATE. Among tumour genetics, del(17p) (HR 3.5, P = 0.001) was strongly associated with ATE risk. Finally, GWAS identified a germline locus at 6q15 independently linked to ATE risk (OR 4.8, P = 3.9 × 10 ⁻⁸ ). Functional annotation implicates vascular enhancer activity and regulation of MAP3K7 and BACH2 . Together, these findings demonstrate distinct temporal patterns of IMiD-associated ATE risk across treatment phases. In addition to clinical risk factors, inherited variation at 6q15 may contribute to individual susceptibility. These results are hypothesis-generating and require validation in independent cohorts but may ultimately inform individualised prevention strategies.

In previous analyses of MAIA, daratumumab plus lenalidomide/dexamethasone (D-Rd) significantly improved progression-free survival and overall survival (OS) versus lenalidomide/dexamethasone (Rd) in transplant-ineligible newly diagnosed multiple myeloma (NDMM). We report results on long-term OS and subsequent antimyeloma therapies from the MAIA final analysis. A protocol amendment (July 20, 2021) led to a long-term extension of MAIA, during which patients were followed for OS. A total of 737 patients were randomized to D-Rd ( n = 368) or Rd ( n = 369). At a median follow-up of 89.3 months (range, 0.0–102.2; interquartile range, 85.3–93.0), median OS was 90.3 months (95% confidence interval [CI], 80.8–not estimable [NE]) with D-Rd versus 64.1 months (56.0–70.8) with Rd (hazard ratio [HR], 0.67; 95% CI, 0.55–0.82); estimated 7-year OS rates were 53.1% (95% CI, 47.8–58.2) and 39.3% (34.1–44.5), respectively. Median time to subsequent antimyeloma treatment was not reached (95% CI, 84.1–NE) for D-Rd versus 42.4 months (33.5–50.6) for Rd (HR, 0.51; 95% CI, 0.41–0.63; P < 0.0001). Death due to adverse events occurred in 84 patients (D-Rd, n = 44/364 [12%]; Rd, n = 40/365 [11%]). With >7 years of follow-up, D-Rd demonstrated a new benchmark for median OS (7.5 years) in transplant-ineligible NDMM, further supporting frontline D-Rd use to maximize survival.

Both the phase 3 MAIA and ALCYONE studies demonstrated significant survival benefit with the addition of daratumumab to standard-of-care Rd (Revlimid [lenalidomide] and dexamethasone; D-Rd) or to VMP (Velcade [bortezomib], melphalan, and prednisone; D-VMP), respectively, vs Rd or VMP alone in transplant-ineligible newly diagnosed multiple myeloma (NDMM). Patients with NDMM are highly susceptible to infection; therefore, gaining a greater understanding of infection incidence may help to mitigate future risk. We conducted a pooled analysis of infection incidence, timing, and management strategies from MAIA and ALCYONE. The median (range) age of the pooled population was 72 (40-93) years. Incidence was higher with D-Rd/D-VMP vs Rd/VMP for grade 3/4 (36.9% vs 22.4%) and grade 5 (3.0% vs 1.5%) infections; however, exposure-adjusted incidence rates were generally comparable between groups. Any-grade infections led to the discontinuation of study treatment in ∼2% of patients across treatment groups. Of the timing intervals explored, the highest incidence of grade 3/4 infection occurred within the first 6-month interval of study treatment initiation in both groups. Median time to the first onset of grade 3/4 infections (per Kaplan-Meier estimates) was 83.3 months and not estimable in the D-Rd/D-VMP and Rd/VMP groups, respectively. Although the rates of D-Rd/D-VMP treatment discontinuation due to infection remained low in MAIA and ALCYONE, clinicians should remain vigilant about infections throughout treatment and follow local guidelines and International Myeloma Working Group recommendations to minimize the risk of infection. These trials were registered at www.ClinicalTrials.gov as NCT02252172 (MAIA) and NCT02195479 (ALCYONE).

Functional high-risk (FHR) multiple myeloma (MM) is defined as an unexpected, early relapse (ER) of disease in the absence of baseline molecular or clinical risk factors (RF), making FHR MM inherently dependent on which RFs were assessed at diagnosis, and what treatment patients received. To establish the true incidence of FHR, we analyzed uniformly treated, transplant-eligible patients from the Myeloma-XI (MyXI) trial that had been profiled for the International Myeloma Society and Working Group (IMS/IMWG) defined high-risk cytogenetic aberrations (HRCA), and the SKY92 gene expression HR signature (GEP-HR). A total of 135 MyXI patients were studied, with a median follow-up of 88 months; 25 (18.5%) experienced ER, defined as relapse <18 months from maintenance randomization post–autologous stem-cell transplantation. Hereof, 15 (60%) were IMS/IMWG-HR at diagnosis, of whom 8 were also GEP-HR. Another 6 patients were GEP-HR only and would have been missed by IMS/IMWG-HR. Among 4 patients with IMS/IMWG– and GEP–standard risk, 2 had isolated HR markers at diagnosis, leaving only 2 patients (8% of ER; 1.5% of all) truly meeting all FHR-criteria. Combined IMS/IMWG-HR and GEP-HR profiling identified 84% of ER, and differentiated long-term outcome across all 135 patients: co-occurring IMS/IMWG and GEP-HR was associated with very short overall survival compared to the absence of both (HR = 13.1; 95% CI, 6.5-26.1, P < .0001), followed by GEP-HR only (HR = 5.1; 95% CI, 2.4-11.1, P < .0001) and IMS/IMWG-HR only (HR = 3.2; 95% CI, 1.6-6.2, P = .0007). Our results support more comprehensive baseline diagnostic profiling to identify those at risk of ER upfront. The trials were registered at the ISRCTN Registry as ISRCTN49407852 and at clinicaltrials.gov as #NCT01554852.

In the MAIA study, daratumumab plus lenalidomide and dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). We report updated efficacy and safety from MAIA (median follow-up, 64.5 months), including a subgroup analysis by patient age (P < 0.0001). Median OS was not reached in the D-Rd group versus 65.5 months in the Rd group (HR, 0.66; 95% CI, 0.53–0.83; P = 0.0003); estimated 60-month OS rates were 66.6% and 53.6%, respectively. D-Rd achieved higher rates of complete response or better (≥CR; 51.1% vs 30.1%), minimal residual disease (MRD) negativity (32.1% vs 11.1%), and sustained MRD negativity (≥18 months: 16.8% vs 3.3%) versus Rd (all P < 0.0001). D-Rd demonstrated clinically meaningful efficacy benefits across age groups. No new safety concerns were observed. Updated results (median follow-up, >5 years) continue to support frontline use of D-Rd in transplant-ineligible patients with NDMM.

Introduction: Multiple myeloma (MM) is a relapsing, debilitating blood cancer which remains incurable despite advances in treatments. Patients typically receive multiple lines of treatment, to which they become refractory, thereby limiting treatment options. B‐cell maturation antigen (BCMA) bispecific antibodies (BsAbs) represent a novel modality of treatment that has significant efficacy for relapsed or refractory patients.The objective was to develop consensus statements for the effective implementation of BCMA BsAbs for relapsed or refractory MM patients within the National Health Service (NHS).Methods: The process employed a modified Delphi methodology. In March 2023, a literature review on the topic of novel treatments for MM was performed using the PubMed database.The process employed a modified Delphi methodology. Following a literature review, a steering group of eight expert clinicians identified and agreed on five main topics of focus and 44 statements. These were then developed into an online survey which was distributed to healthcare professionals working in Levels 1, 2 and 3 haematology centres in the United Kingdom. Results were then shared with the expert panel to determine conclusions. The threshold for consensus agreement was set at 75%.Results: A total of 60 responses were received from all three centre levels. There was representation from all targeted centres. Consensus was achieved in 42 statements (95%) across three broad areas: the patient profile, initiation and step‐up dosing, monitoring and ongoing care, the role of multidisciplinary team and service designs for optimal management, consensus was not achieved for two statements. Given the level of agreement and that the stopping criteria were met, it was decided not to undertake further Delphi rounds.Conclusion: This consensus provides a framework to support the effective introduction of novel treatments for MM in the NHS. The results were used to inform a checklist for use within haematology services when considering the provision of MM care specific to BCMA BsAbs.