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Purpose: Continuous lenalidomide maintenance treatment after autologous stem cell transplantation delivers improvement in progression free and overall survival among newly diagnosed multiple myeloma patients and has been the standard of care in the UK since March 2021. However, there is scant information about its impact on patients’ day-to-day lives. This service evaluation aimed to qualitatively assess patients receiving lenalidomide treatment at a cancer centre in London, in order that the service might better align with needs and expectations of patients. Methods: We conducted 20 semi-structured interviews among myeloma patients who were on continuous lenalidomide maintenance treatment at a specialist cancer centre in London. Members of the clinical team identified potentially eligible participants to take part, and convenience sampling was used to select 10 male and 10 female patients, median age of 58 (range, 45–71). The median treatment duration was 11 months (range, 1–60 months). Participants were qualitatively interviewed following the same semi-structured interview guide, which was designed to explore patient experience and insights of lenalidomide. Reflexive thematic analysis was used for data analysis. Results: Four overarching themes were as follows: (i) lenalidomide: understanding its role and rationale; (ii) reframing the loss of a treatment-free period to a return to normal life; (iii) the reality of being on lenalidomide: balancing hopes with hurdles; (iv) gratitude and grievances: exploring mixed perceptions of care and communication. Results will be used to enhance clinical services by tailoring communication to better meet patients’ preferences when making treatment decisions. Conclusion: This study highlights that most patients feel gratitude for being offered continuous lenalidomide and perceive it as alleviating some fears concerning relapse. It reveals variations in side effects in different age groups; younger patients reported no/negligible side effects, whilst several older patients with comorbidities described significant symptom burden, occasionally leading to treatment discontinuation which caused distress at the perceived loss of prolonged remission. Future research should prioritise understanding the unique needs of younger patients living with multiple myeloma. [ABSTRACT FROM AUTHOR]

Objectives: Bacterial infections are common and a major cause of morbidity and mortality in multiple myeloma (MM). We have investigated the function of polymorphonuclear leukocyte (PMN), the immune system's first line of defense against bacteria, in peripheral blood (PB) and bone marrow (BM) samples from patients with newly diagnosed MM (NDMM), smoldering MM (SMM), monoclonal gammopathy of undetermined significance (MGUS) and healthy controls. Methods: Phagocytosis and oxidative burst in PMN cells from patients and healthy donors were investigated using PhagoTest and PhagoBurst assay. Results: PMN from NDMM, SMM, and MGUS patients had reduced phagocytosis and oxidative burst ability compared with healthy controls. The dysfunction was most prominent in BM samples from MM, SMM, and MGUS patients. Importantly the reduced phagocytosis in MM patients was restored in patients on lenalidomide therapy. Consistently the ability of Escherichia coli stimulated oxidative burst in BM was reduced for the MM, SMM, and MGUS cohort in contrast to the healthy controls and the patients on lenalidomide treatment. Conclusion: Our results show that MM patients have neutrophil dysfunction that could contribute to susceptibility for bacterial infections and that lenalidomide therapy was associated with restored PMN function. [ABSTRACT FROM AUTHOR]

Summary Mantle cell lymphoma (MCL) is a rare lymphoproliferative neoplasm considered incurable, with a median survival of 3–5 years. In recent years, Bruton's tyrosine kinase inhibitors (BTKi) have been introduced, demonstrating high therapeutic activity. However, the prognosis for MCL patients failing ibrutinib therapy is particularly poor, with a survival expectation of a few months. In this phase II trial, we assessed the efficacy and safety of the carfilzomib‐lenalidomide‐dexamethasone (KRD) combination in MCL patients who were relapsed/refractory (R/R) or intolerant to BTKi and in need of treatment. The primary objective of the study was to evaluate the antitumor efficacy of the KRD combination in terms of 12‐month overall survival (12‐month OS). From September 2019 to December 2020, 16 patients were enrolled from 11 Italian centers. After a median follow‐up of 2.37 months (95% CI 0.92–6.47), the 12‐month OS was 13%. The rate of grade 3–4 adverse events (AEs) was 35%, and the overall response rate (ORR) was 19%. These results led to the premature termination of enrollment, as defined in the protocol stopping rules. The efficacy of the KRD combination in advanced‐stage MCL patients who are R/R to BTKi is unsatisfactory and too toxic. [ABSTRACT FROM AUTHOR]

Summary: Due in part to racial disparities and underrepresentation in clinical studies, optimal therapies for Black patients with multiple myeloma remain undefined. This final analysis of GRIFFIN by race showed that the addition of daratumumab (D) to lenalidomide/bortezomib/dexamethasone (RVd) provides clinical benefit among both Black and White transplant‐eligible newly diagnosed patients compared with RVd alone. However, Black patients were more likely to discontinue ≥1 drug due to treatment‐emergent adverse events. In summary, these findings suggest a benefit of D‐RVd front‐line therapy among Black and White patients and underscore the importance of equitable treatment access for all patients. [ABSTRACT FROM AUTHOR]

AbstractLenalidomide (LEN) and rituximab (RTX) have independently improved progression-free survival (PFS) in CLL, leading to interest in use of LEN + RTX (R2) following induction chemoimmunotherapy. Patients with previously untreated CLL received bendamustine + RTX (BR) for 6 cycles, then 24 cycles of R2. LEN dosing was 5–10 mg daily; RTX was given odd cycles (12 doses). The primary endpoint is PFS; secondary endpoints are response and overall survival. Thirty-six patients enrolled, median age 64.5 years. Twenty-nine received R2; 12 completed a full course R2 (33.3%), 5 completed R2 with premature discontinuation of LEN. Dose reductions/holds were most often for neutropenia. Complete response was achieved in 33.3%. After median >4 years follow-up, 2-year and 3-year PFS were 86.1% and 69.4%. Five-year overall survival was 92.3%. R2 maintenance may improve PFS after BR induction, and a lower dose of 5 mg/day and ≤1 year of R2 may be most tolerable (NCT00974233). [ABSTRACT FROM AUTHOR]

This article discusses a study on the use of targeted therapy with de-escalation chemotherapy for elderly patients with primary central nervous system lymphoma (PCNSL). The study examined four cases of PCNSL patients over 60 years old and found that a combination of rituximab, orelabrutinib, and lenalidomide resulted in complete remission for all patients. The treatment also improved the patients' functional status and quality of life. The study suggests that this treatment option may be beneficial for PCNSL patients who cannot tolerate intensive chemotherapy. [Extracted from the article]

This article discusses the successful treatment of a patient with scleromyxedema (SMX) and multiple myeloma (MM) using a combination of daratumumab, lenalidomide, and dexamethasone. SMX is a rare skin condition characterized by waxy papules, nodules, and skin thickening, often associated with monoclonal gammopathy. The patient in this case study experienced a rapid and sustained remission of skin lesions after undergoing a 12-month treatment plan with the aforementioned medications. This treatment combination shows promise as an effective strategy for managing SMX. [Extracted from the article]

MicroRNAs (miRNAs), particularly miR-16 and miR-21, play a crucial role in multiple myeloma (MM) pathogenesis by regulating gene expression. This study evaluated the prognostic significance of circulating miR-16 and miR-21 expression levels in 48 patients with MM at diagnosis treated with lenalidomide–dexamethasone (LD) compared with 15 healthy individuals (HI). All patients were treated with LD, 13 at first line and 35 at relapse, of whom 21 were tested twice at diagnosis and before LD initiation. The results revealed significantly lower levels of miR-16 and miR-21 in patients than in HIs, both at diagnosis and relapse, with decreased miR-16 levels at diagnosis, indicating improved overall survival (OS) (p value 0.024). Furthermore, miR-16 and miR-21 levels were associated with disease markers, while both correlated with the depth of response and mir-16 with sustained response to LD treatment. Ratios of both miR-16 and miR-21 expression levels (prior to LD treatment/diagnosis) below two predicted a shorter time to response (p = 0.027) and a longer time to next treatment (p = 0.042), respectively. These findings suggested a prognostic value for serum miR-16 and miR-21 levels in MM, as their expression levels correlated with disease variables and treatment outcomes. [ABSTRACT FROM AUTHOR]

Objectives and Methods: We conducted a multicenter retrospective study to analyze the safety and efficacy of DPd versus DKd in daratumumab naïve RRMM patients treated in real‐world practice. Results: A total of 187 patients with RRMM were included in the analysis; 128 patients received DPd, and 59 patients received DKd. A vast majority (80%) of patients had lenalidomide refractory disease and nearly 50% had bortezomib refractory disease. The overall response and complete response rates were 76% and 34% in the DPd group versus 80% and 51% in the DKd group, respectively. With a median follow up of 36 months for the entire patient population, median PFS and OS in the DPd versus DKd groups were 12, 12, 37, and 35 months, respectively. The most common grade 3+ adverse events in the DPd versus DKd groups were neutropenia (32% vs. 7%), anemia (14% vs. 10%), thrombocytopenia (13% vs. 15%), and cardiovascular events (4% vs. 15%), respectively. Both DPd and DKd appeared to be a safe and effective treatment options for RRMM. Conclusions: While there were more cytopenias associated with DPd and more cardiovascular side effects with DKd, there were no significant differences in the survival outcomes with these two regimens. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndromes (MDS) encompass a heterogeneous set of acquired bone marrow neoplastic disorders characterized by ineffective hematopoiesis within one or more bone marrow lineages. Nearly half of MDS patients carry cytogenetic alterations, with del(5q) being the most prevalent. Since its first description, del(5q) was consistently correlated with a typical clinical phenotype marked by anemia, thrombocytosis, and a low risk of evolving into acute leukemia. Presently, the World Health Organization (WHO) classification of myeloid neoplasms recognizes a specific subtype of MDS known as "myelodysplastic neoplasm with low blast and isolated del(5q)" identified by the sole presence of 5q deletion or in combination with one other abnormality excluding −7/del(7q). Several studies have sought to unravel the biological processes triggered by del(5q) in the development of MDS, revealing the involvement of various genes localized in specific regions of chromosome 5 referred to as common deleted regions (CDR). This intricate biological landscape makes the MDS cells with del(5q) exceptionally sensitive to lenalidomide. Several studies have confirmed the efficacy of lenalidomide in this context. Regrettably, the response to lenalidomide is not conclusive, prompting ongoing research into biological mechanisms that drive patients toward leukemia and strategies to circumvent lenalidomide resistance and disease progression. [ABSTRACT FROM AUTHOR]

Lenalidomide and rituximab (R2) is an effective frontline treatment for patients with indolent B-cell non-Hodgkin lymphoma (iNHL). We investigated the safety and efficacy of addition of the proteasome inhibitor ixazomib to R2 for treatment of iNHL through a phase I/II clinical trial for high-risk patients. Twenty patients were enrolled, 18 were treated. The target dose of ixazomib 4 mg weekly was achieved during dose escalation. The most common treatment-related adverse events (AEs) were low grade gastrointestinal, rash, neuropathy, and myalgia/arthralgia. There were 33% grade 2 and 17% grade 3 infections. With median follow-up of 5.2 years, four patients discontinued treatment due to lymphoma progression. Best overall response rate (ORR) was 61.2% [55.6% CR, 5.6% PR): 22.2% had stable disease and 16.7% had disease progression. Kaplan-Meier estimates of progression free and overall survival (OS) were 73% and 87% at 36 months, respectively. R2 can safely be combined with ixazomib for treatment-naïve iNHL patients. [ABSTRACT FROM AUTHOR]

Once-weekly carfilzomib at 56 mg/m2 plus immunomodulatory drugs and dexamethasone has shown efficacy and tolerability treating early relapsed/refractory multiple myeloma (RRMM). The phase 2 SELECT study (NCT04191616) evaluated efficacy/safety of weekly carfilzomib, pomalidomide, and dexamethasone (KPd) in early RRMM patients refractory to lenalidomide. All 52 treated patients were refractory to prior treatment, and 19 (37%) were triple-class refractory. Overall response rate (ORR; primary endpoint) was 58% (35% ≥ very good partial response, 6% ≥ complete response); median response duration was 20.3 months. Minimal residual disease negativity (10−5) was achieved in 10% of patients. Median progression-free survival was 11.1 months; median overall survival was 18.8 months. Adverse events (AEs) were consistent with the known safety profile including grade ≥3 treatment-emergent AEs reported in 67% of patients. Although the primary endpoint of ORR was not met, KPd showed meaningful clinical benefits in lenalidomide-refractory RRMM patients, including those who were daratumumab-refractory and/or triple-class refractory. [ABSTRACT FROM AUTHOR]

First‐line treatment of multiple myeloma, a prevalent blood cancer lacking a cure, using anti‐CD38 daratumumab antibody and lenalidomide is often inadequate due to relapse and severe side effects. To enhance drug safety and efficacy, an antibody‐drug conjugate, TE‐1146, comprising six lenalidomide drug molecules site‐specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE‐1146 is prepared using the HighDAR platform, which employs i) a maleimide‐containing "multi‐arm linker" to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn2+‐binding cysteine at the C‐termini of a reconfigured daratumumab for site‐specific drug bundle conjugation. It is shown that TE‐1146 remains intact and effectively enters CD38‐expressing tumor cells, releasing lenalidomide, leading to enhanced cell‐killing effects compared to lenalidomide/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE‐1146 precisely delivers lenalidomide to target CD38‐overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc‐dependent effector functions to kill tumor cells. [ABSTRACT FROM AUTHOR]

Background: Consolidation therapy improves the duration of response among patients with primary central nervous system lymphoma (PCNSL). Lenalidomide maintenance has shown encouraging results in older patients with PCNSL. Herein, we performed a retrospective, single‐center analysis to evaluate the effect of lenalidomide maintenance on the duration of response in patients with newly‐diagnosed PCNSL. Methods: Sixty‐nine adult patients with PCNSL who achieved complete remission or partial remission (PR) after induction therapy were enrolled. The median age of patients was 58.0 years. The maintenance group (n = 35) received oral lenalidomide (25 mg/day) for 21 days, every 28 days for 24 months; the observation group did not undergo any further treatment. Results: After a median follow‐up of 32.6 months, the maintenance group experienced fewer relapse events. However, the median progression‐free survival (PFS) was similar between groups (36.1 vs. 30.6 months; hazard ratio, 0.78; 95% confidence interval, 0.446). Lenalidomide maintenance significantly improved PFS and overall survival (OS) only among patients who experienced PR after induction. The median duration of lenalidomide maintenance was 18 months; lenalidomide was well tolerated and minimally impacted the quality of life. Conclusions: The present study was the first to evaluate lenalidomide maintenance as a frontline treatment among patients with PCNSL, PFS and OS did not improve, although the safety profile was satisfactory. [ABSTRACT FROM AUTHOR]

Objectives: To analyze the impact of prior therapies on outcomes with selinexor, bortezomib, and dexamethasone (SVd) versus bortezomib and dexamethasone (Vd) in 402 patients with relapsed/refractory multiple myeloma (RRMM) in the phase 3 BOSTON trial. Methods: Post hoc analysis of progression‐free survival (PFS), overall survival (OS), and safety for lenalidomide‐refractory, proteasome inhibitor (PI)‐naïve, bortezomib‐naïve, and one prior line of therapy (1LOT) patient subgroups. Results: At a median follow‐up of over 28 months, clinically meaningful improvements in PFS were noted across all groups with SVd. The median SVd PFS was longer in all subgroups (lenalidomide‐refractory: 10.2 vs. 7.1 months, PI‐naïve: 29.5 vs. 9.7; bortezomib‐naïve: 29.5 vs. 9.7; 1LOT: 21.0 vs. 10.7; p <.05). The lenalidomide‐refractory subgroup had longer OS with SVd (26.7 vs. 18.6 months; HR 0.53; p =.015). In all subgroups, overall response and ≥very good partial response rates were higher with SVd. The manageable safety profile of SVd was similar to the overall patient population. Conclusions: With over 2 years of follow‐up, these clinically meaningful outcomes further support the use of SVd in patients who are lenalidomide‐refractory, PI‐naïve, bortezomib‐naïve, or who received 1LOT (including a monoclonal antibody) and underscore the observed synergy between selinexor and bortezomib. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the impact of prior exposure and refractoriness to lenalidomide or proteasome inhibitors (PIs) on the effectiveness and safety of ixazomib–lenalidomide–dexamethasone (IRd) in relapsed/refractory multiple myeloma (RRMM). Methods: INSURE is a pooled analysis of adult RRMM patients who had received IRd in ≥2 line of therapy from three studies: INSIGHT MM, UVEA‐IXA, and REMIX. Results: Overall, 391/100/68 were lenalidomide‐naïve/−exposed/−refractory and 37/411/110 were PI‐naïve/−exposed/−refractory. Median duration of therapy (DOT) was 15.3/15.6/4.7 months and median progression‐free survival (PFS) was 21.6/25.8/5.6 months in lenalidomide‐naïve/exposed/refractory patients. Median DOT and PFS in PI‐naïve/exposed/refractory patients were 20.4/15.2/6.9 months and not reached/19.8/11.4 months, respectively. The proportion of lenalidomide‐naïve/exposed/refractory patients in INSIGHT and UVEA‐IXA who discontinued a study drug due to adverse events (AEs) was ixazomib, 31.6/28.2/28.0% and 18.6/6.7/10.5%; lenalidomide, 21.9/28.2/16.0% and 16.1/6.7/10.5%; dexamethasone, 18.4/20.5/16.0% and 10.6/0/10.5%, respectively. The proportion of PI‐naïve/exposed/refractory patients in INSIGHT and UVEA‐IXA who discontinued a study drug due to AEs was: ixazomib, 44.4/28.8/27.8% and 22.2/16.7/15.7%; lenalidomide, 33.3/22.0/19.4% and 16.7/15.9/11.8%; dexamethasone, 33.3/17.4/16.7% and 16.7/9.5/7.8%, respectively. REMIX AE discontinuation rates were unavailable. Conclusion: IRd appeared to be effective in RRMM patients in routine clinical practice regardless of prior lenalidomide or PI exposure, with better outcomes seen in lenalidomide‐ and/or PI‐nonrefractory versus refractory patients. [ABSTRACT FROM AUTHOR]

Summary Multiple myeloma (MM) is an incurable plasma cell cancer in the bone marrow. Immunomodulatory drugs, such as lenalidomide (LEN) and pomalidomide, are backbone agents in MM treatment, and LEN resistance is commonly seen in the MM clinic. In this study, we presented that heterogeneous nuclear ribonucleoprotein U (hnRNPU) affected MM resistance to LEN via the regulation of target mRNA translation. hnRNPULow MM cells exhibited upregulated CRBN and IKZF1 proteins, stringent IKZF1/3 protein degradation upon LEN addition and increased sensitivity to LEN. RNA pulldown assays and RNA electrophoretic mobility shift assays revealed that hnRNPU bound to the 3′‐untranslated region of CRBN and IKZF1 mRNA. A sucrose gradient assay suggested that hnRNPU specifically regulated CRBN and IKZF1 mRNA translation. The competition of hnRNPU binding to its target mRNAs by small RNAs with hnRNPU‐binding sites restored MM sensitivity to LEN. hnRNPU function in vivo was confirmed in an immunocompetent MM mouse model constructed by the inoculation of Crbn‐humanized murine 5TGM1 cells into CrbnI391V/+ mice. Overall, this study suggests a novel mechanism of LEN sensitivity in which hnRNPU represses CRBN and IKZF1 mRNA translation. [ABSTRACT FROM AUTHOR]

Introduction: Ixazomib, lenalidomide, and dexamethasone (IRd) have been approved for the treatment of relapsed/refractory multiple myeloma (RRMM) based on the results of the TOURMALINE‐MM1. Objectives and Methods: We conducted a retrospective–prospective analysis of 106 RRMM patients (pts) treated with IRd in 21 centers in Northern Italy, with the aim to evaluate the efficacy and safety of IRd in real life. Results: At IRd initiation, 34% of pts were aged ≥75 (median 72.5), 8.5% had an ECOG performance status ≥2, 54.7% of evaluable pts carried high‐risk cytogenetic abnormalities [del17p and/or t(4;14) and/or t(14;16) and/or 1 g gain/amp], 60.2% had received ≥2 prior lines of therapy (pLoT), 57.5% were lenalidomide (Len)‐exposed (including both Len‐sensitive and Len‐refractory pts), and 22% were Len‐refractory. Main G ≥3 adverse events (AEs) were thrombocytopenia (16%) and neutropenia (12.3%). G ≥3 non‐hematologic AEs included infections (9.4%) and GI toxicity (diarrhea 5.7%, hepatotoxicity 2.8%), VTE, skin rash, and peripheral neuropathy were mainly G1‐2. The overall response rate was 56.4% (≥VGPR 30%). With a median follow‐up of 38 m, median PFS (mPFS) was 16 m and the 1‐year OS rate was 73%. By subgroup analysis, an extended PFS was observed for pts achieving ≥VGPR (mPFS 21.2 m), time from diagnosis to IRd ≥5 years (26.2 m), 1 pLoT (34.4 m), Len‐naïve (NR), age ≥70 (20 m). In pts exposed to Len, non‐refractory in any prior line and immediately prior to IRd, mPFS was 16 and 18 m, respectively. An inferior PFS was seen in Len‐refractory pts (4.6 m). By multivariate analysis, independent predictors of PFS were age ≥70 (HR 0.6), time from diagnosis ≥5 years (HR 0.32), refractoriness to Len in any prior line (HR 3.33), and immediately prior (HR 4.31). Conclusion: IRd might be effective and safe in RRMM pts with an indolent disease, in early lines of treatment, and who proved Len‐sensitive, independent of age, and cytogenetic risk. [ABSTRACT FROM AUTHOR]

Nearly all patients with multiple myeloma eventually relapse or become refractory to treatment. Lenalidomide is increasingly administered in the frontline until disease progression or intolerance to therapy, resulting in the need for highly effective, lenalidomide-sparing options. In this study, carfilzomib plus daratumumab and dexamethasone were evaluated against lenalidomide-sparing, pomalidomide-containing triplets using matching-adjusted indirect comparison in the absence of head-to-head data. The analyses utilized long-term follow-up data from the CANDOR study (NCT03158688). Treatment with carfilzomib, daratumumab, and dexamethasone resulted in significantly longer progression-free survival (hazard ratio 0.60 [95% confidence interval: 0.37, 0.88])vs. pomalidomide plus bortezomib and dexamethasone, and numerically longer progression-free survival (hazard ratio 0.77 [95% confidence interval: 0.50, 1.08]) vs. daratumumab plus pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma and previous lenalidomide exposure, the majority of whom were lenalidomide refractory. Carfilzomib plus daratumumab and dexamethasone offers a highly effective, lenalidomide-sparing treatment option for this population. [ABSTRACT FROM AUTHOR]

Background: Relapsed or refractory follicular lymphoma (rrFL) is an incurable disease associated with shorter remissions and survival after each line of standard therapy. Many promising novel, chemotherapy-free therapies are in development, but few are licensed as their role in current treatment pathways is poorly defined. Methods: The REFRACT trial is an investigator-initiated, UK National Cancer Research Institute, open-label, multi-centre, randomised phase II platform trial aimed at accelerating clinical development of novel therapies by addressing evidence gaps. The first of the three sequential novel therapy arms is epcoritamab plus lenalidomide, to be compared with investigator choice standard therapy (ICT). Patients aged 18 years or older with biopsy proven relapsed or refractory CD20 positive, grade 1-3a follicular lymphoma and assessable disease by PET-CT are eligible. The primary outcome is complete metabolic response by PET-CT at 24 weeks using the Deauville 5-point scale and Lugano 2014 criteria. Secondary outcomes include overall metabolic response, progression-free survival, overall survival, duration of response, and quality of life assessed by EQ-5D-5 L and FACT-Lym. The trial employs an innovative Bayesian design with a target sample size of 284 patients: 95 in the ICT arm and 189 in the novel therapy arms. Discussion: Whilst there are many promising novel drugs in early clinical development for rrFL, understanding the relative efficacy and safety of these agents, and their place in modern treatment pathways, is limited by a lack of randomised trials and dearth of published outcomes for standard regimens to act as historic controls. Therefore, the aim of REFRACT is to provide an efficient platform to evaluate novel agents against standard therapies for rrFL. The adaptive Bayesian power prior methodology design will minimise patient numbers and accelerate trial delivery. Trial registration: ClinicalTrials.gov: NCT05848765; 08-May-2023. EudraCT: 2022-000677-75; 10-Feb-2022. [ABSTRACT FROM AUTHOR]

Background: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent non‐Hodgkin lymphomas (iNHL). Median survival for iNHL is approximately 20 years. Because standard treatments are not curative, patients often receive multiple lines of therapy with associated toxicity—rationally designed, combination therapies with curative potential are needed. The immunomodulatory drug lenalidomide was evaluated in combination with rituximab for the frontline treatment of FL in the phase 3 RELEVANCE study. Ibrutinib, an oral Bruton tyrosine kinase inhibitor, is active in NHL and was evaluated in combination with lenalidomide, rituximab, and ibrutinib (IRR) in a phase 1 study. Methods: The authors conducted an open‐label, phase 2 clinical trial of IRR for previously untreated FL and MZL. The primary end point was progression‐free survival (PFS) at 24 months. Results: This study included 48 participants with previously untreated FL grade 1–3a (N = 38), or MZL (N = 10). Participants received 12, 28‐day cycles of lenalidomide (15 mg, days 1–21 cycle 1; 20 mg, cycles 2–12), rituximab (375 mg/m2 weekly in cycle 1; day 1 cycles 2‐12), and ibrutinib 560 mg daily. With a median follow‐up of 65.3 months, the estimated PFS at 24 months was 78.8% (95% confidence interval [CI], 68.0%–91.4%) and 60‐month PFS was 59.7% (95% CI, 46.6%–76.4%). One death occurred unrelated to disease progression. Grade 3–4 adverse events were observed in 64.6%, including 50% with grade 3–4 rash. Conclusions: IRR is highly active as frontline therapy for FL and MZL. Compared to historical results with lenalidomide and rituximab, PFS is similar with higher grade 3–4 toxicity, particularly rash. The study was registered with ClinicalTrials.gov (NCT02532257). After 5 years of follow‐up from a phase 2 clinical trial of ibrutinib, lenalidomide, and rituximab in previously untreated patients with follicular and marginal zone lymphoma, the 5‐year progression‐free survival rate was 59.7% and the overall survival rate was 97.9%. [ABSTRACT FROM AUTHOR]

Background: Anti‐myelin‐associated glycoprotein (MAG) neuropathy is a debilitating demyelinating polyneuropathy with no approved therapies. Our primary objective was to ascertain lenalidomide safety and maximum tolerated dose (MTD) in anti‐MAG neuropathy. Methods: This phase 1b, open‐label, single‐arm, dose‐finding trial was conducted from 2019 through 2022. The original design included a dose‐escalation/extension phase followed by a dose‐expansion phase. Three doses of lenalidomide were evaluated: 10, 15, and 25 mg. The main outcome was the MTD. Results: Eleven patients enrolled (10 men), with a mean age of 67.6 years (SD = 6.18, range 58–77 years) and mean disease duration of 8.5 years (SD = 10.9, range 1–40 years). The study terminated early due to higher‐than‐expected non‐dose‐limiting toxicity venous thromboembolism (VTE) events. The calculated MTD was 25 mg (posterior mean of toxicity probability was 0.01 with a 95% credible interval of 0.00, 0.06), but a recommended phase 2 dose of 15 mg was advised. For secondary exploratory outcomes, only EQ‐5D (−0.95, 95% CI −1.81 to −0.09) and total IgM (−162 mg/dL, 95% CI −298 to −26) showed signs of improvement by month 12. Conclusions: Lenalidomide was associated with higher‐than‐expected VTE events in anti‐MAG neuropathy patients, despite a calculated MTD of 25 mg. A recommended phase 2 dose of 15 mg was advised. Lenalidomide did not improve disability or impairment at 12 months, although this study was not powered for efficacy. The risks of long term lenalidomide may outweigh benefit for patients with anti‐MAG neuropathy. Any future efficacy study should address VTE risk, as current myeloma guidelines appear inadequate. Trial Registration: Lenalidomide in Anti‐MAG Neuropathy: Phase 1b Study, ClinicalTrials.gov Identifier: NCT03701711, https://clinicaltrials.gov/ct2/show/NCT03701711. First submitted October 10, 2018. First patient enrolled in January 2019. [ABSTRACT FROM AUTHOR]

Summary: Improving outcomes for older patients with acute myeloid leukaemia remains an unmet need. As part of the LI‐1 trial, we evaluated lenalidomide (LEN) in combination with low‐dose cytosine arabinoside (LDAC) in patients aged >60 years unfit for intensive therapy and compared this to LDAC alone. Two hundred and two patients, randomised 1:1, were evaluable. Overall response rate (CR + CRi) was higher for LDAC + LEN versus LDAC (26% and 13.7% respectively p = 0.031). However, there was no difference in overall survival between the arms (14% and 11.5% at 2 years for LDAC + LEN and LDAC respectively). The addition of LEN was associated with increased toxicity and supportive care requirements. [ABSTRACT FROM AUTHOR]

The objective of this study is to examine the effectiveness and safety of zanubrutinib, rituximab, and lenalidomide (ZR2) in unfit patients with diffuse large B-cell lymphoma (DLBCL). Thrombosis or bleeding risk of ZR2 regimen, especially when antiplatelet agents were co-prescribed, was also evaluated. We retrospectively reviewed unfit newly diagnosed (ND) and refractory or relapsed (R/R) patients with DLBCL who were administered with ZR2 regimen in two medical centers between December 2019 and February 2022. Response rates, progression-free survival (PFS), overall survival (OS), bleeding adverse events (AEs), and thrombosis episodes were analyzed. Furthermore, we investigated the effects of zanubrutinib alone or in combination with lenalidomide on platelet functions in vitro and in vivo. A total of 30 unfit patients (13 ND DLBCL and 17 R/R DLBCL patients) who received ZR2 regimen were enrolled in the study (median age: 69.5 years). The ultimate ORRs for the ND DLBCL and R/R DLBCL were 77.0% and 50.1%, respectively. The median follow-up was 16.6 months. The median PFS and OS were not achieved during the follow-up time. Subcutaneous hemorrhage AEs occurred in four cases, three cases suffered severe bleeding events, and thrombosis events were observed in two patients. ZR2 regimen inhibited platelet functions (aggregation, clot retraction, spreading and activation) in vitro and in vivo function testing especially in response to collagen. ZR2 is an efficient treatment option for unfit patients with DLBCL and could be well tolerated. Notably, this regimen inhibited platelet functions. Antiplatelet agents should be used with caution in patients treated with this regimen. [ABSTRACT FROM AUTHOR]

Treatment of lenalidomide refractory (Len-R) multiple myeloma (MM) patients still represents an unmet clinical need. In the last years, daratumumab-bortezomib-dexamethasone (D-VD) combination was extensively used in this setting, even though only a small fraction of Len-R patients was included in the pivotal trial. This real-life study aimed to evaluate the efficacy and safety of the D-VD regimen in a cohort that exclusively enrolled Len exposed or refractory MM patients. The study cohort included 57 patients affected by relapsed/refractory MM. All patients were previously exposed to Len, with 77.2% being refractory. The overall response rate (ORR) was 79.6% with 43% of cases obtaining at least a very good partial response (VGPR). The D-VD regimen showed a favorable safety profile, with low frequency of grade 3–4 adverse events, except for thrombocytopenia observed in 21.4% of patients. With a median follow-up of 13 months, median progression-free survival (PFS) was 17 months. No significant PFS differences were observed according to age, ISS, LDH levels, type of relapse, and high-risk FISH. Len exposed patients displayed a PFS advantage as compared to Len refractory patients (29 vs 16 months, p = 0.2876). Similarly, patients treated after Len maintenance showed a better outcome as compared to patients who had received a full-dose Len treatment (23 vs 13 months, p = 0.1728). In conclusion, our real-world data on D-VD combination showed remarkable efficacy in Len-R patients, placing this regimen as one of the standards of care to be properly taken into account in this MM setting. [ABSTRACT FROM AUTHOR]

Introduction: CC chemokine receptor 4 (CCR4), which is involved in leukocyte migration, is expressed in most tumor cells in patients with adult T-cell leukemia/lymphoma (ATLL). Case Presentation: Here we report the case of a 78-year-old man diagnosed with lymphoma-type ATLL expressing CCR4. The patient was administered two cycles of lenalidomide but died because of sepsis 5 months after the initial diagnosis. Autopsy revealed ATLL cells at several sites. Immunohistochemical analysis revealed that these ATLL cells had reduced CCR4 expression. Conclusion: The present case suggests that treatment should be carefully determined in ATLL with reference to a history of lenalidomide use and CCR4 expression. [ABSTRACT FROM AUTHOR]

Introduction: TEMPI syndrome is a rare and acquired condition which is characterized by five classical features: telangiectasias, erythrocytosis with elevated erythropoietin, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting. The classical treatment is based on bortezomib which can achieve variable responses. Relapse or refractory disease may occur, so other treatment strategies can be proposed. Case Presentation: We describe the case of a 54-year-old male followed for a refractory TEMPI syndrome who achieved complete remission after a second-line therapy composed of daratumumab-, lenalidomide-, and dexamethasone-based regimen (DLd). He achieved a complete remission with dramatic improvement of his renal function, restitution of a normal blood oxygen, and disappearance of polycythemia. Conclusion: This case highlights the effectiveness of an association of DLd to treat refractory TEMPI syndrome. We also provide arguments for an association between TEMPI syndrome and monoclonal gammopathy of renal significance. [ABSTRACT FROM AUTHOR]

Background: Bortezomib, lenalidomide and dexamethasone (VRd) is now the standard‐of‐care induction therapy for newly diagnosed transplant‐eligible multiple myeloma patients, replacing bortezomib, cyclophosphamide and dexamethasone (VCD) therapy. Lenalidomide can negatively impact stem cell yield because of its myelosuppressive effects, although studies have shown that the latter can be overcome with the use of cyclophosphamide for peripheral blood stem cell (PBSC) mobilisation. Aims and Methods: To investigate whether lenalidomide impacts on PBSC mobilisation and to evaluate the optimal mobilisation strategy post VRd induction, we performed a retrospective review of 56 myeloma patients at a single centre who had PBSC mobilisation between January 2019 and March 2021 and compared three cohorts: (i) VCD induction; mobilisation with granulocyte colony‐stimulating factor (G‐CSF) alone (n = 23); (ii) four cycles VRd induction; mobilisation with G‐CSF and cyclophosphamide (G‐CSF + Cyclo) (n = 20); and (iii) three cycles VRd induction; mobilisation with G‐CSF alone (n = 13). Results: There was no difference in the mean total CD34 count between VCD and VRd patients who had G‐CSF mobilisation (6.27 × 106/kg vs 5.50 × 106/kg, P > 0.99). VRd patients mobilised with G‐CSF + Cyclo achieved higher mean total CD34 counts compared with G‐CSF alone (8.89 × 106/kg vs 5.50 × 106/kg, P = 0.04). The majority of VRd patients who had G‐CSF + Cyclo (19 of 20; 95%) collected sufficient cells for two or more autologous stem cell transplants (ASCTs), regardless of whether this was required, compared with eight of 13 (62%) VRd patients who had G‐CSF alone. Conclusion: We conclude that successful PBSC mobilisation for at least one ASCT is possible after three cycles of VRd induction using G‐CSF alone. The upfront use of a cyclophosphamide‐based mobilisation strategy has a role in patients who have had VRd induction, where the aim is to collect enough stem cells for two or more ASCTs. [ABSTRACT FROM AUTHOR]

Introduction: For primary cutaneous diffuse large B-cell lymphoma, leg-type (PCDLBCL-LT), there are no uniform recommendations for second-line treatment in case of relapse. Case Presentation: Here, we present the case of an elderly relapsed/refractory PCDLBCL-LT patient who obtained a prolonged clinical complete remission with lenalidomide. Conclusion: Lenalidomide as single agent led to an unexpected long complete response with manageable toxicity. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a rare non-Hodgkin lymphoma that frequently becomes chemoresistant over time. The distinct mechanisms of ibrutinib and lenalidomide provided a judicious rationale to explore the combination with anti-CD20 immunotherapy. In this phase 1b study (NCT02446236), patients (n=25) with relapsed/refractory MCL received rituximab with escalating doses of lenalidomide (days 1–21) and ibrutinib 560mg (days 1–28) of 28-day cycles. The MTD for lenalidomide was 20mg; most common grade ≥3 adverse events were skin rashes (32%) and neutropenic fever (24%). The best ORR was 88%, CR rate was 83%, and median duration of response (DOR) was 36.92months (95% CI 33.77, 51.37). Responses were seen even in refractory patients or with high-risk features (e.g. blastoid variant, TP53 mutation, Ki-67>30%). R2I was safe and tolerable in patients with R/R MCL. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) and its precursor states, smoldering myeloma (SM) and monoclonal gammopathy of undetermined significance (MGUS) are associated with increased incidence of thrombosis, however the cause of this is unknown. Lenalidomide treatment of MM substantially improves patient survival, although significantly increases thrombotic risk by an unknown mechanism. This pilot study aimed to establish the impact of MM and its treatment with Lenalidomide on platelet function. We analyzed platelet function in MGUS, SM and MM compared to healthy controls. We report an increase in platelet reactivity in MGUS, SM, and MM where increases in fibrinogen binding, P-selectin exposure, altered receptor expression, elevated levels of aggregation and enhanced sensitivity to agonist stimulation were observed. We also demonstrate an increase in patient platelet reactivity post Lenalidomide treatment compared to pre-treatment. We show Lenalidomide treatment of platelets ex vivo increased reactivity that was associated with formation of larger thrombi at arterial shear rates but not venous shear rates. This study demonstrates a clear increase in platelet reactivity and prothrombotic potential in patients with MGUS, SM and MM which is elevated further upon treatment with Lenalidomide. Our observations suggest that more detailed studies are warranted to determine mechanisms of thrombotic complications to enable the development of new preventative strategies that specifically target platelets. [ABSTRACT FROM AUTHOR]

In very rare cases of monoclonal gammopathy, insulin-binding paraprotein can cause disabling hypoglycaemia. We report a 67-year-old man re-evaluated for hyperinsulinaemic hypoglycaemia that persisted despite distal pancreatectomy. He had no medical history of diabetes mellitus or autoimmune disease but was being monitored for an IgG kappa monoclonal gammopathy of undetermined significance. On glucose tolerance testing, hyperglycaemia occurred at 60 min (glucose 216 mg/dL) and hypoglycaemia at 300 min (52 mg/dL) concurrent with an apparent plasma insulin concentration of 52 850 pmol/L on immunoassay. Laboratory investigation revealed an IgG2 kappa with very high binding capacity but low affinity (Kd 1.43 x 10-6 mol/L) for insulin. The monoclonal gammopathy was restaged as smouldering myeloma not warranting plasma cell-directed therapy from a haematological standpoint. Plasma exchange reduced paraprotein levels and improved fasting capillary glucose concentrations. Lenalidomide was used to treat disabling hypoglycaemia, successfully depleting paraprotein and leading to resolution of symptoms. [ABSTRACT FROM AUTHOR]

Summary: Previous studies suggest that postautologous stem cell transplant (ASCT) recovery of polyclonal immunoglobulin from immunoparesis in patients with multiple myeloma is a positive prognostic marker. We performed a longitudinal analysis of polyclonal immunoglobulin concentrations and unique B‐cell sequences in patients enrolled in the phase 3 ATLAS trial that randomized 180 subjects to either carfilzomib, lenalidomide, dexamethasone (KRd) or lenalidomide (R) maintenance. In the KRd arm, standard‐risk patients with minimal residual disease negativity after six cycles de‐escalated to R alone after cycle 8. One year from the initiation of maintenance at least partial recovery of polyclonal immunoglobulin was observed in more patients on the R arm (58/66, p < 0.001) and in those who de‐escalated from KRd to R (27/38, p < 0.001) compared to the KRd arm (9/36). In patients who switched from KRd to R, the concentrations of uninvolved immunoglobulin and the number of B‐cell unique sequences increased over time, approaching values observed in the R arm. There were no differences in progression‐free survival between the patients with at least partial immunoglobulin recovery and the remaining population. Our analysis indicates that patients receiving continuous therapy after ASCT experience prolonged immunoparesis, limiting prognostic significance of polyclonal immunoglobulin recovery in this setting. [ABSTRACT FROM AUTHOR]

Objectives: Lenalidomide (LEN) is used to treat multiple myeloma (MM) and shows in vitro synergy with KappaMab (KM), a chimeric antibody specific for Kappa Myeloma antigen, an antigen exclusively expressed on the surface of kappa‐restricted MM cells. Lenalidomide, dexamethasone (DEX) and KM control MM via multiple immunomodulatory mechanisms; however, there are several additional effects of the drug combination on immune cells. Lenalidomide can increase T cell and NKT cell cytotoxicity and dendritic cell (DC) activation in vitro. We investigated the immune cell populations in bone marrow of patients treated with KM, LEN and low‐dose DEX in kappa‐restricted relapsed/refractory MM ex vivo and assessed association of those changes with patient outcome. Methods: A cohort (n = 40) of patients with kappa‐restricted relapsed/refractory MM, treated with KM, LEN and low‐dose DEX, was analysed using a mass cytometry panel that allowed identification of immune cell subsets. Clustering analyses were used to determine significant changes in immune cell populations at time periods after treatment. Results: We found changes in five DC and 17 T‐cell populations throughout treatment. We showed an increase in activated conventional DC populations, a decrease in immature/precursor DC populations, a decrease in activated CD4 T cells and an increase in effector‐memory CD4 T cells and effector CD8 T cells, indicating an activated immune response. Conclusion: These data characterise the effects of LEN, DEX, and KM treatment on non‐target immune cells in MM. Treatment may support destruction of MM cells by both direct action and indirect mechanisms via immune cells. [ABSTRACT FROM AUTHOR]

Relapsed/Refractory Diffuse Large B Cell Lymphoma have a dismal prognosis in need of innovative treatments. This prospective phase 2 study enrolled 32 patients between 2013 and 2017 with Relapsed/Refractory Diffuse Large B Cell Lymphoma treated with Rituximab and Lenalidomide (R2). Median age was 69 years (40–86), 90.1% had received at least 2 prior lines of treatment, 81% were defined as having High Risk disease according to our criteria and ECOG performance status was > 2 in 51.6%. Patients received a median number of 2 cycles of R2 (1–12). With a median follow up of 22.6 months, the objective response rate was 12.5%. Median progression free survival was 2.6 months (95% CI, [1.7–2.9]) and median overall survival was 9.3 months (95% CI, [5.1–Not estimable]). This study therefore did not achieve its primary endpoint and the R2 regimen cannot be recommended in Relapsed/Refractory Diffuse Large B Cell Lymphoma patients with High Risk features. [ABSTRACT FROM AUTHOR]

POEMS syndrome is a rare disorder which has been increasingly recognized. The clonal origin is controversial. Some people argue that POEMS syndrome originates from abnormal plasma cell clones. So, treatment frequently targets the plasma cell clone. Nevertheless, others believe that both plasma cells and B cells can be the potential culprit in POEMS syndrome. A 65-year-old male came to the emergency department of our hospital with the complaints of bilateral soles numbness and weight loss for half a year, abdominal distension for half a month, and chest tightness and shortness of breath for one day. He was then diagnosed as POEMS syndrome complicated with monoclonal B-cell lymphocytosis (non-CLL type). A standard bendamustine plus rituximab (BR) regimen combined with low dose of lenalidomide was administered. After four cycles of treatment, the ascites of the patient was absent and the neurological symptom disappeared. The renal function, the IgA level, and the VEGF level all returned to normal. POEMS syndrome, a multi-system disorder, is easily misdiagnosed. The clonal origin of POEMS syndrome is controversial and needs further study. For now, there are no approved treatment regimens. Treatments mainly target the plasma cell clone. This case suggested that other therapy besides anti-plasma cell treatment may also be effective in POEMS syndrome. We report a patient with POEMS syndrome who achieved complete response after treatment with the combination of a standard BR regimen and low dose of lenalidomide. POEMS syndrome's pathological mechanisms and therapies warrant further studies. [ABSTRACT FROM AUTHOR]

In the absence of head-to-head comparisons across relapsed/refractory multiple myeloma (RRMM) treatments following the approval of the oral proteasome inhibitor ixazomib, in combination with lenalidomide and dexamethasone (IRd), we conducted an indirect comparison of the efficacy of IRd relative to several RRMM therapies using Bayesian fixed-effects network meta-analysis (NMA) models. Data for the NMA were obtained through a systematic literature review (conducted in June 2020), which identified randomized controlled trials (base case) and observational studies (extended network analysis) reporting overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). In the base case, IRd was associated with a significantly longer PFS than lenalidomide and dexamethasone (Rd), bortezomib monotherapy (V), dexamethasone (Dex), and pomalidomide and dexamethasone (Pom-dex), a significantly shorter PFS than daratumumab, lenalidomide, and dexamethasone (DRd), and a PFS comparable to elotuzumab, lenalidomide, and dexamethasone (ERd) and carfilzomib, lenalidomide, and dexamethasone (KRd). IRd was associated with a significantly longer OS than V, Dex, and Pom-dex, and an OS comparable to Rd, ERd, KRd, and DRd. The ORR of IRd was significantly higher than Rd, V, and Dex, significantly lower than KRd and DRd, and comparable to Pom-dex and ERd. The extended network analyses and sensitivity analyses were consistent with the base case. This NMA shows that IRd is relatively efficacious among RRMM treatments. Being an oral regimen, IRd is also convenient to manage. IRd could be a preferable treatment option for many patients with RRMM, particularly those seeking an efficacious and convenient therapeutic option. [ABSTRACT FROM AUTHOR]

Background: While quadruplet induction therapies deepen responses in newly diagnosed multiple myeloma patients, their impact on peripheral blood stem cell (PBSC) collection remains incompletely understood. This analysis aims to evaluate the effects of prolonged lenalidomide induction and isatuximab- or elotuzumab-containing quadruplet induction therapies on PBSC mobilization and collection. Methods: A total of 179 transplant-eligible patients with newly diagnosed MM treated at a single academic center were included. The patients were evaluated based on PBSC mobilization and collection parameters, including overall collection results, CD34+ cell levels in peripheral blood, leukapheresis (LP) delays, overall number of LP sessions, and the rate of rescue mobilization with plerixafor. The patients underwent four different induction regimens: Lenalidomide, bortezomib, and dexamethasone (RVd, six 21-day cycles, n = 44), isatuximab-RVd (six 21-day cycles, n = 35), RVd (four 21-day cycles, n = 51), or elotuzumab-RVd (four 21-day cycles, n = 49). Results: The patients' characteristics were well balanced across the different groups. Collection failures, defined as the inability to collect three sufficient PBSC transplants, were rare (n = 3, 2%), with no occurrences in the isatuximab-RVd and elotuzumab-RVd groups. Intensified induction with six 21-day cycles of RVd did not negatively impact the overall number of collected PBSCs (9.7 × 106/kg bw versus 10.5 × 106/kg bw, p = 0.331) compared to four 21-day cycles of RVd. Plerixafor usage was more common after six cycles of RVd compared to four cycles (16% versus 8%). Addition of elotuzumab to RVd did not adversely affect overall PBSC collection (10.9 × 106/kg bw versus 10.5 × 106/kg bw, p = 0.915). Patients treated with isatuximab-RVd (six cycles) had lower numbers of collected stem cells compared to those receiving RVd (six cycles) induction (8.8 × 106/kg bw versus 9.7 × 106/kg bw, p = 0.801), without experiencing significant delays in LP or increased numbers of LP sessions in a multivariable logistic regression analysis. Plerixafor usage was more common after isatuximab plus RVd compared to RVd alone (34% versus 16%). Conclusions: This study demonstrates that stem cell collection is feasible after prolonged induction with isatuximab-RVd without collection failures and might be further explored as induction therapy. Trial registration: Patients were treated within the randomized phase III clinical trials GMMG-HD6 (NCT02495922, 24/06/2015) and GMMG-HD7 (NCT03617731, 24/07/2018). However, during stem cell mobilization and -collection, no study-specific therapeutic intervention was performed. [ABSTRACT FROM AUTHOR]

Simple Summary: High-dose therapy with melphalan followed by autologous stem cell transplantation and lenalidomide maintenance has long been the standard of care for newly diagnosed patients with multiple myeloma. However, it is unclear how lenalidomide dosage or experienced side effects govern patients' quality of life during long-term treatment. The LenaMain trial (NCT00891384) investigated lenalidomide maintenance at a high (25 mg) and a low dose (5 mg) and demonstrated that dosage had no impact on patients' quality of life. Instead, high baseline scores for global health were maintained throughout the trial without difference between treatment arms which supports the feasibility of continuous lenalidomide treatment with a dose tailored to patients' quality of life. Introduction: The LenaMain trial (NCT00891384) reported increased progression-free survival with 25 mg of lenalidomide maintenance compared to 5 mg. Here, we report the patient-reported outcomes. Materials and Methods: Scores obtained from the EORTC Quality of Life Questionnaire C30 were analyzed for longitudinal changes from baseline within the groups as well as cross-sectional scores. Results: Compliance rates were high, with 95.7% at baseline and 70% during maintenance. At study entry, scores were high for functioning and low for symptoms. During maintenance, the median global health status/quality of life (GHS/QoL) was constant, without significant differences over time (median GHS/QoL: 68 at baseline and 58 for Len high and 68 for Len low at 2 years) and between treatment arms (mean change < 2). Similarly, most functional scale domains were constant. Notably, diarrhea increased consistently for both treatment arms (baseline: −1.905 (range: −5.78–1.97); end of year 2: 16.071 (range: 5.72–26.42); p < 0.05). The subgroup analysis showed that neither disease activity, duration of treatment, nor adverse events affected the health-related quality of life (HR-QoL) or utility. Conclusion: High baseline scores were maintained throughout the trial without significant differences between the Len dosages, which supports continuous treatment with a dose tailored to patients' HR-QoL. [ABSTRACT FROM AUTHOR]

Posterior reversible encephalopathy syndrome (PRES) is a disorder of cerebrovascular dysregulation. To our knowledge, we present the first case of lenalidomide‐induced PRES in English. A 59‐year‐old woman with history of multiple myeloma status post stem cell transplant and induction triple therapy 6 months ago with partial remission and subsequent high‐dose melphalan 1 month ago presented with progressive vision loss for 1 week. Her systolic blood pressure was >180 mmHg, and neurological examination demonstrated decreased vision bilaterally. Brain MRI revealed significant T2 hyperintensity restricted to temporal and occipital lobes and left occipital parenchymal hemorrhage and diffuse leptomeningeal enhancement. She had a witnessed generalized tonic–clonic seizure and EEG that captured an electrographic seizure originating from the occipital lobe. Her vision improved rapidly after discontinuing the lenalidomide. She was discharged to rehab with a normal neurological examination. We report the first English case of presumed lenalidomide induced PRES in a patient undergoing multiple myeloma treatment. [ABSTRACT FROM AUTHOR]

This article discusses a case series on the use of lenalidomide for the prevention of recurrent erythema multiforme (EM). EM is a rare hypersensitivity reaction characterized by target lesions on the skin and involvement of multiple mucosae. The main causes of EM are infectious agents, particularly herpes simplex virus (HSV). The study included seven patients with recurrent EM who were treated with lenalidomide. The results showed that lenalidomide was effective in preventing EM recurrences in six of the seven patients, with no significant adverse effects. The study suggests that lenalidomide may be a promising option for the prevention of recurrent EM. [Extracted from the article]

Summary: Diffuse large B‐cell lymphoma (DLBCL) patients with relapsed or refractory (RR) disease have poor outcomes with current salvage regimens. We conducted a phase 2 trial to analyse the safety and efficacy of adding lenalidomide to R‐ESHAP (LR‐ESHAP) in patients with RR DLBCL. Subjects received 3 cycles of lenalidomide 10 mg/day on days 1–14 of every 21‐day cycle, in combination with R‐ESHAP at standard doses. Responding patients underwent autologous stem‐cell transplantation (ASCT). The primary endpoint was the overall response rate (ORR) after 3 cycles. Centralized cell‐of‐origin (COO) classification was performed. Forty‐six patients were included. The ORR after LR‐ESHAP was 67% (35% of patients achieved complete remission). Patients with primary refractory disease (n = 26) had significantly worse ORR than patients with non‐refractory disease (54% vs. 85%, p = 0.031). No differences in response rates according to the COO were observed. Twenty‐eight patients (61%) underwent ASCT. At a median follow‐up of 41 months, the estimated 3‐year PFS and OS were 42% and 48%, respectively. The most common grade ≥3 adverse events were thrombocytopenia (70% of patients), neutropenia (67%) and anaemia (35%). There were no treatment‐related deaths during LR‐ESHAP cycles. In conclusion, LR‐ESHAP is a feasible salvage regimen with promising efficacy results for patients with RR DLBCL. [ABSTRACT FROM AUTHOR]

Background: Bortezomib-melphalan-prednisone (VMP) and lenalidomide-dexamethasone (Rd) remain the standard treatments for transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). This study aimed to compare real-world benefits between the two regimens. We also were interested in exploring efficacy according to subsequent therapy following VMP or Rd. Methods: A total of 559 NDMM patients treated with VMP (n = 443, 79.2%) or Rd (n = 116, 20.8%) was recruited retrospectively from a multicenter database. Results: Rd provided more benefits than VMP—overall response rate: 92.2 vs. 81.8%, p = 0.018; median progression-free survival (PFS): 20.0 vs. 14.5 months, p <0.001; second PFS (PFS2): 43.9 vs. 36.9 months, p = 0.012; overall survival (OS): 100.1 vs. 85.0 months, p = 0.017. Multivariable analysis revealed significant benefits of Rd over VMP, with hazard ratios of 0.722, 0.627, and 0.586 for PFS, PFS2, and OS, respectively. In propensity score-matched cohorts with matched VMP (n = 201) and Rd (n = 67) arms to balance baseline characteristics, Rd still showed significantly better outcomes for PFS, PFS2, and OS than VMP. Following VMP failure, triplet therapy showed significant benefits for response and PFS2; after Rd failure, PFS2 with carfilzomib-dexamethasone was significantly better than bortezomib-based doublet treatment. Conclusion: These real-world findings may assist with better selection between VMP and Rd as well as subsequent therapy for NDMM. [ABSTRACT FROM AUTHOR]

Introduction: Autologous hematopoietic stem cell transplant is an important treatment modality used to achieve long-term remission in people with multiple myeloma. Complications include chemotherapy-related toxicity or infection. Rarely, clinical features consistent with autologous graft-versus-host disease, otherwise known as auto-aggression syndrome, is possible. Auto-aggression syndrome appears more commonly in patients with multiple myeloma, hypothesized to be a result of underlying immune dysregulation, conditioning chemotherapy, or treatment with immunomodulating agents. Case report: A 66-year-old female with multiple myeloma underwent an autologous stem cell transplant with melphalan conditioning chemotherapy followed by maintenance therapy with lenalidomide. Transplant was complicated by engraftment syndrome versus auto-aggression syndrome. After lenalidomide maintenance therapy initiation, she required hospitalization for auto-aggression syndrome. Management and outcome: Auto-aggression syndrome with gastrointestinal, hepatic, and dermatologic involvement as demonstrated by skin punch biopsy, elevated reg3α, ST2, elafin, eosinophilia, transaminitis, and persistent diarrhea beyond the engraftment period were noted. Topical and systemic steroids with a prolonged taper resulted in symptom resolution. Discussion: Acute graft-versus-host disease is a complication once considered unique to allogeneic stem cell transplant recipients, but a similar syndrome termed "auto-aggression syndrome" may be seen following autologous transplant. Auto-aggression syndrome should be suspected when complications extend beyond the normal engraftment syndrome period following autologous transplant, particularly in people with multiple myeloma, and/or those who have received prior immunomodulating therapy. There should be a low threshold for obtaining biopsies in the setting of suspected auto-aggression syndrome. Early recognition and prompt initiation of corticosteroids with prolonged tapers may prevent auto-aggression syndrome relapse and readmissions. [ABSTRACT FROM AUTHOR]

Background: For patients with multiple myeloma (MM) who have undergone autologous stem cell transplant (auto-SCT), the immunomodulatory agent lenalidomide is a first-line option for maintenance therapy. Because longer durations of lenalidomide maintenance are associated with improved survival, identifying strategies to avoid premature cessation of maintenance is an important priority in the post-transplant setting. Objectives: The primary objective of this analysis was to identify specific clinical predictors of lenalidomide treatment duration that could guide optimal medication management. Key secondary objectives included predictors of intolerable toxicity, rationale for lenalidomide dose reduction/discontinuation, and characterization of dose adjustments. Study Design: This retrospective, multi-center cohort study included adults with MM who underwent auto-SCT and initiated maintenance lenalidomide between 01/01/2012 and 02/28/2021. Variables assessed as potential predictors of maintenance duration or intolerable toxicity included age, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status at time of auto-SCT, renal function, initial lenalidomide dose, use of combination maintenance therapy, and cytogenetic risk category. Results: Among 299 patients included, the median age at time of auto-SCT was 62 years (range 30–77). The majority of patients had standard-risk cytogenetics (64%) and an ECOG performance status of 0 or 1 (72%). In the overall population, the median duration of maintenance was 1.3 years (range 0.3–8.6 years). The median initial dose of lenalidomide was 10 mg daily (range 2.5–25 mg). During the study period, 35% of patients had a dose reduction due to toxicity, 21% stopped lenalidomide due to disease progression, and 19% stopped due to toxicity. Multivariate linear regression analyses did not identify any significant predictors of lenalidomide duration or discontinuation due to intolerable toxicity. The most frequently reported toxicities leading to discontinuation were cytopenias, rash, and fatigue. Conclusion: This analysis did not identify any significant risk factors to predict the duration of lenalidomide maintenance or discontinuation for toxicity following auto-SCT in patients with MM. While limited by the retrospective design and relatively small sample size, our findings suggest that a priori lenalidomide dose reductions based on patient co-morbidities or performance status may not substantially affect the duration of lenalidomide maintenance. [ABSTRACT FROM AUTHOR]

Background: Carfilzomib is a selective proteasome inhibitor approved for treating relapsed or refractory multiple myeloma (RRMM). Carfilzomib improves overall survival (OS) and progression‐free survival (PFS); however, treatment with carfilzomib results in a higher incidence of cardiovascular and renal toxicity. More than 70% of patients with RRMM in clinical practice do not meet the eligibility criteria for randomized clinical trials (RCT). OS and PFS are negatively influenced by complications, concomitant medications and prior treatments. Therefore, we assessed the risk factors influencing the OS and time to next treatment (TTNT) in the real world. TTNT has emerged as a relevant alternative clinical endpoint to PFS. Methods: A retrospective analysis of a large claims database prepared during the post‐marketing stages in Japan was performed. The patients treated with carfilzomib for the first time were identified. Multivariable Cox proportional hazards regression analysis was performed to evaluate the risk factors influencing OS and TTNT following carfilzomib treatment. Results: A total of 732 patients with RRMM who received carfilzomib‐containing chemotherapy between April 2014 and September 2021 were identified. Multivariable Cox regression analysis for OS and TTNT showed a significantly higher hazard ratio (HR) of 1.48 (95% confidence interval [Cl]: 1.10–2.00; p = 0.010) and 1.38 (95% Cl: 1.15–1.65; p < 0.001), respectively, for patients with renal impairment compared to those without renal impairment. Multivariable Cox regression analysis for OS and TTNT showed a significantly higher HR of 1.80 (95% Cl: 1.27–2.55; p = 0.0010) and 1.38 (95% Cl: 1.14–1.66; p < 0.001), respectively, for patients with prior lenalidomide treatment compared to those without prior lenalidomide treatment. Conclusion: Complication of renal impairment and prior lenalidomide treatment could be risk factors influencing OS and TTNT during carfilzomib treatment. [ABSTRACT FROM AUTHOR]

In this issue of Leukemia & Lymphoma, Arribas et al. describe 3 cases of acute lymphoblastic leukemia (ALL) arising post lenalidomide maintenance following autologous stem cell transplantation (ASCT) for the treatment of multiple myeloma (MM) [[1]]. Further evidence is required to determine whether an MRD-guided treatment cessation strategy is applicable to patients with high-risk cytogenetic markers as well as to the transplant-ineligible and relapsed myeloma cohorts on lenalidomide maintenance. Clinical correlates and prognostic impact of clonal hematopoiesis in multiple myeloma patients receiving post-autologous stem cell transplantation lenalidomide maintenance therapy. Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the myeloma XI trial. [Extracted from the article]

In young patients, autologous stem cell transplantation (ASCT) is considered the standard of care consolidation strategy after first-line therapy followed by maintenance therapy with lenalidomide (LEN) which has been demonstrated to delay disease relapse/progression [[3], [5]]. B-cell acute lymphoblastic leukemia after lenalidomide maintenance therapy; a deleterious adverse event that needs further investigation. Parrondo et al. reported 14 cases of ALL after MM and compared them to 56 patients with non-MM therapy-related ALL in terms of biological characteristics, treatment outcomes and survival. Unique characteristics and outcomes of therapy-related acute lymphoblastic leukemia following treatment for multiple myeloma. [Extracted from the article]

Lenalidomide, a well-established drug for the treatment of multiple myeloma, significantly enhances patients' survival. Previous clinical studies have demonstrated that its main side effect is an increased risk of thrombotic events. However, the underlying mechanism remains unexplored. Therefore, this study aims to elucidate the mechanism and offer insights into the selection of clinical thrombotic prophylaxis drugs. Firstly, we conducted a retrospective analysis of clinical data from 169 newly diagnosed multiple myeloma patients who received lenalidomide. To confirm the impact of lenalidomide on thrombosis formation, FeCl3-induced thrombosis and deep venous thrombosis models in mice were established. To investigate the effects of lenalidomide on platelet function, both in vivo and in vitro experiments were designed. During the follow-up period, 8 patients developed thrombotic events, including 8 venous and 1 arterial. Further investigation using mice models demonstrated that lenalidomide significantly promoted the formation of venous thrombosis, consistent with clinical findings. To elucidate the underlying mechanism, assays were conducted to assess platelet function and coagulation. We observed that lenalidomide did not have any noticeable impact on platelet function, both in vitro and in vivo, while administration of lenalidomide resulted in significant decreases in prothrombin time, thrombin time, and prothrombin time ratio in patients, as well as a remarkable reduction in tail-bleeding time in mice. The administration of lenalidomide had no significant impact on platelet function, which may affect venous thrombus formation by affecting coagulation. Therefore, anticoagulant drugs may be superior to antiplatelet drugs in the selection of clinical thrombus prophylaxis. [ABSTRACT FROM AUTHOR]