Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma.

BACKGROUND: The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown. METHODS: We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles. RESULTS: In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively. CONCLUSIONS: Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).

Predictors of unsustained measurable residual disease negativity in patients with multiple myeloma.

ABSTRACT: The prognostic impact of achieving and in particular maintaining measurable residual disease (MRD) negativity in multiple myeloma is now established; therefore, identifying among MRD-negative patients the ones at higher risk of losing MRD negativity is of importance. We analyzed predictors of unsustained MRD negativity in patients enrolled in the FORTE trial (NCT02203643). MRD was performed by multiparameter flow cytometry (sensitivity of 10-5) at premaintenance and every 6 months thereafter. The cumulative incidence (CI) of MRD resurgence and/or progression was analyzed in MRD-negative patients. A total of 306 of 474 (65%) MRD-negative patients were analyzed. After a median follow-up of 50.4 months from MRD negativity, 185 of 306 (60%) patients were still MRD negative and progression free, 118 (39%) lost their MRD-negative status, and 3 patients (1%) died without progression. Amp1q vs normal (4-year CI, 63% vs 34), ≥2 concomitant high-risk cytogenetic abnormalities vs 0 (4-year CI, 59% vs 33%), circulating tumor cells at baseline (high vs low at 4-year CI, 62% vs 32%), and time-to-reach MRD negativity postconsolidation vs preconsolidation (4-year CI, 46% vs 35%) were associated with a higher risk of unsustained MRD negativity in a multivariate Fine-Gray model. During the first 2 years of maintenance, patients receiving carfilzomib-lenalidomide vs lenalidomide alone had a lower risk of unsustained MRD negativity (4-year CI, 20% vs 33%).

Mezigdomide is effective alone and in combination with menin inhibition in preclinical models of KMT2A-r and NPM1c AML.

ABSTRACT: Small molecules that target the menin-KMT2A protein-protein interaction (menin inhibitors) have recently entered clinical trials in lysine methyltransferase 2A (KMT2A or MLL1)-rearranged (KMT2A-r) and nucleophosmin-mutant (NPM1c) acute myeloid leukemia (AML) and are demonstrating encouraging results. However, rationally chosen combination therapy is needed to improve responses and prevent resistance. We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with lenalidomide or iberdomide has modest single-agent activity yet can synergize with menin inhibitors. Recently, the novel IKAROS degrader mezigdomide was developed with greatly enhanced IKAROS protein degradation. In this study, we show that mezigdomide has increased preclinical activity in vitro as a single-agent in KMT2A-r and NPM1c AML cell lines, including sensitivity in cell lines resistant to lenalidomide and iberdomide. Further, we demonstrate that mezigdomide has the greatest capacity to synergize with and induce apoptosis in combination with menin inhibitors, including in MEN1 mutant models. We show that the superior activity of mezigdomide compared with lenalidomide or iberdomide is due to its increased depth, rate, and duration of IKAROS protein degradation. Single-agent mezigdomide was efficacious in 5 patient-derived xenograft models of KMT2A-r and 1 NPM1c AML. The combination of mezigdomide with the menin inhibitor VTP-50469 increased survival and prevented and overcame MEN1 mutations that mediate resistance in patients receiving menin inhibitor monotherapy. These results support prioritization of mezigdomide for early phase clinical trials in KMT2A-r and NPM1c AML, either as a single agent or in combination with menin inhibitors.

Mass spectrometry-based assessment of M protein in peripheral blood during maintenance therapy in multiple myeloma.

ABSTRACT: Mass spectrometry (MS) can detect multiple myeloma-derived monoclonal proteins in the peripheral blood (PB) with high sensitivity, potentially serving as a PB assay for measurable residual disease (MRD). This study evaluated the significance of PB MS MRD negativity during posttransplant therapy in patients with newly diagnosed multiple myeloma. Serum samples from 138 patients treated in the phase 3 ATLAS trial of posttransplant maintenance with either carfilzomib, lenalidomide, and dexamethasone, or with lenalidomide alone were analyzed using EXENT MS methodology. We established feasibility of measuring MRD by MS in the PB in the posttransplant setting, despite unavailability of pretreatment calibration samples. There was high agreement between MRD by MS in the PB and paired bone marrow (BM) MRD results at the 10-5 threshold, assessed by either next-generation sequencing (NGS) or multiparameter flow cytometry (MFC) (70% and 67%, respectively). Agreement between PB MS and both BM MRD methods was lowest early after transplant and increased with time. MS negativity was associated with improved progression-free survival (PFS), which, in landmark analysis, reached statistical significance after 18 cycles after transplant. Combined PB/BM MRD negativity by MFC or NGS was associated with superior PFS compared with MRD negativity by only 1 modality. Sustained MS negativity carried similar prognostic performance to sustained BM MRD negativity at the 10-5 threshold. Overall, posttransplant MS assessment was feasible and provided additional prognostic information to BM MRD negativity. Further studies are needed to confirm the role and optimal timing of MS in disease evaluation algorithms. The ATLAS trial is registered at www.clinicaltrials.gov as #NCT02659293.

ctDNA improves prognostic prediction for patients with relapsed/refractory MM receiving ixazomib, lenalidomide, and dexamethasone.

ABSTRACT: It remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed/refractory multiple myeloma (RRMM). Here, we performed targeted-capture sequencing using bone marrow plasma cells (BMPCs) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis-associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, whereas KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the 6 relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and ≥2 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index, classifying patients into 3 categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM. This study is a part of the C16042 study, which is registered at www.clinicaltrials.gov as #NCT03433001.

Daratumumab, carfilzomib, lenalidomide, and dexamethasone with tandem transplant for high-risk newly diagnosed myeloma.

ABSTRACT: High-risk (HR) cytogenetics are associated with poor outcomes in newly diagnosed multiple myeloma (NDMM), and dedicated studies should address this difficult-to-treat population. The phase 2 study 2018-04 from the Intergroupe Francophone du Myelome evaluated feasibility of an intensive strategy with quadruplet induction and consolidation plus tandem transplant in HR transplant-eligible (TE) NDMM. HR cytogenetics were defined by presence of del(17p), t(4;14), and/or t(14;16). Treatment consisted of daratumumab-carfilzomib-lenalidomide-dexamethasone (D-KRd) induction, autologous stem cell transplantation (ASCT), D-KRd consolidation, second ASCT, and daratumumab-lenalidomide maintenance. The primary end point was feasibility. Fifty patients with previously untreated NDMM were included. Median age was 57. Del(17p), t(4;14), and t(14;16) were found in 40%, 52%, and 20% of patients, respectively. At data cutoff, the study met the primary end point with 36 patients completing second transplant. Twenty patients discontinued the study due to stem cell collection failure (n = 8), disease progression (n = 7), adverse event (n = 4), or consent withdrawal (n = 1). Grade 3 to 4 D-KRd induction/consolidation-related adverse events (>5% of patients) were neutropenia (39%), anemia (12%), thrombocytopenia (7%), and infection (6%). The overall response rate was 100% for patients completing second transplant, including 81% complete response. Premaintenance minimal residual disease (MRD) negativity rate (10-6) was 94%. After a median follow-up of 33 months, the 30-month progression-free survival (PFS) and overall survival were 80% and 91%, respectively. In conclusion, D-KRd with tandem transplant is feasible in patients with HR TE-NDMM and resulted in high response rates and PFS. This trial was registered at www.clinicaltrials.gov as #NCT03606577.

Randomized study of induction with bendamustine-rituximab ± bortezomib and maintenance with rituximab ± lenalidomide for MCL.

ABSTRACT: Although initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine plus rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance after induction is often used. Thus, the open-label, randomized phase 2 ECOG-ACRIN Cancer Research Group E1411 trial was designed to test 2 questions: (1) does addition of bortezomib to BR induction (BVR) and/or (2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012 to 2016, 373 previously untreated patients, 87% aged ≥60 years, were enrolled in this trial. At a median follow-up of 7.5 years, there is no difference in the median PFS of BR compared with BVR (5.5 vs 6.4 years; hazard ratio [HR], 0.90; 90% confidence interval [CI], 0.70-1.16). There were no unexpected additional toxicities with BVR treatment compared with BR, with no impact on total dose/duration of treatment received. Independent of the induction treatment, addition of lenalidomide did not significantly improve PFS, with median PFS in R vs LR (5.9 vs 7.2 years; HR, 0.84; 90% CI, 0.62-1.15). Most patients completed the planned 24 cycles of LR at the scheduled dose. In summary, adding bortezomib to BR induction does not prolong PFS in treatment-naïve MCL, and LR maintenance was not associated with longer PFS compared with R alone after BR. Nonetheless, the >5-year median PFS outcomes in this prospective cooperative group trial indicate the efficacy of BR followed by R maintenance as highly effective initial therapy for older patients with MCL. This trial was registered at www.clinicaltrials.gov as #NCT01415752.

Lenalidomide and dexamethasone maintenance with or without ixazomib, tailored by residual disease status in myeloma.

From November 2014 to May 2017, 332 patients homogeneously treated with bortezomib, lenalidomide, and dexamethasone (VRD) induction, autologous stem cell transplant, and VRD consolidation were randomly assigned to receive maintenance therapy with lenalidomide and dexamethasone (RD; 161 patients) vs RD plus ixazomib (IRD; 171 patients). RD consisted of lenalidomide 15 mg/d from days 1 to 21 plus dexamethasone 20 mg/d on days 1 to 4 and 9 to 12 at 4-week intervals, whereas in the IRD arm, oral ixazomib at a dose of 4 mg on days 1, 8, and 15 was added. Therapy for patients with negative measurable residual disease (MRD) after 24 cycles was discontinued, whereas those who tested positive for MRD remained on maintenance with RD for 36 more cycles. After a median follow-up of 69 months from the initiation of maintenance, the progression-free survival (PFS) was similar in both arms, with a 6-year PFS rate of 61.3% and 55.6% for RD and IRD, respectively (hazard ratio, 1.136; 95% confidence interval, 0.809-1.603). After 2 years of maintenance, treatment was discontinued in 163 patients with negative MRD, whereas 63 patients with positive MRD continued with RD therapy. Maintenance discontinuation in patients tested negative for MRD resulted in a low progression rate (17.2% at 4 years), even in patients with high-risk features. In summary, our results show the efficacy of RD maintenance and support the safety of maintenance therapy discontinuation in patients with negative MRD at 2 years. This trial was registered at www.clinicaltrials.gov as #NCT02406144 and at EudraCT as 2014-00055410.

Clinical decision-making and treatment of myelodysplastic syndromes.

ABSTRACT: The myelodysplastic syndromes (MDSs) constitute a profoundly heterogeneous myeloid malignancy with a common origin in the hemopoietic stem cell compartment. Consequently, patient management and treatment are as heterogeneous. Decision-making includes identifying risk, symptoms, and options for an individual and conducting a risk-benefit analysis. The only potential cure is allogeneic stem cell transplantation, and albeit the fraction of patients with MDS who undergo transplant increase over time because of better management and increased donor availability, a majority are not eligible for this intervention. Current challenges encompass to decrease the relapse risk, the main cause of hematopoietic stem cell transplantation failure. Hypomethylating agents (HMAs) constitute firstline treatment for higher-risk MDSs. Combinations with other drugs as firstline treatment has, to date, not proven more efficacious than monotherapy, although combinations approved for acute myeloid leukemia, including venetoclax, are under evaluation and often used as rescue treatment. The treatment goal for lower-risk MDS is to improve cytopenia, mainly anemia, quality of life, and, possibly, overall survival. Erythropoiesis-stimulating agents (ESAs) constitute firstline treatment for anemia and have better and more durable responses if initiated before the onset of a permanent transfusion need. Treatment in case of ESA failure or ineligibility should be tailored to the main disease mechanism: immunosuppression for hypoplastic MDS without high-risk genetics, lenalidomide for low-risk del(5q) MDS, and luspatercept for MDS with ring sideroblasts. Approved therapeutic options are still scarcer for MDS than for most other hematologic malignancies. Better tools to match disease biology with treatment, that is, applied precision medicines are needed to improve patient outcome.

Lenalidomide plus rituximab for the initial treatment of frail older patients with DLBCL: the FIL_ReRi phase 2 study.

Treatment of diffuse large B-cell lymphoma (DLBCL) in older patients is challenging, especially for those who are not eligible for anthracycline-containing regimens. Fondazione Italiana Linfomi (FIL) started the FIL_ReRi study, a 2-stage single-arm trial to investigate the activity and safety of the chemo-free combination of rituximab and lenalidomide (R2) in ≥70-year-old untreated frail patients with DLBCL. Frailty was prospectively defined using a simplified geriatric assessment tool. Patients were administered a maximum of 6 28-day cycles of 20 mg oral lenalidomide from days 2 to 22 and IV rituximab 375 mg/m2 on day 1, with response assessment after cycles 4 and 6. Patients with partial response or complete response (CR) at cycle 6 were administered lenalidomide 10 mg/d from days 1 to 21 for every 28 cycles for a total of 12 cycles or until progression or unacceptable toxicity. The primary end point was the overall response rate (ORR) after cycle 6; the coprimary end point was the rate of grade 3 or 4 extrahematological toxicity. The ORR was 50.8%, with 27.7% CR. After a median follow-up of 24 months, the median progression-free survival was 14 months, and the 2-year duration of response was 64%. Thirty-four patients experienced extrahematological toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥3. The activity of the R2 combination was observed in a significant proportion of subjects, warranting further exploration of a chemo-free approach in frail older patients with DLBCL. This trial was registered at EudraCT as #2015-003371-29 and clinicaltrials.gov as #NCT02955823.

Tafasitamab and lenalidomide in large B-cell lymphoma: real-world outcomes in a multicenter retrospective study.

ABSTRACT: In this real-world evaluation of tafasitamab-lenalidomide (TL) in relapsed or refractory LBCL, patients receiving TL had higher rates of comorbidities and high-risk disease characteristics, and substantially lower progression-free survival and overall survival, compared with the L-MIND registration clinical trial for TL.

Safety and efficacy of tafasitamab with or without lenalidomide added to first-line R-CHOP for DLBCL: the phase 1b First-MIND study.

Anti-CD19 immunotherapy tafasitamab is used in combination with lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant. Open-label, phase 1b, First-MIND study assessed safety and preliminary efficacy of tafasitamab + R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) ± lenalidomide as first-line therapy in patients with DLBCL. From December 2019 to August 2020, 83 adults with untreated DLBCL (International Prognostic Index 2-5) were screened and 66 were randomly assigned (33 per arm) to R-CHOP-tafasitamab (arm T) or R-CHOP-tafasitamab-lenalidomide (arm T/L) for 6 cycles. Primary end point was safety; secondary end points included end-of-treatment (EoT) overall response rate (ORR) and complete response (CR) rate. All patients had ≥1 treatment-emergent adverse event, mostly grade 1 or 2. Grade ≥3 neutropenia and thrombocytopenia occurred, respectively, in 57.6% and 12.1% (arm T) and 84.8% and 36.4% (arm T/L) of patients. Nonhematologic toxicities occurred at similar rates among arms. R-CHOP mean relative dose intensity was ≥89% in both arms. EoT ORR was 75.8% (CR 72.7%) in arm T and 81.8% (CR 66.7%) in arm T/L; best ORR across visits was 90.0% and 93.9%. Eighteen-month duration of response and of CR rates were 72.7% and 74.5% (arm T) and 78.7% and 86.5% (arm T/L); 24-month progression-free and overall survival rates were 72.7% and 90.3% (arm T) and 76.8% and 93.8% (arm T/L). Manageable safety and promising signals of efficacy were observed in both arms. Potential benefit of adding tafasitamab + lenalidomide to R-CHOP is being investigated in phase 3 frontMIND (NCT04824092). This study is registered at www.clinicaltrials.gov as #NCT04134936.

High-dose melphalan treatment significantly increases mutational burden at relapse in multiple myeloma.

High-dose melphalan (HDM) improves progression-free survival in multiple myeloma (MM), yet melphalan is a DNA-damaging alkylating agent; therefore, we assessed its mutational effect on surviving myeloma cells by analyzing paired MM samples collected at diagnosis and relapse in the IFM 2009 study. We performed deep whole-genome sequencing on samples from 68 patients, 43 of whom were treated with RVD (lenalidomide, bortezomib, and dexamethasone) and 25 with RVD + HDM. Although the number of mutations was similar at diagnosis in both groups (7137 vs 7230; P = .67), the HDM group had significantly more mutations at relapse (9242 vs 13 383, P = .005). No change in the frequency of copy number alterations or structural variants was observed. The newly acquired mutations were typically associated with DNA damage and double-stranded breaks and were predominantly on the transcribed strand. A machine learning model, using this unique pattern, predicted patients who would receive HDM with high sensitivity, specificity, and positive prediction value. Clonal evolution analysis showed that all patients treated with HDM had clonal selection, whereas a static progression was observed with RVD. A significantly higher percentage of mutations were subclonal in the HDM cohort. Intriguingly, patients treated with HDM who achieved complete remission (CR) had significantly more mutations at relapse yet had similar survival rates as those treated with RVD who achieved CR. This similarity could have been due to HDM relapse samples having significantly more neoantigens. Overall, our study identifies increased genomic changes associated with HDM and provides rationale to further understand clonal complexity.

Optimizing the value of lenalidomide maintenance by extended genetic profiling: an analysis of 556 patients in the Myeloma XI trial.

Prediction of individual patient benefit from lenalidomide (Len) maintenance after autologous stem cell transplant (ASCT) remains challenging. Here, we investigated extended molecular profiling for outcome prediction in patients in the National Cancer Research Institute Myeloma XI (MyXI) trial. Patients in the MyXI trial randomized to Len maintenance or observation after ASCT were genetically profiled for t(4;14), t(14;16), t(14;20), del(1p), gain(1q), and del(17p) and co-occurrence of risk markers was computed. Progression-free survival (PFS), subsequent progression (PFS2), and overall survival (OS) were calculated from maintenance randomization, and groups were compared using Cox proportional hazards regression. Of 556 patients, 17% with double-hit multiple myeloma (MM) (≥2 risk markers), 32% with single-hit (1 risk marker), and 51% without risk markers were analyzed. Single-hit MM derived the highest PFS benefit from Len maintenance, specifically, isolated del(1p), del(17p), and t(4;14), with ∼40-fold, 10-fold, and sevenfold reduced risk of progression or death (PFS), respectively, compared with observation. This benefit translated into improved PFS2 and OS for this group of patients compared with observation; median PFS was 10.9 vs 57.3 months for observation vs Len maintenance. Patients with isolated gain(1q) derived no benefit, and double-hit MM limited benefit (regardless or risk lesions involved) from Len maintenance. Extended genetic profiling identifies patients deriving exceptional benefit from Len maintenance and should be considered for newly diagnosed patients to support management discussions along their treatment pathway. This trial was registered at www.isrctn.com/ISRCTN49407852 as # ISRCTN49407852.

Whole-genome analysis identifies novel drivers and high-risk double-hit events in relapsed/refractory myeloma.

Large-scale analyses of genomic data from patients with newly diagnosed multiple myeloma (ndMM) have been undertaken, however, large-scale analysis of relapsed/refractory MM (rrMM) has not been performed. We hypothesize that somatic variants chronicle the therapeutic exposures and clonal structure of myeloma from ndMM to rrMM stages. We generated whole-genome sequencing (WGS) data from 418 tumors (386 patients) derived from 6 rrMM clinical trials and compared them with WGS from 198 unrelated patients with ndMM in a population-based case-control fashion. We identified significantly enriched events at the rrMM stage, including drivers (DUOX2, EZH2, TP53), biallelic inactivation (TP53), noncoding mutations in bona fide drivers (TP53BP1, BLM), copy number aberrations (CNAs; 1qGain, 17pLOH), and double-hit events (Amp1q-ISS3, 1qGain-17p loss-of-heterozygosity). Mutational signature analysis identified a subclonal defective mismatch repair signature enriched in rrMM and highly active in high mutation burden tumors, a likely feature of therapy-associated expanding subclones. Further analysis focused on the association of genomic aberrations enriched at different stages of resistance to immunomodulatory agent (IMiD)-based therapy. This analysis revealed that TP53, DUOX2, 1qGain, and 17p loss-of-heterozygosity increased in prevalence from ndMM to lenalidomide resistant (LENR) to pomalidomide resistant (POMR) stages, whereas enrichment of MAML3 along with immunoglobulin lambda (IGL) and MYC translocations distinguished POM from the LEN subgroup. Genomic drivers associated with rrMM are those that confer clonal selective advantage under therapeutic pressure. Their role in therapy evasion should be further evaluated in longitudinal patient samples, to confirm these associations with the evolution of clinical resistance and to identify molecular subsets of rrMM for the development of targeted therapies.

Autologous HSCT with novel agent-based induction and consolidation followed by lenalidomide maintenance for untreated multiple myeloma.

Triplet regimen comprising proteasome inhibitors, immunomodulatory drugs, and dexamethasone (DEX) is a recommended induction/consolidation therapy for multiple myeloma (MM) patients eligible for transplant. In this Japanese phase II study conducted from 2017 to 2019, newly diagnosed MM patients aged 20-65 received four induction cycles with bortezomib (Bor), lenalidomide (Len), and DEX (VRD), followed by Bor and high-dose melphalan with autologous stem cell rescue. Subsequently, they underwent four consolidation cycles with carfilzomib, Len, and DEX (KRD), followed by Len maintenance until disease progression. A total of 141 patients were analyzed. In an intent-to-treat population, the complete or better response post induction was 19.9%, rising to 39.7%, 58.9%, and 62.4% after transplant, consolidation, and 1-year maintenance, respectively. With a median follow-up of 38 months, the 3-year progression-free survival (PFS) rate was 83.5% and the 3-year overall survival rate was 92.5%. Severe adverse events (≥grade 3) occurred in ~30% of patients; however, there was no treatment-related mortality. These findings clearly showed the tolerability and effectiveness of this protocol. Nevertheless, patients with high-risk cytogenetics showed a trend toward lower 3-year PFS than those without (77.8% vs. 89.4%, p = 0.051), and ultra-high-risk cytogenetics (≥2 high-risk cytogenetics) had an even worse prognosis, with 61.2% 3-year PFS. To overcome this situation, a more potent treatment strategy incorporating novel agents such as the CD38-antibody should be assessed in future studies.

Safety and efficacy of ibrutinib in combination with rituximab and lenalidomide in previously untreated follicular and marginal zone lymphoma: An open label, phase 2 study.

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).

A randomised evaluation of low-dose cytosine arabinoside plus lenalidomide versus single-agent low-dose cytosine arabinoside in older patients with acute myeloid leukaemia: Results from the LI-1 trial.

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.

Multiple myeloma refractory to lenalidomide: A systematic literature review of trials and real-world evidence.

The growing use of frontline lenalidomide treatment in multiple myeloma (MM) is increasing the proportion of lenalidomide-refractory patients, which may limit the efficacy of subsequent lines of treatment (LOT). This systematic literature review (January 2008-October 2023) of clinical trials (CT) and real-world studies (RW) assessed treatment outcomes in adults with relapsed/refractory MM (RRMM) who were previously treated with ≥1 LOT, progressed and were lenalidomide-refractory. Medline, EMBASE and additional electronic databases were searched for articles published in English. Primary outcomes included progression-free survival (PFS), overall survival (OS) and overall/objective response rate (ORR); 24 CT and 19 RW were included. For CT, the population-weighted mean of median PFS (CT = 14) and OS (CT = 6) were shorter in the lenalidomide-refractory cohort (months: 8.8 [n = 2699] and 21.7 [n = 1066], respectively) than the intent-to-treat population (months: 13.8 [n = 5380] and 35.9 [n = 2264], respectively); the population-weighted (N = 2142) mean ORR for lenalidomide-refractory patients (CT = 18) was 56.0%. RW reported considerable variation in PFS (RW = 7), OS (RW = 8) and ORR (RW = 8); and median PFS (RW = 2; months) was lower in lenalidomide/bortezomib-refractory (5.5/5.5; n = 81/n = 25) versus lenalidomide-refractory (7.3/8.0; n = 81/n = 61) patients. These data provide evidence that clinical trials and real-world outcomes are suboptimal in lenalidomide-refractory patients with RRMM, highlighting the need to improve treatment options for this population.

Decreased RNA-binding protein heterogeneous nuclear ribonucleoprotein U improves multiple myeloma sensitivity to lenalidomide.

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.