Immunomodulatory Agent Lenalidomide Research Articles

A Phase I Trial Evaluating the Addition of Lenalidomide to Patients with Relapsed/Refractory Multiple Myeloma Progressing on Ruxolitinib and Methylprednisolone.

Ruxolitinib (RUX), an orally administered selective Janus kinase 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both pre-clinically and clinically. This study aims to evaluate whether LEN can achieve clinical activity among patients with multiple myeloma progressing on the combination of RUX and methylprednisolone (MP). In this part of a phase I, multicenter, open-label study, we evaluated the safety and efficacy of RUX and MP for patients with multiple myeloma with progressive disease who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens; we also determined the safety and efficacy of adding LEN at the time of disease progression from the initial doublet treatment. Initially, all subjects received oral RUX 15 mg twice daily and oral MP 40 mg every other day. Those patients who developed progressive disease according to the International Myeloma Working Group criteria then received LEN 10 mg once daily on days 1-21 within a 28-day cycle in addition to RUX and MP, which were administered at the same doses these patients were receiving at the time progressive disease developed. Twenty-nine subjects (median age 64 years; 18 [62%] male) were enrolled in this part of the study and initially received the two-drug combination of RUX and MP. The median number of prior therapies was six (range 3-12). The overall response rate from this two-drug combination was 31% and the clinical benefit rate was 34%. The best responses were 1 very good partial response, 8 partial responses, 1 minor response, 12 stable disease, and 7 progressive disease. The median progression-free survival was 3.5 months (range 0.5-36.2months). The median time to response was 3.0 months. The median duration of response was 12.5 months (range 2.8-36.2 months). Twenty (69%) patients whoshowed progressive disease had LEN added to RUX and MP; all patients had prior exposure to LEN and all but one patient was refractory to their last LEN-containing regimen. After the addition of LEN, the overall response rate was 30% and the clinical benefit rate was 40%. The best responses of patients following the addition of LEN were 2 very good partial responses, 4 partial responses, 2 minor responses, 8 stable disease, and 4 progressive disease. The median time to response was 2.6 months (range 0.7-15.0 months). The median duration of response was not reached. The median progression-free survival following the addition of LEN was 3.5 months (range 0.3-25.9 months). For patients with multiple myeloma, treatment with RUX and MP is effective and well tolerated, and LEN can be used to extend the benefit of this RUX-based treatment. This study is registered with ClinicalTrials.gov, NCT03110822, and is ongoing.

A Phase 1 Trial Evaluating the Addition of Lenalidomide to Relapsed/Refractory Multiple Myeloma Patients Progressing on Ruxolitinib and Methylprednisolone

Background Ruxolitinib (RUX), an orally administered selective JAK 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma (MM) effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both preclinically and clinically. Although we have previously demonstrated that LEN and steroid refractory MM patients respond to the addition of RUX, no studies have evaluated whether LEN can achieve clinical activity among those progressing on the combination of RUX and methylprednisolone. Methods Patients included those with MM showing progressive disease (PD) who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens. Initially, subjects received oral RUX 15 mg twice daily and oral methylprednisolone 40 mg every other day. Those patients who developed PD according to International Myeloma Working Group criteria had LEN 10 mg once daily days 1-21 on a 28-day cycle added to RUX and methylprednisolone which were administered at the same doses they were receiving at the time of PD. Results A total of 29 subjects were enrolled and initially received the combination of RUX and methylprednisolone. Follow up was until June 30, 2023. The median number of prior therapies was 6 (range, 3-12). The overall response rate (ORR) was 31% and the clinical benefit rate (CBR) was 34%. The best responses were 1 very good partial response (VGPR), 8 partial responses (PR), 1 minor response (MR), 12 stable disease (SD), and 7 PD. The median progression-free survival (PFS) was 3.5 mo (range, 0.5-36.2 mo). The median time to response was 3.0 mo (n=10). The median duration of response (DOR) was 12.5 mo (range, 2.8-36.2 mo). Twenty (69%) showed PD and had LEN added to the RUX and methylprednisolone combination: all of these patients were refractory to their last LEN-containing regimen. After the addition of LEN, the ORR was 30% and CBR was 40%. The best responses of patients following the addition of LEN were 2 VGPR, 4 PR, 2 MR, 8 SD, and 4 PD. The majority of patients (71%) who initially achieved a > MR to the two-drug combination responded following the addition of LEN whereas only 23% of patients who did not initially achieve a > MR responded to the addition of the third drug. The median time to response was 2.6 mo (range, 0.7-15 mo). The median DOR was undefined (range, 1.2-10.9 mo). The median PFS was 3.5 mo (range, 0.3-25.9 mo). The median PFS2 (including time from first treatment to end of study or June 30, 2023) was 7.3 mo (range, 0.5-39.9). Treatment was well tolerated with no additional toxicity identified following the addition of LEN. Interestingly, PFS2 was predicted by the patient's baseline serum B-cell maturation level; patients with values above the median (128 ng/mL) had significantly shorter PFS2 than those below it (3.5 mo vs. undefined, p = 0.0337). Conclusion The addition of LEN to heavily, previously treated relapsed/refractory MM patients progressing on RUX and methylprednisolone shows significant clinical activity. This three-drug combination is well tolerated and is able to extend the benefit of RUX-based treatment for these patients. The promising results from this phase 1 clinical trial demonstrate a potential novel, all oral therapeutic approach for treating RRMM patients.

Marsun, a Phase III, Multicenter, Open Label, Randomized, Controlled Study Investigating Mosunetuzumab-Lenalidomide Versus Investigator Choices in Patients with Relapsed or Refractory Marginal Zone Lymphoma (R/R MZL)

Background MZLs are the second most common indolent NHL (iNHL) and comprise three distinct subtypes: (i) extranodal MZL (EMZL), mostly represented by MALT lymphoma; (ii) nodal MZL (NMZL); and (iii) splenic MZL (SMZL). For patients with high tumor burden based on GELF criteria, and patients with symptoms related to disease, first-line treatments rely on immuno-chemotherapy to reach high response rates at the cost of substantial toxicities notably in elderly patients. To date, R/R MZL remain a therapeutic challenge without clear standard of care treatment between immuno-chemotherapy, targeted therapies (i.e. BTK/PI3K inhibitors or the immunomodulatory agent lenalidomide (Len)), mainly because of an underrepresentation of MZL in the “indolent NHL” trials. Mosunetuzumab is a CD20xCD3 T-cell-engaging bispecific antibody designed to redirect T-cell cytotoxic activity against B-cells with promising efficacy results as monotherapy in various B-cell NHL. Lenalidomide was approved in the USA for R/R MZL based on data from MAGNIFY (MZL=45 patients) and AUGMENT (MZL=63 patients) and previous results of a phase IB study showed that mosunetuzumab in combination with Lenalidomide has a manageable safety profile and encouraging activity in patients with R/R follicular lymphomas (Morschhauser F. et al. ASH 2021) Here we present details of a trial in progress investigating the efficacy and the safety of mosunetuzumab-lenalidomide, a chemo-free regimen, compared to investigator choice, in patients with R/R MZL in need of systemic treatment and not eligible for local therapy such as radiotherapy or surgery. Methods This is an open label, multi-center, international, randomized phase III trial to compare the efficacy of Mosunetuzumab-Lenalidomide with investigator choices exclusively in R/R MZL patients. Patients with a proven diagnosis of EMZL, SMZL or NMZL and previously treated with at least one and no more than three prior systemic treatments are eligible. Previous treatment lines must include at least one systemic line with a drug targeting CD20 (monoclonal antibody at least 2 cycles) with or without chemotherapy (CHOP, bendamustine, CVP, chlorambucil) or targeted treatment such as ibrutinib. Patients will be stratified according to MZL subtype and time to progression of disease after first-line within 2 years. Mosunetuzumab will be administered subcutaneously (21 days C1, then 28 days C2-12) and lenalidomide will be given PO 20 mg/day from Day 1 to Day 21 from cycles C2 to C6. For each patient, investigator choice must be decided before randomization between R-Len (12 cycles) and R-chemotherapy (R-Bendamustine or R-CHOP followed by a 6 months maintenance). Both arms will have the same one-year fixed duration. The primary efficacy endpoint for comparison is progression-free survival (PFS) as determined by investigator (Lugano criteria 2014). Secondary objectives include CR24 (CR at 24 months) as determined by investigator and by central review according to Lugano criteria 2014 based on PET results, overall response rate and CR other than CR24 as determined by investigator, or by central review based on PET result according to Lugano criteria 2014. 260 patients are planned to be enrolled in France, Belgium, Germany, Italy and Portugal with FPI expected in Q3 2023 and approximately 4-year accrual period. The study will comprise a first stage of 10 patients in a safety cohort with mosunetuzumab-lenalidomide followed by a stage 2 with patients randomized 1:1 to receive M-len or investigator choice (125 patients per arm). The sponsor of the trial is the Lymphoma Academic Research Organisation (LYSARC) in collaboration with GLA and FIL with the support of F.Hoffmann-La Roche Ltd.

Preliminary Results from a Phase I/II Study of Pomalidomide Plus Rituximab, Ifosfamide, Carboplatin, and Etoposide for Relapsed or Refractory Diffuse Large B-Cell Lymphoma (PRIDE)

Background: Relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) patients have limited treatment options and are associated with poor prognosis. Outcomes are particularly poor following immunochemotherapy failure or relapse within 12 months of induction. The addition of the immunomodulatory agent lenalidomide (Len) to rituximab plus ifosfamide-carboplatin-etoposide (RICE) was shown to be feasible with promising efficacy in some studies. Pomalidomide (Pom) is a third-generation immunomodulatory drug that has shown excellent therapeutic activity against relapsed/refractory primary central nervous system lymphoma (PCNSL) with an acceptable toxicity profile. We conducted a phase I/II study combining Pom with RICE (PRICE) as a salvage regimen in first-relapse or primary refractory DLBCL (ChiCTR2100049327). Here we report the phase I results of the study. Methods: In phase I of the study, patients receive escalating doses of pomalidomide (2 mg, 3 mg, or 4 mg daily on d1-10) along with R-ICE therapy every 21 days by 3+3 design. Patients with CR or PR but not eligible for ASCT receive continuous pomalidomide as maintenance therapy for 12 months. The primary objective was to determine the maximum tolerated dose (MTD) or recommended dose, based on the occurrence of treatment-related DLTs. Secondary objectives included tumor response and safety. Results: At data cut-off (July 11, 2023), 14 patients were screened and 10 eligible patients were enrolled. 9 patients had been treated in the first 2 dose-escalation cohorts: 6 patients at 2 mg and 6 patients at 3 mg. Patient characteristics at baseline are shown in Table I. DLT was observed in two patients in the 3 mg cohort (grade 4 thrombocytopenia and grade 4 rash). MTD was determined as 2 mg. Grade (G) ≥ 3 TRAEs were leukopenia (4 patients), lymphopenia (3 patients), thrombocytopenia (3 patients), neutropenia (3 patients), rash (1 patient) and myelosuppression (1 patient). No death was related to the treatment. Five patients (55.6%) achieved an objective response including four patients (44.4%) with CR. ORR for the MTD dose level was (4/6) 66.7% with 3 CR and 1 PR. Notably, among the 7 patients with MYD88 mutations, which are associated with enhanced NF-κB activity, 4 achieved CR and 1 achieved PR. Conclusion: The addition of pomalidomide to the widely used RICE salvage regimen is feasible, and results in promising response rates in this DLBCL population that mostly with non-GCB subtype and double expression. MTD was reached and RP2D was determined to be 2 mg. Further studies are needed to evaluate the efficacy of this regimen, particularly in patients with MYD88 mutations.

Predictors of Lenalidomide Refractory Relapse Timing With Newly Diagnosed Multiple Myeloma: A FIRST Trial Subanalysis

Introduction/BackgroundMultiple myeloma (MM) is considered an incurable cancer. Patients with newly diagnosed MM (NDMM) are at risk for relapse within 1 year of frontline therapy. The immunomodulatory agent lenalidomide combined with dexamethasone (Rd) may be used as treatment for NDMM or relapsed MM, including in patients ineligible for autologous stem cell transplant. PatientsThis subanalysis of the phase III FIRST trial characterized patients with transplant-ineligible NDMM who experienced relapse while receiving Rd therapy by relapse timing (early [<12 months] versus late [≥12 months]) and type (CRAB vs. non-CRAB). MethodsThe Kaplan-Meier product limit method was used to estimate time-to-event endpoints, including progression-free survival (PFS) and overall survival (OS). Factors associated with the odds of late relapse were identified by logistic regression with univariate and multivariate analyses using a binary outcome (relapse at <12 vs. ≥12 months) in patient-, disease-, and treatment-specific baseline variables. ResultsPatients with early refractory relapse had functionally high-risk disease and inferior outcomes. In patients with early relapse versus those with late relapse, median OS (95% CI) was 26.8 months (21.9-32.8) versus 63.9 months (57.0-78.0), median OS from disease progression to death was 19.9 months (16.0-25.5) versus 36.4 months (27.9-47.0), and median PFS from randomization to second progression was 19.1 months (17.3-22.5) versus 42.1 months (37.4-44.9). Lactate dehydrogenase, baseline β2 microglobulin, and myeloma subtype were shown to predict time to relapse. ConclusionsClinicians could use these factors to consider more aggressive treatment regimens for those at highest risk of early relapse.

Patient-derived MicroOrganoSpheres (MOS) and precision clinical decision-making for patients with multiple myeloma.

8047 Background: There are many multiple myeloma (MM) treatments and nearly all patients undergo continual cycles of treatment, response, and resistance. Selecting an effective therapeutic strategy is of critical importance; but there is currently a lack of patient-derived MM models that can enable functional precision medicine to help real-time clinical decision-making to guide individual patient treatment. Methods: We show a method to rapidly establish MM patient-derived MicroOrganoSheres (MOS), which are microscale, droplet-sized patient avatars that sustain the native tumor niche, including both stromal and immune compartments. We generated first-of-its-kind data showing that MM MOS predicted patient treatment outcomes and have the potential to guide clinical treatment decisions. We further developed high-throughput drug screen to demonstrate MM MOS response to FDA-approved single and combination therapies and developed MOS assays to predict patient responses to immunotherapies including bispecific and phagocytosis-inducing antibodies. Results: MM MOS established from patient bone marrow (BM) biopsies preserved CD138/CD38 tumor cells, stromal (e.g., osteoblast) cells, and all major immune cell populations (T, NK, B, macrophage, dendritic, and myeloid-derived suppressor cells) for 11 days in culture. We performed single and combo drug testing on MOS derived from 7 MM patients within 10 days of biopsy collection. Patients went on receiving treatments and their responses were assessed using International Myeloma Working Group response criteria. The MOS assay predicted responses of both treatment-naïve and refractory patient to standard-of-care regimens, including combinations of proteasome inhibitors (bortezomib, carfilzomib), immunomodulatory agents (lenalidomide) and DCEP. Moreover, the BM biopsy-derived MOS enabled high-throughput drug testing of single agents and combinations in 9-dose titrations, providing clinicians the ability to evaluate alternative treatment options. Furthermore, because MOS retain the immune compartments of the original tumor niche, we were able to evaluate patients’ response to bispecific T cell engagers and developed a phagocytosis assay to measure anti-tumor phagocytosis activity, which showed efficacy in both single-agent and combo settings. Multi-modal profiling and an AI image analysis pipeline provided robust measurements that confirmed the unique phenotypic profile of each patient sample, highlighting the critical unmet need to guide each patient to the optimal treatment. Conclusions: Based on this groundbreaking feasibility study, a subsequent clinical trial of 40 patients is current under IRB review to further validate the clinical power of MM MOS to predict patient outcome and to demonstrate utility as a viable functional precision medicine approach to inform treatment decisions in the clinic.

Predictors of lenalidomide maintenance duration after autologous stem cell transplant in patients with multiple myeloma.

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. 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. 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. 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. 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.

Эффективность терапии даратумумабом в реальной клинической практике у пациентов с рецидивирующей/рефрактерной множественной миеломой

Introduction. Despite the availability and high effectiveness of modern anticancer drugs used to treat patients with multiple myeloma (MM), most patients inevitably develop disease relapses and refractoriness to the ongoing therapy. The prognosis in patients with relapsed MM and refractoriness to the main classes of anticancer drugs (proteasome inhibitors and immunomodulators) remains poor, and the median overall survival (OS) is only 8 months. Daratumumab is the first fully human IgG1-κ monoclonal antibody that binds with high affinity to the CD38 protein on the surface of myeloma cells, has a direct effect on the tumor, and also has an immunomodulatory mechanism of action. In clinical trials, daratumumab has been shown high effective and safety when used as monotherapy in patients with relapsed and double refractory MM. Aim. To evaluate the effectiveness and safety of daratumumab monotherapy in patients with relapsed/refractory multiple myeloma (RRMM) in real-life clinical practice. Materials and methods. We analyzed 32 patients with RRMM (14 men and 18 women) aged 41–76 years (median 65 years) from two hematological centers in the city of Novosibirsk. In 65.6% of patients, stage IIIA according to Durie-Salmon, stage I–II according to the ISS (in 65.6 and 28.1% of patients, respectively), ECOG performance status 0–1 (in 37.5 and 43.7% of patients, respectively) were diagnosed. Bone-related soft tissue plasmacytomas were recorded in 56.3% of patients, high lactate dehydrogenase activity was noted in 12 (37.5%) patients. The median number of prior lines of therapy was 2 (range 2–4). All patients had previously received proteasome inhibitors (bortezomib) and immunomodulatory agents (lenalidomide). Autologous hematopoietic stem cells transplantation was performed in 34.4% of patients. Double refractory MM was registered in 24 (75%) of 32 patients. The median time from diagnosis of MM to initiation of daratumumab therapy was 73.1 months (range 18–144 months). Daratumumab was administered as monotherapy at a dose of 16 mg/kg intravenously weekly (cycles 1–2), every other week (cycles 3–6), and then monthly. Results. The median duration of therapy with daratumumab was 12.2 months (range 4–22 months). The overall response rate (complete response + very good partial response (vgPR) + partial response (PR)) was 67.7%; vgPR – in 9 (29%) patients, PR – in 12 (38.7%), stable disease (SD) was registered in 19.4% of patients, respectively. The median time to response was 3.5 months (range 2.5–6). The median duration of response was 7.9 months (95% confidence interval (CI) 4.7–11.5). The median progression-free survival (PFS) was 19.1 months (95% CI 15.3–23.6), and the 12- and 18-month PFS were 91% and 50%, respectively. The median OS was not reached, and the 12- and 18-month OS values were 100% and 96.3%, respectively. The depth of the response had a statistically significant effect on the PFS (18-month PFS was 100% in the vgPR and PR subgroups and 81% in the SD subgroup, respectively (χ2 = 19.207, p &lt; 0.001)). Therapy with daratumumab was accompanied with a favorable toxicity profile. In 37.5% of patients, grade 1 and 2 infusion reactions were noted, in 6.2% grade ≥ 3, in one patient, therapy was discontinued due to an infusion reaction of the 3rd degree. Fatigue, upper and lower respiratory tract infections (15.6% and 12.5%, respectively), anemia (15.6%), thrombocytopenia (6.2%), and neutropenia (6.2%) were recorded in 15.6% of patients. Conclusion. Therapy with daratumumab is an effective and safe treatment for RRMM.

Management of MDS with Isolated Del(5q) Patients in the European MDS (EUMDS) Registry: A Report on 197 Cases

Background 'MDS with isolated del(5q) is a specific WHO 2016 subtype of MDS with characteristic morphological genomic features, and response of anemia to the immunomodulatory agents lenalidomide (LEN). LEN is approved in this indication, although Erythropoiesis Stimulating Agents (ESA) and red blood cell transfusion (RBCT) are still regarded first line options for anemia management. We analysed the characteristics and outcome of 197 MDS with del(5q) patients in the prospective international EUMDS registry. Methods Patients included in EUMDS registry are diagnosed and treated according to local or national recommendations. Treatment options (LEN, ESA, RBCT only) are thus in part influenced by local routines and reimbursement systems. Patient follow-up is recorded electronically every 6 months ("visit") in a central database. Standard descriptive methods and time to event analyses were used to examine differences in baseline factors by diagnosis, treatment response and overall survival (OS). Results Of 2469 EUMDS patients, 197 (8%) met criteria for 'MDS with isolated del(5q)'. Median follow-up was 4.3 yrs (3.8 years for all EUMDS patients). 77% were female, and median age was 73y. In comparison to the EUMDS patients lacking del(5q), patients with MDS with isolated del(5q) were lower risk at diagnosis (IPSS and IPSS-R, p<0.001), had lower Hb and higher platelet count (both p<0.001),and were more likely to have been transfused at registration (p=0.05) as well as during follow up (p<0.001). To date, 168/197 patients received one or more active interventions. First line treatment was RBCT in 96 patients and ESA in 55 patients. In total, 92 patients received LEN, 17 as 1st line, 41 as 2nd line and 34 as 3rd line treatment. Median time on treatment was 369.5 days. Mean baseline serum epo (sEPO) (available for 108/197 patients) was 317.8 IU/ L, compared with 148.9 IU/L for all EUMDS Registry patients. Of 92 patients who received LEN, 29 also received anti-coagulants and 24 patients received concurrent ESAs. As 26 patients were not transfused prior to starting LEN, it is difficult to make comparisons between treated and non-treated groups. Fifty patients were transfusion dependent before LEN. Of there, 76% have responded. Response duration was longer in patients treated with LEN prior to the initiation of regular RBCT (88% vs 60%). Response rates varied depending on transfusion dose-density prior to initiation of LEN and were highest in del(5q) patients with low RBCT burden. Response duration to LEN was broadly comparable to previously published clinical trial data, namely 4.5 study intervals (maximum of 27 months) in patients without prior RBCT vs. 3 intervals (maximum of 18 months) in patients with prior RBCT. Compared with RBC transfusion dose density interval before starting LEN (mean 1.059), dose density interval decreased in the first visit after starting LEN (mean 0.867). Haemoglobin levels increased from 8.8 g/dL before LEN, to 10.3g/dL at visit after starting LEN. No difference in OS or disease progression (to higher risk MDS or AML) was noted for patients treated with LEN vs. not ( OS - adjusted Hazard Ratio, age and sex, 95% Confidence Interval: 0.67 [95% CI:0.35-1.29], LEN treatment as a time-dependent variable). Conclusion EUMDS is uniquely placed to describe 'real-world’ management of patients with 'MDS with isolated del(5q)’ from diagnosis. Response rate to LEN therapy appeared to be higher, and response duration longer in patients with no prior RBCT. More than half of transfusion dependent patients will respond to LEN.

PB2144: PEARL: A STUDY TO ASSESS THE EFFICACY AND SAFETY OF PENPULIMAB PLUS LENALIDOMIDE, RITUXIMAB, GEMCITABINE AND OXALIPLATIN IN PATIENTS WITH RELAPSED/REFRACTORY DIFFUSE LARGE B CELL LYMPHOMA

Background: Relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) patients have limited treatment strategies and are associated with poor prognosis, so it is necessary to explore the treatment options for these patients. Penpulimab, an anti-PD1 antibody of IgG1 isotype, has demonstrated high response rate and very good tolerance, and is now approved in R/R classic Hodgkin lymphoma. The immunomodulatory agent lenalidomide has demonstrated direct anti-tumor effects in lymphoma. The regimen of rituximab, gemcitabine and oxaliplatin is used for the treatment of R/R DLBCL, which is recommend by current National Comprehensive Cancer Network guideline. Aims: The PEARL study aims to assess the efficacy and safety of penpulimab Plus lenalidomide, rituximab, gemcitabine and oxaliplatin (Pen-R2-GemOx) in Patients With R/R DLBCL. Methods: PEARL (NCT05186558) is a Phase II, multicenter, single-arm, open label study (Figure 1). An estimated 54 patients will be enrolled. Eligible patients are aged 18 to 80 years with relapsed or refractory after one prior treatment, CD20-positive DLBCL, and Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. All patients will be treated with Pen-R2-GemOx scheme (penpulimab, 200 mg, q2w, d0; lenalidomide, 10 mg, d1-7; rituximab, 375 mg/m2, d0; gemcitabine, 1000 mg, d1; oxaliplatin, 100 mg/m2, d1; 14d/cycle) during induction therapy, and they will be assessed the efficacy after four cycles by computed tomography (CT). Patients who achieve stable disease/progressive disease (SD/PD) will exit the study. Patients who achieve complete response/unconfirmed complete response/partial response (CR/CRu/PR) will receive Pen-R2-GemOx again for two cycles and be assessed the efficacy by positron emission tomography-CT (PET-CT). Afterwards, patients who achieve PD will withdraw the study. Patients who achieve CR/CRu/PR and are eligible for autologous stem cell transplantation (ASCT) will undergo ASCT, while patients who are not eligible for ASCT will directly receive penpulimab and lenalidomide as maintenance treatment. During maintenance treatment, the combination of penpulimab and lenalidomide will be used for 6 months, followed by lenalidomide monotherapy for 18 months. The primary endpoint is CR rate. Secondary endpoints include progression-free survival (PFS) rate, overall survival (OS) rate of 2 years and toxicity. Patients will be followed up from their end-of-induction treatment visit until the end of the study, including clinical evaluation every 3 months in the first year and every 6 months in the second year for patients undergoing ASCT and maintenance treatment. The expected study duration from first patient’s first visit to last patient’s last visit is approximately 3 years. Enrollment for the study will begin in Q2 of 2022. Results: Results for this study are not yet available. Image:Summary/Conclusion: Conclusion for this study is not yet available.

The EHA Research Roadmap: Malignant Lymphoid Diseases.

The EHA Research Roadmap: Malignant Lymphoid Diseases.

Smart Stop: A Phase II Study of Lenalidomide, Tafasitamab, Rituximab, and Acalabrutinib Alone and with Chemotherapy in Patients with Newly Diagnosed DLBCL

Smart Stop: A Phase II Study of Lenalidomide, Tafasitamab, Rituximab, and Acalabrutinib Alone and with Chemotherapy in Patients with Newly Diagnosed DLBCL

Trial in Progress: Pomalidomide Plus Rituximab, Ifosfamide, Carboplatin, and Etoposide for Relapsed or Refractory Diffuse Large B-Cell Lymphoma (PRIDE)

Backgrounds: Relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) patients have limited treatment options and are associated with poor prognosis. Patients generally receive salvage therapy as rituximab, ifosfamide, carboplatin and etoposide (R-ICE), followed by consolidation with high-dose therapy (HDT) and autologous stem cell transplantation (ASCT). However, only approximately 50% of patients can proceed to ASCT and only half of these achieve durable remission post-transplant. New therapeutic strategies are needed to improve response rates and to prevent recurrence following ASCT. The immunomodulatory agent lenalidomide has demonstrated direct anti-tumor effects in lymphoma. Some studies found that the addition of lenalidomide to the widely used R-ICE salvage regimen is feasible and results in promising response rates in R/R DLBCL patients. Pomalidomide is a third-generation immunomodulatory drug that has shown excellent therapeutic activity against relapsed/refractory primary central nervous system lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL) with an acceptable toxicity profile. We aim to determine the safety, tolerability and efficacy of pomalidomide in combination with R-ICE in R/R DLBCL patients.Study Design and Methods: PRIDE (ChiCTR2100049327) is a phase I/II trial of pomalidomide plus R-ICE (PR-ICE) as a salvage regimen for first-relapse or primary refractory DLBCL. In phase I of the study, patients receive escalating doses of pomalidomide (2mg, 3mg or 4mg daily on d1-10) along with R-ICE therapy every 21 days by standard 3+3 design until the MTD has been determined. In stage II, all subjects receive three cycles of R-ICE plus pomalidomide, dosing as RP2D. Patients with CR or PR but not eligible for ASCT receive continuous pomalidomide as maintenance therapy for 12 months. Key eligibility criteria are as follows: histologically confirmed DLBCL; relapsed or refractory after one prior treatment for DLBCL; age 18-75 years; absolute neutrophil count >1500 /mm 3; platelet count > 75,000/mm 3; calculated creatinine clearance of over 60 mL/min by Cockroft-Gault formula; total bilirubin < 1.5×ULN; AST and ALT < 3×ULN. The primary endpoint of phase II is the CR rate after PR-ICE induction treatment. The CR rate for R-ICE in R/R DLBCL was estimated to be approximately 35%. We hypothesize that the addition of POM to R-ICE could increase the CR rate by approximately 20%. For phase II, it requires a sample size of 44 evaluable patients (one-sided alpha = 0.05, power 80%, dropout rate of 15%). Eligible patients who receive at least one dose of PRICE will be included in the efficacy and safety analyses. The 95% CI of CR was calculated using Clopper-Pearson method. The Kaplan-Meier method was used to estimate PFS and OS. All these analyses were conducted using SAS 9.4 software. Enrollment for phase I will begin in Q4 of 2021. [Display omitted] DisclosuresNo relevant conflicts of interest to declare. OffLabel Disclosure:Pomalidomide is indicated for the treatment of adult patients: in combination with dexamethasone, for patients with multiple myeloma (MM) who have received at least two prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on or within 60 days of completion of the last therapy in China. The abstract presents the rationale for the use of generic pomalidomide in combination with R-ICE, a combination that is not approved in China at present.

Developing next generation immunomodulatory drugs and their combinations in multiple myeloma.

Multiple Myeloma (MM) is an incurable malignancy with current treatment choices primarily comprising combination regimens implemented with a risk-adapted approach. Cereblon (CRBN)-targeting immunomodulatory agents (IMiDs®) lenalidomide (LEN) and pomalidomide (POM) play a central role in combination regimens due to their pleiotropic antitumor/immunomodulatory mechanisms that synergize with many anti-myeloma approved or developmental agents. Currently, more potent next generation cereblon E3 ligase modulators (CELMoDs®) - iberdomide (IBER) and CC-92480 are in clinical development. With an expanding number of active agents/therapeutic modalities and a myriad of combinatorial possibilities, physicians and drug developers share an opportunity and challenge to combine and sequence therapies to maximize long-term patient benefit. Understanding drug mechanisms and their application in combination settings as well as the unique disease biology considerations from newly diagnosed (NDMM), relapsed/refractory (RRMM), and maintenance settings will be vital to guide the development of future MM therapies centered on a backbone of IMiD or CELMoD agents. Key aspects of drug activity are critical to consider while evaluating potential combinations: direct antitumor effects, indirect antitumor cytotoxicity, immune surveillance, and adverse side effects. In addition, the treatment journey from NDMM to early and late MM relapses are connected to genomic and immune changes associated with disease progression and acquisition of resistance mechanisms. Based on the types of combinations used and the goals of therapy, insights into mechanisms of drug activity and resistance may inform treatment decisions for patients with MM. Here we focus on the evolving understanding of the molecular mechanisms of CRBN-binding drugs and how they can be differentiated and suggest a strategic framework to optimize efficacy and safety of combinations using these agents.

Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities.

Simple SummaryThe growing interest in immunotherapy for the treatment of multiple myeloma demands a deep knowledge of the complex interactions between malignant and immune cells within the bone marrow. Indeed, understanding the cellular and molecular mechanisms underlying this network should represent the basis for the design of novel patient-oriented biological therapeutic approaches. Here, we describe the role of the main immune components of the myeloma niche along disease evolution and their implication in impairing/improving the response to anti-cancer treatments. Additionally, we provided an overview of the potential weakness of this pro-tumor interplay, evidencing novel therapeutic opportunities, which deserve future clinical investigations.Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by a multi-step evolutionary path, which starts with an early asymptomatic stage, defined as monoclonal gammopathy of undetermined significance (MGUS) evolving to overt disease in 1% of cases per year, often through an intermediate phase known as “smoldering” MM (sMM). Interestingly, while many genomic alterations (translocation, deletions, mutations) are usually found at early stages, they are not sufficient (alone) to determine disease evolution. The latter, indeed, relies on significant “epigenetic” alterations of different normal cell populations within the bone marrow (BM) niche, including the “evasion” from immune-system control. Additionally, MM cells could “educate” the BM immune microenvironment (BM-IM) towards a pro-inflammatory and immunosuppressive phenotype, which ultimately leads to disease evolution, drug resistance, and patients’ worse outcome. Indeed, it is not a case that the most important drugs for the treatment of MM include immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide) and monoclonal antibodies (daratumumab, isatuximab, and elotuzumab). On these bases, in this review, we describe the most recent advances in the comprehension of the role of the different cells composing the BM-IM, and we discuss the potential molecular targets, which could represent new opportunities to improve current treatment strategies for MM patients.

FOXM1 Is Associated with Development of Therapeutic Resistance in Multiple Myeloma

▪Despite advances in treatment resulting from development of novel therapies, multiple myeloma (MM) remains an incurable disease because of the emergence of therapeutic resistance. To explore mechanisms of acquired resistance to the IMiD® immunomodulatory agent lenalidomide in patients with MM, we performed RNA-seq analysis on 12 paired newly diagnosed MM (NDMM) patient samples of sorted CD138+ cells obtained prior to lenalidomide treatment initiation and after development of resistance. Gene set enrichment analysis using gene ontology biological process categories indicated that a dominant process associated with proliferation was upregulated at relapse. Transcription factor target enrichment analysis revealed that among differentially expressed genes, targets of forkhead box protein M1 (FOXM1), a transcription factor that promotes cell proliferation, were significantly (≈ 50% of FOXM1 target genes, false discovery rate [FDR] < 0.01) upregulated at relapse. FOXM1 expression also was significantly (FDR < 0.01) upregulated by 2.8-fold at relapse. Subsequently, we explored the association of FOXM1 gene expression with response to the IMiD immunomodulatory drug pomalidomide in MM patients relapsed/refractory (RRMM) to prior lenalidomide and proteasome inhibitor-based therapy. This analysis showed that patients with high baseline FOXM1 expression levels had lower response rates and shorter progression-free (median 2.9 vs 7.0 months; nominal logrank P < 2.24×10-6)and overall survival (median 10.4 vs 19.3 months; nominal logrank P < 8.43×10-7) when compared with patients with low baseline FOXM1 expression. Additional in vitro experiments indicated that knockdown of FOXM1 gene expression by short hairpin RNA increased sensitivity of a cell line intrinsically resistant to lenalidomide and pomalidomide, demonstrating an association between lower FOXM1 expression and IMiD agent sensitivity. Although FOXM1 expression has been linked to poor prognosis in NDMM, this work suggests high FOXM1 expression could also be associated with development of resistance to lenalidomide and cross resistance to pomalidomide in RRMM. DisclosuresAmatangelo:Celgene Corporation: Employment. Neri:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Towfic:Celgene Corporation: Employment, Equity Ownership; Immuneering Corporation: Equity Ownership. Bjorklund:Celgene Corporation: Employment. Kang:Celgene Corporation: Employment. Sternberg:Celgene Corporation: Employment. Bahlis:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Trotter:Celgene Institute for Translational Research Europe: Employment; Celgene Corporation: Equity Ownership. Thakurta:Celgene Corporation: Employment, Equity Ownership.

Cyclophosphamide Based Regimens Compared to Plerixafor-Based Regimens for Stem Cell Mobilization in Patients with Multiple Myeloma Result in Higher CD34+ Cell Yield, Lower Cost and Similar Outcome Post Autologous Transplantation

Background: Autologous stem cell transplantation (ASCT) is standard therapy for patients with multiple myeloma (MM). Stem cell mobilization for peripheral blood stem cell collection prior to ASCT is most commonly achieved with cyclophosphamide based chemotherapy regimens and GCSF (Cy-G) or with plerixafor and GCSF (Pler-G). Using a chemotherapy based mobilization regimen for patients with lymphoma has been shown to result in higher CD34+ cell yield and lower cost than plerixafor based regimens (Dhakal, et al. 2016). The question remains if stem cell mobilization regimens impact stem cell collection and ASCT outcomes in patients with MM.Methods: We reviewed 496 patients who received 596 ASCT for MM between January 2005 and December 2015. Data analyzed included stem cell mobilization regimen, number of CD34+ cells collected, number of apheresis procedures, CD34+ cells infused and survival. Univariate and Multivariate Cox Proportional Regression Models were utilized. The purpose of the review was to determine outcome differences between the use of Cy-G for stem cell mobilization vs Pler-G.Results: The median age at transplantation was 61 years (range 39-84) and 59% were male. Cy-G was used for stem cell mobilization for 438 patients (91%) vs 44 patients (9%) who received Pler-G. Significantly greater numbers of CD34+ cells were collected using Cy-G, with a median of 16.17 x 10e6/kg vs a median of 12.47 x 10e6/kg with Pler-G (p=0.0012). Median days of collection were less for Cy-G, 2 vs 3 for Pler-G (p=0.292), although not significant. There was no statistical difference in the dose of CD34+ cells infused, with a median of 5.73 x 10e6/kg for Cy-G vs a median of 5.00 x 10e6/kg for Pler-G. Pre-ASCT therapy using immunomodulatory agents lenalidomide, bortezomib or carfilzomib had no impact on the number of CD34+ cells collected (p=0.3427), number of apheresis procedures (p=0.6336) or CD34+ cell dose infused (p=0.941).OS at 84 months was 58% for patients using Cy-G for stem cell mobilization vs 55% for patients using Pler-G (p=0.9168) indicating no difference. By multivariate analysis, there was no difference in OS between the 2 groups (p=0.488). There was no difference in PFS between the 2 stem cell mobilization regimens by univariate or multivariate analysis (p=0.2737 and p=0.4226). There was no statistical difference (p=0.424) in the incidence of engraftment syndrome based on the stem cell mobilization regimen.Conclusion: For patients with MM, using a Cy-G regimen results in a higher CD34+ cell yield compared to Pler-G. Higher CD 34+ cell yield may be advantageous for patients considering tandem autologous transplantation. Pre-transplant therapy with immunomodulatory agents had no significant impact on CD34+ cell yield or apheresis days. There was no difference in OS or PFS between the 2 groups and no difference in the incidence of engraftment syndrome. The medication cost at our institution for a 70 kg patient receiving cyclophosphamide, dexamethasone and etoposide with GCSF is $8,846.64 compared to $24,846.09 for Pler-G. Cyclophosphamide based regimens for stem cell mobilization results in a higher cell yield with lower cost and equal survival compared to Pler-G in patients with MM. [Display omitted] DisclosuresMcKiernan:Novartis: Speakers Bureau. Siegel:Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau; Merck: Consultancy. Vesole:Takeda: Speakers Bureau; Celgene: Speakers Bureau. Skarbnik:Genentech: Speakers Bureau; Seattle Genetics: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Other: Ad board, Speakers Bureau; Gilead: Speakers Bureau. Biran:Celgene, Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau. Richter:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pecora:Caladrius Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Goy:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics / J&J: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding. Pereiras:Portola Pharmaceutical: Other: stock holder; TEVA: Consultancy.

Treatment with the Novel TOPK Inhibitor OTS514 Exhibits Potent Anti-Myeloma Activity in Pre-Clinical Models

Multiple myeloma (MM) continues to be considered incurable, necessitating new drug discovery. TOPK, a mitotic kinase, is upregulated in many human cancers, including MM, and is associated with proliferation of tumor cells, maintenance of cancer stem cells, and poor patient prognosis. Gene expression profiling shows elevated TOPK transcript levels in the plasma cells (PC) of patients with MM relative to healthy individuals, but not in PC derived from patients diagnosed with MM precursor states MGUS or smoldering myeloma. Western blot analysis of cells from bone marrow aspirates (BMAs) from patients with frank MM shows strong TOPK protein levels in the enriched CD138+ population (MM PCs), but not in the CD138- fraction or in peripheral blood mononuclear cells (PBMCs). In addition, TOPK protein is robustly expressed among all human myeloma cell lines (HMCLs) tested. In this study, we targeted this candidate oncogene with the selective inhibitor OTS514 to assess the contribution of TOPK to MM cell survival.Treatment of HMCLs with the TOPK inhibitor OTS514 causes rapid cleavage of caspase 3 and PARP, and subsequent DNA fragmentation, indicative of a robust apoptotic response. Viability assays reveal potent cell death in a panel of 9 HMCLs, with 72-hour IC50s ranging from 11-29 nM. Importantly, no apparent resistance to TOPK inhibition was observed among six p53-mutant cell lines tested. OTS514 treatment of total marrow mononuclear cells derived from BMAs from patients with MM resulted in robust cell death of CD138+ PC, as measured by flow cytometric analysis of Annexin-V/propidium iodide-stained cells, whereas CD138- cell populations were largely protected from apoptotic death, corroborating the relative lack of TOPK expression in non-PC and suggesting a highly favorable therapeutic index. OTS514 treatment also prevented CD138+ cell outgrowth from MM patients' PBMCs stimulated with IL-3 and IL-6, suggesting TOPK may play a role in maintenance of the putative myeloma stem cell populations.TOPK inhibition causes time- and dose-dependent decreases in both TOPK auto-phosphorylation and total protein levels. Protein expression of known TOPK target FOXM1 is also lost, as well as expression of pro-survival factors, including phospho-Akt. Microarray analysis of H929 cells revealed elevated expression of 73 small nucleolar RNAs (snoRNA), which are involved in ribosome maturation, and this is likely the result of a nucleolar/ribosomal stress response caused by cell cycle perturbation. Gene Set Enrichment Analysis revealed reduced expression of E2F1 target genes and western blot analysis showed a time-dependent decrease in levels of E2F1 in response to OTS514 treatment, suggesting a role of TOPK at the G1 checkpoint.The anti-myeloma activity of OTS514 was also explored in combination with the immunomodulatory agent lenalidomide and found to be exquisitely synergistic; Chou-Talalay combination indices at IC50, IC75, and IC90 were <1 among all HMCL tested. Combination treatment with OTS514 and lenalidomide also led to additive loss of the key MM cell survival proteins IKAROS and IRF4.The modified TOPK inhibitor OTS964, which is more amenable to oral administration, was evaluated in an animal model. H929 cells were xenografted subcutaneously into NOD/SCID mice and daily drug gavage was given at 50 or 100 mg/kg for 14 days after tumors reached 100 mm3. After 14 days of treatment, average tumor volume was reduced by 81% in mice treated with the 100 mg/kg dose of OTS964 relative to controls. The drug was well-tolerated, with minimal and reversible body weight loss in the group receiving the highest dose.TOPK is emerging as a key oncogene in several cancer types. Our data strongly support further study of the mechanistic contribution of TOPK to the development of MM and its inhibition as a potential therapy for MM. DisclosuresPark:OncoTherapy Science, Inc.: Consultancy. Jakubowiak:Amgen Inc., BMS, Celgene, Janssen, Karypharm, Millennium-Takeda, Sanofi, SkylineDX: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Chicago: Employment.

Clinical and Pathological Features of B-Cell Acute Lymphoblastic Leukemia Following Maintenance Treatment with Lenalidomide for Multiple Myeloma

Introduction: The immunomodulatory agent lenalidomide (Len) has improved overall survival (OS) in patients (pts) with multiple myeloma (MM). Pts receiving Len for MM exhibit increased risk of second primary hematologic malignancies, particularly those with melphalan (Mel) exposure, with a high incidence of acute lymphoblastic leukemia (ALL) observed in some series (Palumbo et al., Lancet Oncol, 2014; Tan et al., Hematol Oncol, 2015). Len degrades or down-regulates known B-cell ALL (B-ALL) tumor suppressors (e.g. IZKF1, IZKF3, IRF4); Len-associated ALL remains relatively uncharacterized.Methods: We identified 9 pts at MSKCC diagnosed with ALL from 2008-2016 during or within 4 months of therapy with Len for MM. Diagnostic molecular studies from bone marrow (BM) to characterize B-ALL included Archer FusionPlex (n=4), FoundationOne Heme (n=3) to assess for Philadelphia chromosome (Ph)-like ALL, other hematologic cancer-targeted mutation analyses (n=2), and NGS based clonality testing (Lymphotrack) for characterization and monitoring of clonal IGH rearrangements (n=3).Results: Of the 9 pts (5M, 4F), median ages at MM and B-ALL diagnoses were 59 years (range, 46-77) and 64 years (range, 50-81), respectively. MM was standard-risk by cytogenetic studies in all pts but 1 who had excess 1q. Pts received Len during first induction (n=5) and/or subsequent salvage (n=2) and/or maintenance (n=9). Median length of Len exposure was 57.3 months (range 23.0-69.2). MM therapy included Mel 200 mg/m2 and autologous stem cell rescue (ASCR, n=6) and radiation therapy to sites of osseous disease (n=4). 3 pts did not receive Mel/ASCR. Median time from MM diagnosis to B-ALL diagnosis was 5.6 years (range 3.0-7.7). Len was discontinued between 109 days before B-ALL diagnosis (largely due to cytopenias) and 42 days after B-ALL recognition in BM (median, day of diagnosis).ALL was B-lineage, Ph-negative, and CD10+ in all 9 pts. Biologic characteristics of B-ALL and treatment are noted in Table 1. In pt #6, LymphoTrack studies confirmed B-ALL and MM clones did not share common IgH rearrangement. In 1 pt with CRLF2 rearrangement, withdrawal of Len alone led to resolution of cytopenias and regression of BM blasts, with only residual MRD detectable. He remains in remission w/o further therapy for 7 months.Of 7 pts receiving B-ALL therapy at MSKCC, 6 achieved CR following first induction (PR in 1 pt, who achieved CR following consolidation). 5 of 6 pts w/ MRD assessment achieved MRD-negative CR after induction ± post-remission chemotherapy. 5 of 7 pts treated at MSKCC then underwent allogeneic hematopoietic cell transplantation (AlloHCT). Conditioning was reduced-intensity (fludarabine + busulfan or Mel) in 4 pts and TBI + cyclophosphamide (Cy) in 1 pt. GVHD prophylaxis was tacrolimus + methotrexate (n=3), post-AlloHCT Cy (n=1), or CD34-selection w/o pharmacologic prophylaxis (n=1). One pt died 41 days post-AlloHCT in CR w/o GVHD. 4 remain in continuous MRD-negative CR post-AlloHCT (median f/u 19.0 months, range 4.6-36.5) w/o IBMTR grade 3-4 acute GVHD; 1 developed mild chronic GVHD based on 2015 Consensus criteria. One pt diagnosed with B-ALL at age 81 did not undergo alloHCT and died 27 months post-diagnosis w/o evidence of B-ALL.None of the 9 pts have experienced relapse of B-ALL or yet required further therapy for MM. Median time from B-ALL diagnosis to last f/u is 10.8 months (range 4.1-41.1).Conclusions: B-ALL following maintenance therapy with Len for MM is uncommon but increasingly recognized, even in the absence of prior Mel/ASCR. Activating CRLF2 fusions were observed in 2 of 4 pts undergoing detailed molecular profiling. Despite advanced age and poor risk features in several pts (MLL rearrangement, Ph-like ALL, complex karyotype, loss of TP53), all pts treated at MSKCC achieved CR, largely MRD-negative. None developed relapse of B-ALL. Withdrawal of Len alone was associated with B-ALL regression in 1 pt and may have facilitated the responses observed in others. AlloHCT may be effective for long-term control of B-ALL and MM in such pts as well.Next-generation sequencing-based assays may be considered as a tool to characterize development of clonal lymphoid populations during Len therapy. Further investigation of Len-associated leukemogenesis warrants further consideration, particularly as extended Len therapy is increasingly used in pts with MM and other malignancies. [Display omitted] DisclosuresLandau:Spectrum Pharmaceuticals: Other: Advisory Board, Research Funding; Karyopharm: Consultancy; Pfizer: Honoraria; Janssen: Honoraria; Takeda: Research Funding; Celgene: Other: Advisory Board; Amgen: Research Funding. Hassoun:Oncopeptides AB: Research Funding. Dogan:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Peer Review Institute: Consultancy; Roche Pharmaceuticals: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arcila:Archer: Honoraria; Raindance Tecnologies: Honoraria; Invivoscribe: Honoraria. Park:Amgen: Consultancy.

GENETIC SUBTYPE GUIDED RITUXIMAB‐BASED IMMUNOCHEMOTHERAPY IMPROVES OUTCOME IN NEWLY DIAGNOSED DIFFUSE LARGE B‐CELL LYMPHOMA: FIRST REPORT OF A RANDOMIZED PHASE 2 STUDY

Introduction: Genetic subtypes of diffuse large B-cell lymphoma (DLBCL) have distinct oncogenic pathway feature, gene expression phenotype, and variable clinical outcome. We aimed to investigate whether adding novel targeted agents to R-CHOP (R-CHOP-X) based on genetic subtypes could improve clinical efficacy in newly diagnosed DLBCL. Methods: This was a randomized phase II study comparing R-CHOP-X with R-CHOP in newly diagnosed DLBCL (NCT04025593). Eligible patients were aged 18-80 years, and IPI risk of intermediate or high (IPI≥2). All patients were treated with standard R-CHOP for the first cycle, and were randomized 1:1 to R-CHOP-X or R-CHOP for the remaining 5 cycles. Targeted sequencing was performed on formalin-fixed paraffin-embedded tumor samples at diagnosis. We used a simplified method to classify patients into six genetic subtypes MCD, BN2, N1, EZB, TP53 and NOS, using mutations in 18 genes, BCL2 translocation, and BCL6 fusion. MCD and BN2 patients were treated with BTK inhibitor ibrutinib 420 mg/d, N1 and NOS patients with immunomodulatory agent lenalidomide 25mg d1-10, EZB patients with histone deacetylase inhibitor tucidinostat 20mg d1, 4, 8, 11, and TP53 patients with intravenous demethylating agent decitabine 10 mg/m2 d1-5 followed by standard R-CHOP. The primary endpoint was complete response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS), overall response rate, and safety. Results: A total of 128 patients were enrolled (n = 64 per arm) between July 17th, 2019 to December 29th, 2020. Baseline clinical characteristics were similar between arms, with a median age of 64 (range 25-74), 52% male, 83% ECOG 0-1, 77% stage III/IV, and 65% IPI≥3 for all patients. According to Hans algorithm, 62% patients were categorized as non-germinal B-cell subtype and 36% as MYC/BCL2 double expression. Regarding genetic subtypes, 20%, 18%, 4%, 2%, 16% and 39% patients were classified into MCD, BN2, N1, EZB, TP53, and NOS subtype, respectively. Until March 1st, 2021, all patients received at least 3 cycles of immunochemotherapy and 107 patients were available for response evaluation. The complete and overall response rates were 85% and 91% in R-CHOP-X arm, and 65% and 72% in R-CHOP arm, respectively. With a median follow-up of 14.1 months, 1-year PFS and OS rates were 96% and 98% in R-CHOP-X arm, and 79% and 94% in R-CHOP arm, respectively (PFS: HR 0.22, 95%CI 0.09-0.61; OS: HR 0.28, 95%CI 0.05-1.60). The most common grade 3/4 adverse events (AEs) for R-CHOP-X vs R-CHOP were neutropenia (81% vs 75%), thrombocytopenia (31% vs 11%), anemia (25% vs 20%), and febrile neutropenia (20% vs 11%). For non-hematological AEs, grade 3 infection occurred in 3% vs 2%, grade 3 gastrointestinal bleeding in 2% vs 3% in R-CHOP-X vs R-CHOP arm, respectively. No grade 4 non-hematological AEs were observed. Conclusion: Genetic subtype guided R-CHOP-X showed encouraging response and outcome in DLBCL. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Molecular Targeted Therapies No conflicts of interests pertinent to the abstract.