Lenalidomide Dose Research Articles

Phase I/II Dose-Escalation Study of Lenalidomide in Combination with R-GDP for Treatment of Transplant-Ineligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma Followed By Maintenance Lenalidomide

Introduction Patients with relapsed/ refractory (R/R) diffuse large B-cell lymphoma (DLBCL) whom are transplant-ineligible have limited treatment options. To address this specific treatment challenge, we undertook a clinical trial combining lenalidomide and rituximab (R2) with an established salvage regimen for DLBCL in gemcitabine, dexamethasone, cisplatin (GDP). Methods This was a single-center, open-label, phase I/II dose-escalation study of lenalidomide in combination with R-GDP for treatment of transplant-ineligible R/R DLBCL. The study was divided into a phase I dose-escalation study employing a '3+3' design followed by an expansion (phase II) portion with the recommended phase 2 dosing (RP2D), and a maintenance phase using 10 mg daily for 21 out of a 28-day cycle, for up to 1 year. The primary objective was to determine the maximum tolerated dose (MTD) of lenalidomide when combined with RGDP while secondary objectives was to analyze progression-free (PFS) and overall (OS) survival. Dose-escalation included 4 dose levels (DL) of 10 mg, 15 mg, 20 mg, 25 mg, starting at DL1. Lenalidomide was given for 6 cycles during induction therapy on days 1-21 every 28 days for a total of 6 cycles. The expansion phase used lenalidomide at the RP2D. Based on interim PET-CT assessment after cycle 2 (PET-2), patients in CR completed 2 more cycles of R2-GDP followed by two cycles of R2 and then stopped treatment without lenalidomide maintenance; patients with stable disease (SD) or partial remission (PR) completed 2 more cycles of R2-GDP and repeated PET-CT assessment after cycle 4 (PET-4). Based on PET-4, all responding patients (CR or PR) completed a further 2 cycles followed by maintenance with lenalidomide 10mg/day. Patients who failed to achieve at least PR at the point of PET-4 assessment were deemed treatment failure and stopped study treatment. Results The first patient was enrolled in February 2017. At data cut-off (July 20, 2020), 10 patients were enrolled into the dose-escalation study and a further 9 patients in the phase II part using lenalidomide at the RP2D of 15 mg/day (DL2). The MTD of lenalidomide of 15 mg/day was established after 2 of 3 patients at 20 mg/day (DL3) suffered neutropenic sepsis. The median age was 57.5 years (range, 40-76). Seven patients had primary refractory disease after R-CHOP while 13 had relapsed disease. Median time from first diagnosis to trial enrolment was 11.87 months. Median number of prior treatments were 2, including 4 patients who had previously undergone autologous transplant. After a median follow-up of 23.6 months in surviving patients, overall response rate was 68% (CR, N=7; PR, N=6). Median number of lenalidomide cycles completed in the induction phase was 4. Four patients completed less than 3 lenalidomide cycles due to progressive disease (PD). Nine patients died while on follow-up, 7 from PD and 2 infective deaths related to study treatment. The most common grade 3/4 treatment-emergent adverse events were neutropenia and thrombocytopenia with 4 and 11 patients experiencing at least one episode of grade 3 and 4 neutropenia and thrombocytopaenia, respectively. Out of these patients, 2 had neutropenic sepsis. Six patients went on to receive maintenance lenalidomide, completing a median of 5 cycles. Only one patient completed the planned 12 months of lenalidomide maintenance; 2 patients discontinued due to infective complications, one due to neutropenia, one due to patient's decision to stop without any adverse events documented, and one due to PD. For the entire cohort, median PFS and OS were 4.7 months and 26 months, respectively. Patients with primary refractory disease (N=7) had a median PFS of only 2 months. When these patients were excluded, the remaining (N=13) had a median PFS of 21 months. Conclusion In our cohort of transplant ineligible R/R DLBCL patients R2-GDP resulted in an ORR of 68%. Patients with primary refractory disease did not benefit from study treatment. However, for the remaining patients, the median PFS of 21 months compares favorably with other salvage regimens in this population. Lenalidomide at 15 mg/day may safely augment RGDP responses in chemotherapy-sensitive relapsed DLBCL. Disclosures No relevant conflicts of interest to declare.

Phase I Study of Lenalidomide Combined with Dose-Adjusted EPOCH and Rituximab (EPOCH-R2) in Primary Effusion Lymphoma in Participants with or without HIV (NCT02911142)

Phase I Study of Lenalidomide Combined with Dose-Adjusted EPOCH and Rituximab (EPOCH-R2) in Primary Effusion Lymphoma in Participants with or without HIV (NCT02911142)

Efficacy of Daratumumab Containing Regimens Post Lenalidomide Maintenance in Transplant Eligible Patients: Real-World Experience from the Canadian Myeloma Research Group Database

Introduction Lenalidomide maintenance following autologous stem cell transplant (ASCT) remains a standard of care among transplant eligible patients with newly diagnosed multiple myeloma (NDMM). Many previous clinical trials done in patients following one prior line of therapy either excluded patients progressing on lenalidomide or included a very small proportion of these patients. Given the paucity of data in this setting, the optimal management of patients progressing on lenalidomide maintenance remains unknown. Daratumumab-containing triplet regimens have recently been introduced for these patients, typically in combination with pomalidomide (DPd), lenalidomide (DRd), or bortezomib (DVd). To our knowledge, there is no prospective data to allow comparison of the efficacy of these three regimens in patients progressing on lenalidomide maintenance, which is an increasingly common clinical scenario. Understanding the comparative efficacy, tolerability and toxicity of these regimens in patients progressing on lenalidomide maintenance in the 'real-world' is needed in order to help clinicians make appropriate decisions and guide future studies. Methods The Canadian Myeloma Research Group Database (formerly known as the Myeloma Canada Research Network Database, MCRN-DB) is a prospectively maintained disease specific database with over 7000 patients enrolled from 14 academic sites across Canada with legacy data collected from 2007. The Munster Myeloma database collects myeloma specific information in a German academic center and currently contains data from 800 patients collected from 2005. All consecutive patients treated with daratumumab based regimens in second line following relapse on lenalidomide maintenance were included in the analysis from the two databases analyzed up to 30/06/2020. Results A total of 1380 NDMM patients on lenalidomide maintenance post autologous stem cell transplant were identified in the two databases. From them, 73 patients were included in this analysis as they were treated with daratumumab containing regimen in second line. Specifically, 18 (24.7%) of these patients were treated with DPd, 32 (43.8%) patients with DRd, and 23 (31.5%) patients with DVd. The baseline characteristics, maintenance details, post-maintenance response rates and toxicity for each regimen are shown in Table 1. The median follow-up for the cohort from the time of daratumumab initiation was 8.3 months (range 0.4 - 40.0). Although, a higher proportion of patients in the DPd arm obtained a CR/VGPR compared to DRd or DVd, it did not reach statistical significance (p-value 0.06). The median PFS of the entire cohort was 16.96 months (95% CI 11.47-23.44). The median PFS of the individual regimens was as follows: DPd 17.65 months, DRd not reached and DVd 11.47 months as demonstrated in Figure 1 (p-value =0.46). Conclusion In summary, our results show that daratumumab-based regimens are effective among patients progressing on lenalidomide maintenance in the real world. Despite the small sample size, the results presented here are in line with recent sub-analyses of phase III studies examining the common daratumumab-based regimens used in this setting (CASTOR with median PFS of DVd between 7.8 months in all lenalidomide refractory patients and 27 months in all patients in first relapse; MM014 with median PFS of DPd after lenalidomide refractoriness of 21.8 months). The efficacy of DRd, in which daratumumab is added to an increased dose of lenalidomide, is notable and warrants further evaluation to identify which patients are most likely to benefit. Additional studies with longer follow-up are required to assess the optimal daratumumab-based regimen to be used in this growing population of patients relapsing after lenalidomide maintenance. Disclosures Mian: Janssen: Consultancy, Honoraria; Celgene: Consultancy; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Jimenez-Zepeda:Janssen, Celgene, Amgen, Takeda: Honoraria. McCurdy:Sanofi: Honoraria; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Song:Celgene: Research Funding; Celgene, Janssen, Amgen, Takeda: Honoraria. Leblanc:Celgene: Research Funding; Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. White:Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Stakiw:Roche: Research Funding; Celgene: Honoraria; Lundbeck: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; BMS: Honoraria. Louzada:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kotb:Karyopharm: Current equity holder in publicly-traded company; Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Merck: Honoraria, Research Funding; Sanofi: Research Funding. Reece:Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Amgen: Consultancy, Honoraria; Millenium: Research Funding; BMS: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding.

Subgroup Analyses of Elderly Patients Aged ≥ 70 Years in MAGNIFY: A Phase IIIb Interim Analysis of Induction R2 Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Subgroup Analyses of Elderly Patients Aged ≥ 70 Years in MAGNIFY: A Phase IIIb Interim Analysis of Induction R2 Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Effectiveness and Safety of Ixazomib-Based Therapy in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) Treated Outside the Clinical Trial Setting Via an Early Access Program (EAP) in Europe: Second Interim Analysis of the ‘Use Via Early Access to Ixazomib’ (UVEA-IXA) Study

Effectiveness and Safety of Ixazomib-Based Therapy in Relapsed/Refractory Multiple Myeloma (RRMM) Patients (Pts) Treated Outside the Clinical Trial Setting Via an Early Access Program (EAP) in Europe: Second Interim Analysis of the ‘Use Via Early Access to Ixazomib’ (UVEA-IXA) Study

Clinical Outcomes of Non-Traditional Lenalidomide, Bortezomib, and Dexamethasone Regimens in Multiple Myeloma

Introduction Lenalidomide, bortezomib, and dexamethasone (RVD) is a standard first-line regimen for patients with newly diagnosed multiple myeloma and is associated with high response rates and improvement in progression-free survival and overall survival compared to traditional chemotherapy regimens. Traditional (RVD Classic, RVD Lite) and non-traditional (RVD Premium Lite, RVD Ultra Lite) variations of the RVD regimen are utilized at Dana-Farber Cancer Institute (DFCI) and have not been fully evaluated in terms of safety and tolerability. RVD Premium Lite is administered in a 28-day cycle with weekly bortezomib; whereas, RVD Ultra Lite administers three weekly doses of bortezomib instead of four (Table 1). These two regimens have not been fully evaluated in terms of safety, tolerability, and efficacy. Selection is based on provider preference in addition to flexibility of dosing schedule. The regimens also allow for convenience of weekly dosing while keeping dose intensity. This retrospective, descriptive analysis is the first study to explore the safety, tolerability, and efficacy of four different RVD regimens used at DFCI. Methods This single-center, retrospective, descriptive analysis identified 90 newly diagnosed patients with multiple myeloma treated at DFCI main campus for >2 cycles of an RVD-based regimen in the front-line setting. We reviewed patients started on treatment from January 2017 to December 2019. Patients were excluded if treated primarily at an outside institution or satellite campus. Results A total of 90 patients were included between January 2017 to December 2019, and median age was 69.5 years (range 44-87). Most patients had either standard-risk or unknown cytogenetics. Of the 44 patients with available International Staging System (ISS) information, the majority were R-ISS/ISS I or II. The most common M-protein type at diagnosis was IgG (56.7%), followed by light chain restricted disease (25.6%). In terms of traditional and non-traditional RVD regimens, most patients received RVD Classic (33.3%) or RVD Ultra Lite (32.2%), followed by RVD Lite (23.3%) and RVD Premium Lite (11.1%). Patients in RVD Lite and RVD Ultra Lite groups were of older age when compared to the RVD Classic group (P<0.001). Lenalidomide dosing delays and reductions trended higher in the RVD Classic regimen at 14.3%, followed by RVD Ultra Lite at 12.3%. Bortezomib dosing delays and reductions were similar between the RVD Lite and RVD Classic regimens at 11.8% and 11.2%, respectively. Overall, combined lenalidomide and bortezomib dosing delays/reductions trended higher in the RVD Classic (14.3%/11.2%) and RVD Lite (11.0%/11.8%) compared to RVD Ultra Lite (12.3%/9%) and RVD Premium Lite (10.8%/9.6%). The most common toxicities noted with all variations of the RVD regimen were peripheral neuropathy, cutaneous toxicity, infection, diarrhea, and constipation. The highest rates of adverse events among all RVD regimens were infection and peripheral neuropathy. Peripheral neuropathy was slightly higher in the RVD Premium Lite and RVD Classic regimen at 8.43% and 8.70%, respectively, compared to RVD Lite and RVD Ultra Lite at 7.1% and 7.7%, respectively. No significant difference in toxicities were seen when regimens were compared (p=0.1369). Intolerance leading to therapy change trended higher in the RVD Lite group at 23.8%, followed by RVD Classic and RVD Ultra Lite at 16.7% and 10.3%, respectively. Nineteen percent of patients in the RVD Lite group had minimal response or progression leading to therapy change, which was highest among all RVD regimens. Rate of transplant was highest in the RVD Classic group at 36.7%, followed by RVD Premium Lite at 20%. There was no significant difference in intolerance, minimal response or progression, maintenance, continued induction or planned change, transplant, and death between regimens (p=0.089). In terms of progression-free survival, no differences were seen between the groups (p=0.36). Conclusion In conclusion, the current investigation allowed us to assess the safety, tolerability, and efficacy of traditional and non-traditional variations of the RVD regimen in multiple myeloma used at our institution. There are minimal differences between each regimen when toxicities are managed appropriately. Disclosures Richardson: Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Mo:Celgene/BMS: Membership on an entity's Board of Directors or advisory committees.

Maintenance Therapy with Ipilimumab Plus Lenalidomide after Autologous Stem Cell Transplantation for Patients with Lymphoma

Maintenance Therapy with Ipilimumab Plus Lenalidomide after Autologous Stem Cell Transplantation for Patients with Lymphoma

Abstract PO-63: A phase 2a open-label study of MT-3724, a novel CD20-targeting engineered toxin body, in combination with lenalidomide (LEN) in subjects with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL)

Abstract Background: Engineered toxin bodies (ETBs) are a distinct class of targeted immunotoxins in development by Molecular Templates as anticancer therapeutics. ETBs have a novel mechanism of action that drives a potent and targeted response mediated by antibody-like binding, cellular internalization, and enzymatic ribosomal inhibition via the delivery of a Shiga-like toxin subunit A (SLTA). MT-3724 comprises an anti-CD20 single chain variable fragment genetically fused to SLTA with an approximate molecular weight of 55 kDa and is being developed for the treatment of relapsed or refractory diffuse large B-cell lymphoma (r/rDLBCL). MT-3724 is currently being studied in three ongoing phase 1/2 studies for r/rDLBCL. Methods: MT-3724 is being evaluated in this phase 2a study (NCT03645395) in combination with LEN in adult patients with histologically confirmed, relapsed, or refractory CD20+ B-cell NHL. The primary objectives of this study are to determine the safety and tolerability, including the maximum tolerated dose (MTD), of MT-3724+LEN. Secondary objectives include pharmacokinetics, pharmacodynamics, immunogenicity, and tumor response. The study is being conducted in two parts. Part 1 includes MT-3724 dose escalation over 5 dose cohorts according to the modified 3+3 design and will include up to 24 subjects with CD20+ NHL. Part 2 is designed to assess the safety and tolerability of MT-3724+LEN in the MTD Expansion Cohort, where the dose declared as MTD of MT-3724 in Part 1 will be given in combination with LEN in up to 40 subjects with CD20+ r/rDLBCL. Eligible subjects must have received at least one approved therapy for NHL and must have measurable disease by Lugano criteria. Subjects who have progressed following CAR T-cell therapy, autologous or allogeneic stem cell transplant are also eligible. Serum rituximab level must be negative (<500 ng/mL) at screening because it competes with MT-3724 for binding to CD20. In the first 2 dose cohorts (10 and 25 ug/kg/dose) of Part 1, subjects received MT-3724 IV infusions over 1 hour three times weekly for 2 weeks and LEN (20 mg daily) on Days 1-21 of each 28-day treatment cycle for Cycles 1 and 2. In subsequent cycles, MT-3724 was administered once weekly with continued LEN dosing on Days 1-21. Because of 2 dose-limiting toxicities (grade 2 capillary leak syndrome) in Cohort 2, the dose in Cohort 3 was reduced to 20 ug/kg/dose. The protocol was amended so that in future Cohorts 4 and 5 (25 and 50 ug/kg/dose), MT-3724 will be dosed biweekly for 2 weeks for Cycles 1 and 2 and then once weekly for subsequent cycles. The study is recruiting subjects at multiple study centers. Citation Format: Jason Tache, Deborah A. Katz, Amitabha Mazumder, David Peace, Christine Burnett, Thomas Strack, Elizabeth Bay, Roger Waltzman, Seung Lee. A phase 2a open-label study of MT-3724, a novel CD20-targeting engineered toxin body, in combination with lenalidomide (LEN) in subjects with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-63.

A phase I trial of lenalidomide and radiotherapy in children with diffuse intrinsic pontine gliomas or high-grade gliomas

This study was performed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of the immunomodulatory agent, lenalidomide, when administered daily during 6weeks of radiation therapy to children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG) PATIENTS & METHODS: Children and young adults < 22years of age with newly diagnosed disease and no prior chemotherapy or radiation therapy were eligible. Children with HGG were required to have an inoperable or incompletely resected tumor. Eligible patients received standard radiation therapy to a prescription dose of 54-59.4Gy, with concurrent administration of lenalidomide daily during radiation therapy in a standard 3 + 3 Phase I dose escalation design. Following completion of radiation therapy, patients had a 2-week break followed by maintenance lenalidomide at 116mg/m2/day × 21days of a 28-day cycle. Twenty-nine patients (age range 4-19years) were enrolled; 24 were evaluable for dose finding (DIPG, n = 13; HGG, n = 11). The MTD was not reached at doses of lenalidomide up to 116mg/m2/day. Exceptional responses were noted in DIPG and malignant glioma (gliomatosis cerebri) notably at higher dose levels and at higher steady state plasma concentrations. The primary toxicity was myelosuppression. The RP2D of lenalidomide administered daily during radiation therapy is 116mg/m2/day. Children with malignant gliomas tolerate much higher doses of lenalidomide during radiation therapy compared to adults. This finding is critical as activity was observed primarily at higher dose levels suggesting a dose response.

MM-347: Ixazomib Plus Lenalidomide-Dexamethasone (IRd) vs. Placebo-Rd for Newly Diagnosed Multiple Myeloma (NDMM) Patients Not Eligible for Autologous Stem Cell Transplant: The Double-Blind, Placebo-Controlled, Phase 3 TOURMALINE-MM2 Trial

Context: Continuous Rd-based regimens are among the standards of care in the diverse, transplant-ineligible NDMM patient population. An all-oral triplet may be useful for patients who cannot/prefer not to travel to the clinic frequently. Ixazomib, the first oral proteasome inhibitor (PI), has predictable, manageable toxicities, enabling an all-oral PI-Rd regimen for use in this setting. Objective: Compare IRd vs. placebo-Rd in transplant-ineligible NDMM patients. Interventions: Patients were randomized to ixazomib 4 mg (n=351) or placebo (n=354) plus Rd (28-day cycles). After 18 cycles, dexamethasone was discontinued and lower ixazomib and lenalidomide doses were administered until progression or unacceptable toxicity. Main Outcome Measure: Progression-free survival (PFS) - final analysis. Results: In the IRd vs. placebo-Rd arms, the median age was 73 vs. 74 years (43% vs. 44% ≥75 years), 16% vs. 17% had International Staging System stage III MM, and 38% vs. 41% had high-risk cytogenetics [t(4;14), t(14;16), del(17p), or amp(1q21)]. The median PFS was 35.3 vs. 21.8 months (hazard ratio [HR] 0.830, p=0.073; median follow-up 53.3 vs. 55.8 months). Overall response rates were 82% vs. 80%; depth of response was greater with IRd vs. placebo-Rd (26% vs. 14% complete response [CR], odds ratio [OR] 2.10, p Conclusions: IRd in NDMM demonstrated a strongly positive trend in PFS, improved TTP and CR rate, and improved the poor PFS associated with high-risk cytogenetics, as seen in the TOURMALINE-MM1 study of IRd in relapsed/refractory MM. Safety was consistent with the well-characterized toxicity profile of ixazomib/IRd. IRd is a feasible treatment option for certain transplant-ineligible patients who could benefit from an all-oral triplet combination.

ABCL-135: RE-MIND: A Comparison of Tafasitamab (MOR208) + Lenalidomide (L-MIND) Versus Lenalidomide Monotherapy (Real-World Data) in Transplant-Ineligible Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Context: Tafasitamab (MOR208), a humanized anti-CD19 antibody, combined with lenalidomide (LEN) showed encouraging results in the Phase II, single-arm L-MIND study ( NCT02399085 ) of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplantation (ASCT). Objective: To generate a LEN monotherapy matched comparator cohort for L-MIND using patient-level data to isolate the tafasitamab contribution to the efficacy of the tafasitamab + LEN combination. Design: RE-MIND ( NCT04150328 ), a retrospective observational study, used a Nearest Neighbor ePS-based 1:1 Matching methodology to balance the LEN monotherapy cohort (observational data) and combination cohort (derived from L-MIND) for nine prespecified baseline covariates: age, Ann Arbor stage, last therapy refractoriness, number of prior therapy lines, primary refractoriness, prior ASCT, LDH, neutropenia, and anemia. The primary analysis set included matched patients who received a LEN starting dose of 25 mg/day (as in L-MIND) with sufficient follow-up. Patients: LEN monotherapy-treated patients from the US and EU who met the L-MIND-aligned eligibility criteria: adult patients with R/R DLBCL; 1–3 prior systemic therapies, including 1 CD20-targeting regimen; ASCT-ineligible. Baseline characteristics, LEN dosing, and patient outcomes were collected retrospectively from health records. Main outcome measures: The primary endpoint was investigator-assessed best objective response rate (ORR). Secondary endpoints included overall survival (OS) and complete response (CR) rates. Results: 490 patients were enrolled, of which 140 fulfilled the ePS matching criteria. Following matching, the primary analysis set included 76 patients from each cohort. Baseline characteristics were comparable. The primary endpoint was met. Best ORR was significantly higher in the combination cohort (67.1%) versus the monotherapy cohort (34.2%) (odds ratio 3.89; 95% confidence interval [CI]: 1.90–8.14; p Conclusions: Significantly better ORR, CR, and OS indicate potential synergistic effects of the tafasitamab + LEN combination in ASCT-ineligible R/R DLBCL. RE-MIND demonstrates the utility of real-world data in interpreting non-randomized trials.

A Pilot Study of Lenalidomide Maintenance Therapy after Autologous Transplantation in Relapsed or Refractory Classical Hodgkin Lymphoma.

For patients with relapsed or refractory classical Hodgkin lymphoma (cHL), salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) remains the standard of care. Even with this aggressive treatment strategy, 5-year progression-free survival is ≤50%, and there remains interest in maintenance strategies to improve long-term disease-free survival. Lenalidomide is an immunomodulatory agent with demonstrated activity in multiple subtypes of lymphoma including cHL, and has also been shown to improve both progression-free and overall survival as maintenance therapy after ASCT in multiple myeloma. This multicenter study evaluated maintenance lenalidomide after ASCT for patients with cHL. Patients were enrolled 60 to 90 days post-transplant and received oral lenalidomide on days 1 to 28 of 28-day cycles for a maximum of 18 cycles. Lenalidomide was started at 15 mg daily and increased to maximum of 25 mg daily if tolerated. The primary objective of this study was to assess the feasibility of this regimen, with a goal <30% rate of discontinuation at or before cycle 12 for drug-related reasons. Twenty-seven patients were enrolled and 26 received at least 1 dose of lenalidomide. With a median follow-up of 51.3 months (range, 12.2 to 76.2 months), 23 of 26 patients were alive. Median event-free survival was 9.4 months and median progression-free survival had not been reached, with 17 of 26 patients (65.4%) remaining in remission at last follow-up. Excluding 4 patients who discontinued therapy for progression and 2 who discontinued due to noncompliance, the discontinuation rate at or before cycle 12 was 52%. Treatment was complicated by a high frequency of hematologic adverse events, with 15 patients (58%) experiencing grade 3 to 4 hematologic toxicity and 5 (19%) experiencing grade 4 hematologic toxicity. We conclude that the regimen of maintenance lenalidomide explored in this study is not feasible for patients with cHL immediately following ASCT. An alternative lenalidomide dose or schedule may be better tolerated following ASCT for patients with relapsed or refractory cHL.

Abstract 4436: Combination therapy with an antibody specific for transferrin receptor 1 (ch128.1/IgG1) and bortezomib or lenalidomide results in increased survival in an in vivo model of human multiple myeloma

Abstract Multiple myeloma (MM) is a B-cell proliferative disorder of monoclonal malignant plasma cells. It is the second most common hematologic malignancy in the United States, after non-Hodgkin lymphoma (NHL). Clinical manifestations of MM include osteolytic bone lesions, hypercalcemia, renal failure, anemia, recurrent infections, and neuropathy. Standard treatments for MM include the proteasome inhibitor bortezomib, as well as lenalidomide, a thalidomide analog with immunomodulatory and antiangiogenic properties. Although the use of these two agents in combination with other therapies have significantly improved MM survival, the disease remains incurable. We previously developed a mouse/human chimeric antibody (ch128.1/IgG1) specific for human transferrin receptor 1 (TfR1). TfR1, also known as CD71, is a meaningful target for antibody-based cancer therapy, given its high expression on malignant cells and relevant role in cancer cell pathology. We have reported that treatment of SCID-Beige mice bearing disseminated human KMS-11, MM.1S, or MM.1R myeloma tumors with ch128.1/IgG1 results in significant antitumor activity in early and late disease stages. The mechanism of antitumor activity is Fc-mediated in which macrophages are considered to play a relevant role. Since combining multiple treatments with differing mechanisms of action is an effective antitumor strategy, and given the relevance of bortezomib and lenalidomide in MM therapy, we decided to explore, for the first time, the combination of these two agents with ch128.1/IgG1. We found that treatment with a single dose of ch128.1/IgG1, or multiple doses of bortezomib or lenalidomide used as single agents, results in significant antitumor activity in SCID-Beige mice bearing late stage disseminated human MM.1S tumors. However, this antitumor activity is superior when ch128.1/IgG1 was combined with bortezomib or lenalidomide, showing significantly longer survival compared to each therapy used alone. These results suggest that the addition of a ch128.1/IgG1 therapy arm in a combinatorial treatment regimen involving bortezomib and/or lenalidomide is a promising strategy against human B-cell malignancies such as MM. Citation Format: Pierre V. Candelaria, Miguel Nava, Otoniel Martinez-Maza, Tracy R. Daniels-Wells, Manuel L. Penichet. Combination therapy with an antibody specific for transferrin receptor 1 (ch128.1/IgG1) and bortezomib or lenalidomide results in increased survival in an in vivo model of human multiple myeloma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4436.

Factors Associated with Dose Modification of Lenalidomide Plus Dexamethasone Therapy in Multiple Myeloma.

Long-term combination treatment with lenalidomide and low-dose dexamethasone is important to achieve a curative effect in patients with multiple myeloma (MM). In this study, the plasma concentration of lenalidomide was measured at 3 h after oral administration, when the drug is in the elimination phase and can be easily measured in outpatients, to identify factors that may lead to the discontinuation of this combination therapy. Patients were assigned to continuation or discontinuation of therapy groups, and the baseline characteristics of patients, lenalidomide concentration, and concentration/dose (C/D) ratios reflecting oral clearance were compared between the two groups. The efficacy and severity of adverse events were also compared. The results showed that patients who discontinued or modified treatment had low plasma concentrations of lenalidomide and C/D ratios, indicating high oral clearance of lenalidomide. The estimated creatinine clearance rate was negatively correlated with the C/D ratio. The plasma concentrations of lenalidomide were independent from kidney function and differed significantly among patients. Taken together, the results indicate that low plasma concentrations of lenalidomide and low C/D ratios may lead to discontinuation of combination therapy in patients with MM. This suggests that early measurement of lenalidomide plasma continuation would help to prevent discontinuation of therapy or a delay in modifying the dose of lenalidomide.

Lenalidomide plus R-GDP (R2-GDP) in relapsed/refractory diffuse large B-cell lymphoma: Final results of the R2-GDP-GOTEL trial.

8019 Background: Lenalidomide is an immunomodulatory drug that could reverse rituximab refractoriness in lymphoma patients (pts). We conducted an open label multicenter phase 2 trial testing the efficacy and toxicity of a combination of lenalidomide and rituximab (R2) plus GDP schedule (R2-GDP) in Relapsed/Refractory Diffuse Large B Cell Lymphoma (R/R DLBCL) pts, not suitable for autologous stem cell transplant (ASCT). Methods: Patients with R/R DLBCL previously treated with at least 1 prior line of immunochemotherapy including rituximab, and not candidates for ASCT, were eligible. After a run-in phase period, treatment consisted of an induction phase with lenalidomide (LEN) 10 mg po d1-14, rituximab 375 mg/m2 iv d1, cisplatin 60 mg/m2 iv d1, gemcitabine 750 mg/m2 iv d1 and d8 and dexamethasone 20 mg d1-3, up to a maximum of 6 cycles. Pts without disease progression (DP) entered into a maintenance phase with LEN 10 mg, or last LEN dose received in the induction phase, d1-21 in cycles every 28 days. Primary endpoint was overall response rate (ORR) by investigator assessment. Secondary endpoints included disease free survival (DFS), event free survival (EFS), overall survival (OS), safety and response by cell of origin (COO), type of DLBCL (double-triple hit) and other microenvironment and genomic biomarkers. Results: 79 pts were enrolled between April 2015 and September 2018. Median age was 70 years (range 23-86), 48,7% women. 78 pts were considered for efficacy and safety in the intention to treat (ITT) analysis. With a median follow-up of 13 months at the time of cut-off (November 2019), ORRwas 59.0%, with 32.1% complete responses (CR) and 26.9% partial responses (PR). In the primary refractory population (n = 33), ORR was 45.5%, with 21.2% CR and 24.3% PR. There were no statistically significant differences in ORR with respect to COO. In Double-Hit R/R DLBCL (n = 16), ORR was 37.5% with 25% CR. Median OS was 12.0 months (6.9-17.0). Most common grade 3/4 (G3/4) adverse events were thrombocytopenia (60.2%), neutropenia (60.2%) and anemia (26.9%). Febrile neutropenia occurred in 14.1% pts. Most frequent non-hematologic G3/4 events were asthenia (19.2%), infection (15.3%) and renal insufficiency (6.4%). There were 4 toxic deaths related to the R2-GDP schedule. Conclusions: LEN with Rituximab and GDP (R2-GDP) is feasible and active in R/R DLBCL. Results in the primary refractory DLBCL population are particularly promising. Analysis of COO did not revealed differences in response rates. Immune biomarkers results will be showed at the meeting. Clinical trial information: EudraCT 2014-001620-29 .

Impact of last lenalidomide dose, duration, and IMiD-free interval in patients with myeloma treated with pomalidomide/dexamethasone

AbstractTo gain insights into the characteristics of clinical resistance to lenalidomide, we evaluated the outcomes of 147 consecutive patients with multiple myeloma (MM) homogeneously treated with immunomodulatory imide drugs (IMiDs) pomalidomide and dexamethasone (Pd) for relapsed and/or refractory MM (median, 3 prior lines of treatment). We focused our analysis on the effect of the lenalidomide dose at which resistance was developed, the duration of lenalidomide exposure, and lenalidomide-free interval. On intent to treat, 33% of patients achieved ≥partial remission (PR) with Pd. When Pd was given immediately after lenalidomide, ≥PR was 32% (vs 37% after bortezomib). The response rates were similar for patients that received 5 to 15 mg vs 25 mg of lenalidomide (38.5% vs 30.5%, P = .329). Response rates were higher for patients that had received at least 12 months of lenalidomide (44% vs 27%) and for those with ≥18 months from last lenalidomide dose to pomalidomide dose (65% vs 23%). Median progression-free survival (PFS) and overall survival (OS) were 5 and 12.1 months, respectively, which was similar for patients who received lenalidomide, bortezomib or other regimens just before Pd and similar for patients who were receiving different doses of lenalidomide. IMiD-free interval ≥18 months was associated with longer PFS (10.3 vs 3.9 months, P = .003) and OS (27.1 vs 9.3, P = .008) as well as duration of last lenalidomide therapy ≥12 months (PFS: 7.8 vs 3.2, P = .023; OS: 16.5 vs 7.9, P = .005) even after adjustment for the number of prior therapies, duration of disease, and last lenalidomide dose.

Can Monosomy 7 be Targeted By Next Generation Cereblon-Modulating Agents?

Genomic advances have initiated a new era of precision oncology. Targeted therapeutics can rationally select potentially responsive patient populations and exclude resistant patients based on molecular mechanisms of action. The application of immunomodulatory drugs (IMiDs) evolved from unselective usage to the identification of del(5q) as a target, which then led to mechanistic clues and clarification of its mode of action. Lenalidomide (LEN) has been used in non del(5q) patients with a variable response rate, but the molecular underpinnings for LEN efficacy in this setting are not known. Genomic analyses (Negoro et al., Leukemia 2016) have provided only a marginal improvement in response prediction, suggesting that other factors might be relevant in sensitizing cells to LEN. The effects of LEN are related to its binding affinity to cereblon (CRBN), the substrate adaptor of the CRL4CRBN E3 ubiquitin ligase, a cullin-ring ligase consisting of damaged DNA-binding protein1(DDB1), cullin4a (CUL4A), and regulator of cullins-1 (ROC1). LEN selectively activates CRL4CRBN E3 ubiquitin ligase to selectively degrade CSNK1A1 leading to synthetic lethality in patients with del(5q) that are haploinsufficient (HI) for CSNK1A1. However, LEN and the new generation compounds pomalidomide and iberomide (CC-220) also trigger recruitment and degradation of the zinc finger transcription factors IKAROS (IKZF1, 7p12.2) and AIOLOS (IKZF3, 17p12-q21.1) through CRBN, and therefore promote their proteosomal degradation. The synthetic lethality of these immunomodulator agents relies on expression levels of AIOLOS and IKAROS. Response to those agents depends strictly on low expressions of AIOLOS and IKAROS sensitizing certain cell types (e.g., myeloma). We hypothesized that levels of LEN sensitivity might correlate with expression levels of its targets in selected disease subtypes of myeloid neoplasia (MN). We studied a large cohort of patients with MN (n=3,328) and we identified 122 patients with -7 and 194 patients with del(7q). We noted that for those cases with informative RNA-seq expression, IKAROS exhibited haploinsufficient (HI) mRNA levels in 67% of patients with -7 and 40% in del(7q), as defined based on levels &lt;25%tile of the diploid expression of cases (Kerr, ASH 2019). Since IKAROS is described to be a target of iberomide, we hypothesized that monosomy 7 (-7) but not del(7q) could selectively benefit from this agent, analogous to LEN in del(5q). Consistent with this proposition we further selected 160 hematopoietic cancer cells with available IKZF1 CNV status in a publicly available database of cell drug sensitivity (cancerrx). For all cell lines, the anti-proliferative effect of LEN was described. Cells with monosomy of IKZF1 (CNV=1) had an increased sensitivity to LEN as their IC50 was lower than compared to that of cells with IKZF1 with CNV ≥ 2 (6.1μM vs. 24.3μM). To further validate this prediction, we revisited the responsiveness to LEN (defined by Negoro et al., Leukemia 2016) of non-del(5q) MDS patients (n=79) showing an ORR of 40%. By focusing on patients with alterations in chr7 we identified 10 patients with MDS and high or very high International Prognosis Scoring System-Revised (IPSS-R) risk [6 patients with -7 and 4 patients with del(7q)]. In this cohort LEN response was assessed at 3 and 6 months; 4 out 6 patients with -7 responded to LEN, while del(7q) patients were all refractory (n=4). Responding monosomy 7 patients with complete bone marrow response (n=3) received 10 or 50mg doses of LEN (2 patients had a complex karyotype and 1 had isolated -7). The remaining responding patient had a partial response with hematological improvement. Interestingly, this patients was treated with a 5mg dose of LEN and had a TP53 mutation. In the other 2 patients: one with -7, LEN was discontinued because of pancytopenia associated with treatment, while in the other one -7 could not be confirmed by FISH. In the group of del(7q) patients, complex karyotypes and the presence of del(5q) in 2 did not predict for better response. Our preliminary results suggest that selective application of new generation IMiDS targeting IKAROS have clinical potential in patients with -7. Supportive data from in vitro cellular models will be comprehensively presented. Disclosures Walter: MLL Munich Leukemia Laboratory: Employment. Hutter:MLL Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Nazha:Tolero, Karyopharma: Honoraria; Incyte: Speakers Bureau; Abbvie: Consultancy; Jazz Pharmacutical: Research Funding; Daiichi Sankyo: Consultancy; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

Phase 1 Results of Anti-PD-Ligand 1 (Durvalumab) & Lenalidomide in Patients with Cutaneous T Cell Lymphoma and Correlation with Programmed Death Ligand 1 Expression and Gene Expression Profile

Background: T cells in CTCL are functionally exhausted and are characterized by the expression of immune inhibitory molecules such as PD1 and PD-L1 (Cancer Immunol Res 6; 2018). These findings justify the evaluation of immune checkpoint inhibition to reverse T cell exhaustion in CTCL. We initiated a phase 1/2 clinical trial of lenalidomide and durvalumab to determine the safety and efficacy of this regimen. Durvalumab is a human monoclonal antibody with high affinity and selectivity for PD-L1, targeting exhausted T cells and distinct cells within their environment. Lenalidomide, an oral immunomodulatory drug (IMiD) and analog of thalidomide, has previously shown activity in CTCL (Blood 123; 2014). Durvalumab may restore an anti-tumor immune response, and the combination of durvalumab and lenalidomide may enhance immune checkpoint blockade-induced immune responses. Associations between immune checkpoints, gene expression profile and the clinical efficacy of durvalumab/lenalidomide combination were evaluated. The primary objectives were to determine the recommended phase 2 dose of lenalidomide in combination with durvalumab and safety with primary endpoint of toxicity (using CTCAE 4.03). Secondary end points included objective response rate (ORR) and median duration. Relationships between gene expression profile (GEP), PD-L1 expression, and antitumor activity were exploratory end points. Methods: A Phase 1 portion (NCT03011814) is ongoing to evaluate the safety and tolerability of the durvalumab and lenalidomide combination. Pts are enrolled in sequential cohorts to receive durvalumab (fixed dose at 1500 mg) and dose escalation of lenalidomide (dose level 1 = 10 mg for all cycles; dose level 2 = 10 mg for cycle 1, 15 mg for all subsequent cycles; dose level 3 =10 mg for cycle 1, 15 mg for cycle 2, and 20 mg for all subsequent cycles) to characterize safety, efficacy and antitumor activity. Serial skin samples were collected to assess the impact on the tumor microenvironment and anti-tumor activity. Results: Ten pts. were evaluable for toxicities. Nine patients were evaluable for response with three patients at each dose level. 8 males/2 females, age 29-59 y, with refractory/advanced CTCL, clinical stages IB (1), IIA (3), IIB (4), IIIA (1), and aggressive epidermotropic CD8+ CTCL (1) and a median of prior systemic treatments of 3 (range, 2-4) have been enrolled. Median follow up time was 12 (range, 3-24+) months. No serious AEs or DLTs were observed during the DLT evaluation period (cycles 1-3). The most frequently reported AEs were fatigue (n=7), skin pain (n=4), chills (n=3), anemia (n=3), and leukopenia (4). One grade 3 maculopapular rash (possibly due to lenalidomide) was observed, all other treatment-related AEs were grade 1/2 in severity. Median cycles of treatment were 7 (range, 3-20+) months. Median duration of response was 4 (range, 1- 21+) months. Six pts achieved PR, while 3 pts maintained stable disease. Three pts remain on treatment. Expression panels of several checkpoints (PD1, PD-L1 &amp; ICOS) (Cycle1 Day1 vs Cycle 2 Day15) were analyzed. Detectable levels of PD-L1 but low levels of ICOS are observed in responding pts vs. high PD-L1 and ICOS levels in non-responders. GEP highlights downregulation of TNF-alpha signaling via NFkB, IFN-gamma, and PI3-AKT-mTOR signaling pathways among other pathways. Conclusions: Durvalumab/lenalidomide has significant clinical activity in refractory/advanced CTCL, which will be formally evaluated in the Phase 2 portion. Responses were durable and ongoing, and treatment was well tolerated. Dose escalation is up to lenalidomide 20 mg daily. Our preliminary results from pts on trial demonstrated that immune signatures on skin biopsies at baseline may be predictive of response to checkpoint blockade and yield insights into mechanisms of therapeutic resistance. Disclosures Querfeld: Bioniz: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Soligenix: Other: Investigator; Celgene: Other: Investigator, Research Funding; City of Hope Cancer Center and Beckman Research Institute: Employment; Medivir: Consultancy; Trillium: Consultancy, Other: Investigator, Research Funding; miRagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Kyowa: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Eisai: Other: Investigator; Elorac: Other: Investigator, Research Funding; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator. Palmer:Gilead Sciences: Consultancy. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy.

Combination of Nivolumab, Lenalidomide and Rituximab in Relapsed/Refractory Non-Germinal Center Diffuse Large B Cell Lymphoma: Results from a Dose-Escalation Cohort

Background: Ten to 15% of diffuse large B cell lymphoma (DLBCL) patients exhibit primary refractory disease (nonresponse or relapse within 3 months of therapy) and an additional 20-25% relapse following initial response. There is an unmet need for effective therapeutic regimens in relapsed/refractory (R/R) DLBCL. Lenalidomide is an immune modulator that reverses T cell dysfunction and also inhibits the NFκB pathway, which is constitutively active in non-germinal center (non-GCB) DLBCL. Lenalidomide and nivolumab, an anti-PD-1 antibody, each have single agent activity in R/R DLBCL. Here, we report the results of the dose-escalation cohort of this investigator-initiated, single-arm open-label study of the combination of nivolumab, lenalidomide and rituximab (NiLeRi) in R/R non-GCB DLBCL. Methods: Adult patients with R/R non-GCB DLBCL, as determined by the Hans algorithm, with adequate organ function and an ECOG performance status of ≤2 were eligible for the study. The primary objective was to evaluate the safety of NiLeRi, and determine the maximum tolerated dose (MTD) of lenalidomide in combination with fixed doses of rituximab and nivolumab, using a 3+3 dose escalation design. The secondary objectives were to determine efficacy in terms of overall response rate (ORR), progression free survival (PFS), and overall survival (OS) of patients treated with NiLeRi. All patients received nivolumab IV 3 mg/kg on days 1 and 15 and rituximab IV 375mg/m2 on day 1 of each 28-day cycle. Lenalidomide was initiated at 5 mg po once daily on days 1-21. Additional planned dose levels were 10 mg, 15 mg and 20 mg. Patients were evaluable for toxicity if they received all doses of nivolumab and rituximab and at least 16 doses of lenalidomide during cycle 1 or if they experienced a dose limiting toxicity (DLT), regardless of the number of doses. NiLeRi was given for 8 cycles and patients with partial response could receive lenalidomide and nivolumab for an additional 4 cycles. Response was assessed by PET-CT after 2, 5 and 8 cycles and defined by Lugano criteria. Results: Six patients with non-GCB subtype of DLBCL were enrolled in this study. The median age was 60.5 years (range 28-79), and 5 patients were male. The median number of prior lines of therapy was 4 (range 2-5), and the median IPI score was 3. None of the patients had bone marrow involvement. One patient each had been treated with autologous stem cell transplant (Auto-SCT) and CAR-T cell therapy. One patient withdrew consent before completing cycle 1 and was not evaluable for safety or efficacy. Safety: Five out of the six enrolled patients were evaluable for safety. All patients received lenalidomide 5 mg dose. Two patients experienced DLTs (grade 3 rash) resulting in lenalidomide discontinuation during cycle 2. The most common grade 3/4 toxicities were fatigue (20%), neutropenia (60%), thrombocytopenia (40%), and rash (40%). A total of 3 patients experienced grade 1/2 diarrhea and elevated liver enzymes. One patient experienced a grade 1 infusion reaction with rituximab. Efficacy: Patients who completed at least 1 cycle of therapy were evaluable for response, and this included 5 out of the 6 enrolled patients. The ORR and complete response (CR) rate were both 40%. Patients who responded did so early, with one patient achieving CR after 2 cycles and another patient achieving CR after 5 cycles. The best response seen in patients with primary refractory disease was PR. At a median follow up of 9.5 months, median PFS was 8.4 months (95% CI; 4.3 to not reached), and median OS was not reached. Discussion: This is the first study reporting the safety results of the combination of lenalidomide, nivolumab and rituximab in non-Hodgkin lymphoma. Rash was the most common DLT, limiting dose escalation of lenalidomide above 5mg in this cohort of patients. Two patients experienced durable CR early in the study after 2 and 5 cycles, respectively. This ORR and CR rate of 40% each in this small cohort of patients who had relapsed after multiple prior lines of therapy is encouraging. Correlative studies, including whole exome sequencing of patient samples, are underway, in an attempt to explore predictive markers for response and toxicity. Figure. Disclosures Mason: Sysmex: Honoraria. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. Morgan:Biogen: Equity Ownership; Eli Lilly: Equity Ownership; Vertex: Equity Ownership; Zoetis: Equity Ownership; Pfizer: Equity Ownership; Novo Nordisk: Equity Ownership; Gilead: Equity Ownership; Johnson and Johnson: Equity Ownership; Merck: Equity Ownership. Reddy:Abbvie: Consultancy; Genentech: Research Funding; Celgene: Consultancy; BMS: Consultancy, Research Funding; KITE Pharma: Consultancy. OffLabel Disclosure: Nivolumab and lenalidomide are not FDA approved for use in diffuse large B cell lymphoma

A Phase 1 Trial of Ruxolitinib, Lenalidomide and Methylprednisolone for Patients with Relapsed/Refractory Multiple Myeloma (MM)

Introduction Ruxolitinib (RUX) is an FDA-approved oral, selective inhibitor of Janus kinase (JAK) 1/2 for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea or intermediate or high-risk myelofibrosis (MF). Preclinical studies from our laboratory have demonstrated that RUX in combination with the immunomodulatory agent lenalidomide (LEN) and dexamethasone shows marked anti-myeloma effects both in vitro and in vivo. Furthermore, MUC1 (Mucin 1) is responsible for LEN resistance in MM cells, and RUX blocks its expression in multiple myeloma (MM) cells. Thus, RUX may restore sensitivity to LEN. RUX also downregulates PD-L1 and PD-L2 expression on MM cells and reduces tumor stimulatory M2 macrophage polarization in MM bone marrow. Therefore, a phase 1 trial was conducted to determine the safety and efficacy of RUX in combination with LEN and the steroid methylprednisolone (MP) for relapsed/refractory (RR) MM patients who had previously been treated with LEN/steroids and a proteasome inhibitor (PI) and showed progressive disease at study entry. Methods A traditional 3+3 dose escalation design was used to enroll subjects in four cohorts with planned total enrollment to be 49 patients. Subjects received RUX twice daily continuously, LEN daily on d1-21 of a 28-d cycle and MP orally every other day. In DL0, patients received RUX 5 mg, LEN 5 mg, and MP 40 mg. In DL+1 and +2, both doses of LEN and MP remained unchanged and RUX was escalated to 10 and 15 mg, respectively. DL+3 escalated LEN to 10 mg with MP unchanged and RUX at 15 mg. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results As of March 1, 2019, 43 patients were enrolled, and 40 were evaluable for efficacy. The median age was 65 years (range, 46-81), and 25 (58%) were male. Patients received a median of 6 prior treatments including LEN and steroids to which they were all refractory. No DLTs occurred, and DL+3 was expanded. Among all 40 evaluable patients, the CBR and ORR were 47% and 37%, respectively (1 CR, 4 VGPR, 10 PR and 4 MR), and 16 and 5 patients showed SD and PD. Notably, all 19 patients achieving &gt; MR were refractory to LEN (i.e. progressed while on or within 8 weeks of last dosage). The median PFS for all evaluable patients was 4 months. G3/4 AEs included anemia (16%), sepsis (14%), lymphocytopenia (14%), pneumonia (12%), neutropenia (12%) and hypokalaemia (12%). Most common SAEs included sepsis (14%) and pneumonia (12%). Conclusions This phase 1 trial demonstrates for the first time that a JAK inhibitor, RUX, can overcome refractoriness to LEN and steroids for RRMM patients. This all oral regimen was well tolerated, and reversible Grade 3/4 cytopenias occurred in only a small minority of patients. These promising results are leading to expansion of the current clinical trial to 78 patients, and represent a potential novel therapeutic approach for treating MM. Disclosures Berenson: Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Sanofi: Consultancy; Amgen: Consultancy, Speakers Bureau; Sanofi: Consultancy; OncoTracker: Equity Ownership, Other: Officer; OncoTracker: Equity Ownership, Other: Officer; Takeda: Consultancy, Speakers Bureau; Incyte Corporation.: Consultancy, Research Funding; Incyte Corporation.: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Swift:Bristol Mayers Squib: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Jansen: Consultancy, Honoraria. Eades:Celgene: Other: Stock. Boccia:Genentech: Speakers Bureau; DSI: Speakers Bureau; AMAG: Consultancy; AstraZeneca: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau. OffLabel Disclosure: The goal of this clinical trial is to establish ruxolitinib in combination with lenalidomide and methylprednisolone as the therapy for relapse/refractory multiple myeloma patients.