Pomalidomide Research Articles

KarMMa-3: A Phase 3 Study of Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Directed CAR T Cell Therapy Vs Standard Regimens in Relapsed and Refractory Multiple Myeloma

KarMMa-3: A Phase 3 Study of Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Directed CAR T Cell Therapy Vs Standard Regimens in Relapsed and Refractory Multiple Myeloma

Economic Evaluation of Daratumumab and Pomalidomide and Dexamethasone Versus Isatuximab and Pomalidomide and Dexamethasone for Patients with Relapsed or Refractory Multiple Myeloma

Background. Although several new treatments are available for patients with multiple myeloma (MM), most patients eventually relapse at a median time of 8.0 months (95%CI: 6.3-8.9). Patients with relapsed and refractory MM (R/R MM) who have had several lines of previous therapy or who are refractory to lenalidomide and proteasome inhibitors require alternative options. Daratumumab and isatuximab are monoclonal antibodies that bind to the human CD38 receptor. Phase II/III clinical trials showed that isatuximab (ISA) or daratumumab (DARA) in combination with pomalidomide (POM-d) and low-dose dexamethasone (DEXA) significantly improve progression-free survival (PFS) in patients with R/R MM. No studies have assessed the comparative efficacy and cost-effectiveness of both regimens in management of R/R MM. We performed an indirect comparison of both regimens in terms of PFS and overall survival (OS) and evaluated the cost-effectiveness and cost-utility of DARA+POM-d+DEXA and ISA+POM-d+DEXA from a US payer's perspective. Methods. A partitioned survival model was developed to create three health states (pre-progression, progression, and death). The model was run three times with different time horizons (one, three and five years). To simulate health outcomes for each treatment regimen, transition probabilities between the three health states were derived from parametric exponential and lognormal distributions fitted to Kaplan-Meier (KM) curves of PFS and OS of the phase Ib clinical trial (Chari et al.; Blood 2017) for DARA+POM-d+DEXA and the phase III clinical trial (Attal et al.; Lancet 2019) for ISA+POM-d+DEXA. Wholesale acquisition costs (WAC) were obtained from RedBook for each regimen. Pre-progression costs included costs of regimens; premedication (50 mg diphenhydramine, 650 mg acetaminophen, 50 mg ranitidine); managing side effects; routine care and monitoring; and medication administration. Costs were inflated based on the medical consumer price index to the second quarter of 2020. Utilities were obtained from literature and assumed the same for both interventions. Annual discount rate of 3.5% was applied for costs and outcomes beyond the first year. The life years (LY) and quality adjusted LY (QALY) for each treatment, and the incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) were estimated in both base and probabilistic sensitivity analyses (PSA:10,000 simulations). The cost-effectiveness plane (CEP) and cost-effectiveness acceptability curves (CEAC) were plotted. Results. In the naïve patient simulation, median PFS and OS were estimated to be 9.5 months and 18 months for DARA+POM-d+DEXA, and 14.5 months and 26 months for ISA+POM-d +DEXA. As shown in the table below, ISA+POM-d+DEXA is associated with greater LY and QALY gains at one-, three- and five-year time horizons. The costs of ISA+POM-d+DEXA at one- and three- year time horizons are less than that of DARA+POM-d+DEXA, which resulted in saving (decremental) ICERs. At 5 years' time horizon, ISA+POM-d+DEXA was associated with incremental benefits (0.57 LY, 0.35 QALY) and incremental costs of $88,271 when compared with DARA+POM-d+DEXA. Per the CEAC plot, the probability that ISA+POM-d+DEXA is cost-effective was 100%, 65% and 23% at a willingness to pay threshold (WTP) of $100,000 per QALY in one-, three- and five-year time horizons. Conclusions. Clinically, ISA+POM-d+DEXA is associated with incremental survival gains of ~1 month and quality-adjusted survival gains of 0.5 month than DARA+POM-d+DEXA when patients are treated for one year. The benefits increase with treatment duration to reach ~7 months life year gains and 4 months quality-adjusted life year gains if patients treated for 5 years. Due to its lower total costs, Isatuximab based-regimen yielded saving ICERs at one and three years. However, ISA+POM-d+DEXA cost exceeded DARA+POM-d+DEXA at 5 years' time horizon to yield an ICER above the WTP. Disclosures McBride: Merck: Speakers Bureau; Pfizer: Consultancy; Sandoz: Consultancy; MorphoSys: Consultancy; Bristol-Myers Squibb: Consultancy; Coherus BioSciences: Consultancy, Speakers Bureau. Abraham:Celgene: Consultancy; Terumo: Consultancy; Rockwell Medical: Consultancy; Janssen: Consultancy; Mylan: Consultancy; Sandoz: Consultancy; Coherus BioSciences: Research Funding, Speakers Bureau; MorphoSys: Consultancy.

Management of Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Novel Therapies in Routine Clinical Practice in Germany

Management of Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Treated with Novel Therapies in Routine Clinical Practice in Germany

Abstract 5630: Anti-BCMA bispecific tool therapy against Vk*MYC multiple myeloma is enhanced by IMiDs

Abstract BCMA is an ideal target antigen for myeloma immunotherapy as it is specifically expressed by plasma cells and T cell-engaging, BCMA-bispecific antibodies show potent tumor killing activity in human multiple myeloma (MM). However, a lack of longevity, potential immunotoxicity, and efficacy in high tumor burden situations are limitations to effective clinical utility. In order to optimize this therapeutic approach, we performed in vitro and in vivo assessments of a BCMA bispecific tool using the Vk*MYC immunocompetent mouse model of MM. Analysis at gene and protein level revealed variable levels of BCMA in Vk*MYC tumors, mirroring the heterogeneity of BCMA observed in human MM. In addition, we found that treatment with a gamma secretase inhibitor enhanced BCMA expression in Vk*MYC MM cells, similar to observations from patients. Having found the Vk*MYC model as a suitable model for BCMA targeted therapy, we treated Vk*MYC de novo and transplant mice with the BCMA targeting tool and established that the treatment was safe and efficacious (significant reduction in M-spike levels compared to control antibody). However, the response was transient and modest activity was noted in high tumor burden setting, likely because of poor T cell infiltration. Therefore, we hypothesized that combining BCMA therapy with agents capable of debulking the tumors would prolong and deepen therapeutic benefits and thus selected IMiDs for their anti-tumor and immunomodulatory properties. Because mice are resistant to therapy with IMiDs, we generated a humanized transgenic mouse strain with robust human CRBN expression and crossed it with the Vk*MYC mouse to obtain a novel immunocompetent, IMiD-responsive model, Vk*MYChCRBN. When combined with the IMiD pomalidomide (POM), bispecific-directed T cell control of MM was enhanced relative to bispecific alone. M-spike levels in two different transplantable models were reduced regardless of tumor burden. In addition, POM increased T cell effector activation, proliferation, and cytokine production. We also monitored transient weight loss unique to the bispecific-POM combination. Following this promising combinatorial result in vivo, we studied the relative roles of POM on target vs. effector cells by an in vitro killing assay using Vk*MYC tumor and splenocytes with or without expression of CRBN. Separately from the direct tumoricidal effects of POM on the tumor, we observed T cell-intrinsic effects of POM on the enhancement of BCMA-bispecific directed tumor lysis that correlated with T cell activation and proliferation. In summary, POM potentiated BCMA-CD3 bispecific directed T cell cytolysis of MM in the Vk*MYChCRBN animal model by enhancing effector cell activation, proliferation, cytokine production and directly reducing tumor burden. These results support ongoing preclinical studies of the benefits of combining standard of care therapy with potent T cell immunotherapy for MM. Citation Format: Erin W. Meermeier, Meaghen E. Sharik, Seth J. Welsh, Caleb K. Stein, Victoria M. Garbitt, Sochilt Brown, Kennedi T. Todd, Marco Bergsagel, P. Leif Bergsagel, Marta Chesi. Anti-BCMA bispecific tool therapy against Vk*MYC multiple myeloma is enhanced by IMiDs [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 5630.

Preferential solvation of pomalidomide, an anticancer compound, in some binary mixed solvents at 298.15 K

Abstract Preferential solvation of pomalidomide (PMD) was explored in dimethyl sulfoxide (DMSO)-dimethylformamide (DMF), DMSO-tetrahydrofuran (THF), DMSO-methanol (MeOH), DMSO-isopropanol, DMSO-water, water-DMF, water-THF, water-MeOH, and water–isopropanol binary mixed solvents at 298.15 K. Bosch-Rose model was utilized to determine the electronic transition energies (ET) and other preferential solvation parameters, describing solute-solute and solute-solvent interactions. We found that λmax situation shifted with dielectric constant of the pure solvents meaningfully. According to the obtained results, ET enhanced and λmax shifted to the lower wavelengths as the percentage of DMSO decreased in the binary mixtures, remarking the important role of DMSO for stabilizing the excited state (π⁎) of PMD chromophore via efficient intermolecular solute-solvent interactions. In addition, the aqueous binary systems showed an optimum point for the ET values as the percentage of water changed in the solutions. The local mole fraction of the solvents in the cybotactic region was also estimated to describe the specific and non-specific interactions in the systems.

A Simple and Rapid LC-MS/MS Method for Therapeutic Drug Monitoring of Lenalidomide

Immunomodulatory drugs lenalidomide (LENA) and pomalidomide (POMA) are synthetic compounds derived by modifying the chemical structure of thalidomide to improve its potency and reduce its side effects. LENA is used as a treatment for myeloma and blood disorders called myelodysplastic syndromes. The maximum clinical dose of LENA for some haematological cancers is generally ≤25 mg. Therapeutic drug monitoring (TDM) is important for the individualization of drug dosage. A highly sensitive and high performance liquid chromatography tandem mass spectrometry (LC–MS/MS) assay was developed and validated for the quantification of LENA in human plasma. LENA was extracted from human plasma by liquid-liquid extraction by ethyl acetate and analysed using a reversed phase isocratic elution on a Poroshell 120 EC-C18, (4.6 - 50 mm, 2.7μm) column. 0.1% formic acid: methanol (10:90% v/v), was used as mobile phase and detection was performed by triple quadrupole mass spectrometry LC-MS/MS using jet stream electrospray ionization in negative mode. POMA was used as the internal standard (IS). Analyte and IS were detected by tandem mass spectrometry using MRM of precursor–product ion transitions with 0.100 s dwell time, at m/z 258.0 > 213.0 for LENA and m/z 272.0 > 161.0 for POMA. The calibration curves were consistently accurate and precise over the concentration range of 20 ng/mL to 1000 ng/mL in plasma for LENA. This novel LC–MS/MS method competes with all the regulatory requirements and shows satisfactory accuracy and precision. It is sufficiently sensitive for the performance of pharmacokinetic, bioequivalence and TDM studies in humans.

Lenalidomide and pomalidomide potently interfere with induction of myeloid-derived suppressor cells in multiple myeloma.

An increase in immunosuppressive myeloid-derived suppressor cells (MDSCs) is associated with disease progression and treatment resistance in multiple myeloma (MM). We investigated the mechanisms underlying MDSC induction, and sought to discover a strategy for prevention of MDSC induction in MM. Using a transwell co-culture system, four of nine examined human myeloma-derived cell lines (HMCLs) were potent in inducing monocytic (M)-MDSCs from normal peripheral blood mononuclear cells (PBMCs). As the results, we identified that secretion of C-C motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF) by myeloma cells is a prerequisite for induction of MDSCs in MM. The immunomodulatory drug (IMiD) compounds, such as lenalidomide (LEN) and pomalidomide (POM), were identified as potent inhibitors of MDSC induction through bidirectional molecular effects of cereblon (CRBN)-dependent and -independent downregulation of CCL5 and MIF in myeloma cells; and downregulation of C-C motif chemokine receptor 5, a receptor for CCL5, and induction of interferon regulatory factor 8, a critical transcription factor for monocytic differentiation, in PBMCs. In the present study of the molecular mechanisms underlying MDSC induction, we identified a novel effect of LEN and POM of inhibiting MDSC induction via overlapping regulatory effects in myeloma cells and normal PBMCs.

A real-world comparative analysis of pomalidomide (POM) and other antimyeloma treatments following lenalidomide (LEN) discontinuation among patients with multiple myeloma.

e19337 Background: In clinical trials, POM has demonstrated favorable clinical outcomes in patients with multiple myeloma (MM) who received prior LEN. Few studies, however, have examined POM treatment for MM in the community oncology setting. This retrospective cohort study compared treatment patterns and outcomes between patients who received a post-LEN treatment, either POM or another antimyeloma regimen. Methods: Adult patients with MM in the US Oncology Network (USON) who initiated a post-LEN treatment within 60 days of LEN discontinuation between Jan 1, 2016 and May 1, 2018, were not clinical trial participants, and had ≥ 2 subsequent clinic visits, were eligible. Data were sourced from USON’s iKnowMed electronic health records. Among patients observed to have discontinued treatment, time to treatment discontinuation (TTTD) was estimated from date of initiation of post-LEN treatment (index treatment) to date of discontinuation. Among patients who started a new treatment after the index treatment, time to next treatment (TTNT) was estimated from date of initiation of index treatment until date of initiation of the next treatment. TTTD and TTNT were analyzed using the Kaplan–Meier (KM) method across the whole study sample; patients who did not discontinue or start a next treatment were censored. Results: Of 547 eligible patients, 155 (28.3%) initiated POM and 392 (71.7%) initiated another antimyeloma regimen. Demographic characteristics were similar between the groups (for all patients, median age was 68 years, 54.5% patients were male and 71.7% were white). In total, 74.2% and 83.7% of patients discontinued the index treatment in the POM and other-treatment groups, respectively. Among the entire study population, KM estimates of median TTTD were 3.5 months (95% CI 2.8–4.6) and 1.9 months (95% CI 1.6–2.4) in the POM and other-treatment group, respectively (log-rank P < 0.001). In total, 65.2% and 71.2% of patients initiated subsequent treatment in the POM and other-treatment groups, respectively. KM estimates of median TTNT were 6.2 months (95% CI 4.5–7.8) and 4.5 months (95% CI 3.9–5.3) in the POM and other-treatment groups, respectively (log-rank P = 0.38). Conclusions: For patients with MM the use of POM following LEN treatment resulted in longer TTNT and TTTD compared with those who received other antimyeloma therapy. These findings support the use of POM treatment after LEN as an option for patients with relapsed/refractory MM.

First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).

8500 Background: CC-92480 is a novel cereblon E3 ligase modulator (CELMoD) agent designed for rapid, maximal degradation of Ikaros and Aiolos. In vitro, it has enhanced antiproliferative and tumoricidal activity in MM cell lines, including those resistant to lenalidomide (LEN) and pomalidomide (POM), with strong immune stimulatory activity. Methods: A phase 1, multicenter, dose-escalation study evaluated the maximum tolerated dose (MTD), recommended phase 2 dose, safety, tolerability, and pharmacokinetics of CC-92480 + DEX in heavily pretreated RRMM pts. Eligible pts had progression on or within 60 days of their last MM therapy and were either resistant or intolerant to, or not otherwise candidates for currently available therapies. Several treatment schedules tested escalating doses of CC-92480 + DEX (40 mg; 20 mg if ≥75 yrs). Results: As of Dec 24, 2019, 66 pts had received CC-92480 + DEX. Median age was 67 yrs (range 40–78), median number of prior regimens was 6 (range 2–13). Prior therapies included stem cell transplantation (67%), bortezomib (92%), LEN (89%), POM (83%), and anti-CD38 antibodies (78%). CC-92480 doses explored included 0.1–1.0 mg QD (10/14 days × 2), 0.8–1.0 mg QD (21/28 days), 0.2–0.8 mg BID (3/14 days × 2), and 1.6–2.0 mg QD (7/14 days × 2). MTD was 1.0 mg for both 10/14 × 2 and 21/28 schedules. Grade 3–4 treatment-emergent adverse events (TEAEs) were reported in 58 (88%) pts. Most frequent grade 3–4 TEAEs included neutropenia (53%), infections (30%), anemia (29%), and thrombocytopenia (17%), with 9% grade 3 fatigue. Among different cohorts,10 pts had dose-limiting toxicities (the majority related to neutropenia). Overall response rate (ORR) was 21% (9 very good partial responses [VGPRs]; 5 PRs) for efficacy evaluable population (n = 66). Efficacy was dose and schedule dependent; across two 1.0 mg QD schedules (10/14 × 2 and 21/28), 10 of 21 (48%) pts responded (7 VGPR and 3 PR), with response independent of immunomodulatory drug (IMiD) refractoriness. Plasma exposure increase and peripheral blood Ikaros and Aiolos degradation were dose dependent. Ikaros and Aiolos significantly decreased in bone marrow plasma cells of LEN- and POM-refractory pts. Conclusions: TEAEs of CC-92480 were mainly related to myelosuppression in heavily pretreated, including triple-class-refractory, RRMM pts. Promising activity with 48% ORR at therapeutic doses was observed. The study is ongoing to further optimize dose and schedule, with combination studies underway and dose expansion cohorts planned. Clinical trial information: NCT03374085 .

Neuroprotection by the Immunomodulatory Drug Pomalidomide in the Drosophila LRRK2WD40 Genetic Model of Parkinson's Disease.

The search for new disease-modifying drugs for Parkinson’s disease (PD) is a slow and highly expensive process, and the repurposing of drugs already approved for different medical indications is becoming a compelling alternative option for researchers. Genetic variables represent a predisposing factor to the disease and mutations in leucine-rich repeat kinase 2 (LRRK2) locus have been correlated to late-onset autosomal-dominant PD. The common fruit fly Drosophila melanogaster carrying the mutation LRRK2 loss-of-function in the WD40 domain (LRRK2WD40), is a simple in vivo model of PD and is a valid tool to first evaluate novel therapeutic approaches to the disease. Recent studies have suggested a neuroprotective activity of immunomodulatory agents in PD models. Here the immunomodulatory drug Pomalidomide (POM), a Thalidomide derivative, was examined in the Drosophila LRRK2WD40 genetic model of PD. Mutant and wild type flies received increasing POM doses (1, 0.5, 0.25 mM) through their diet from day 1 post eclosion, until postnatal day (PN) 7 or 14, when POM’s actions were evaluated by quantifying changes in climbing behavior as a measure of motor performance, the number of brain dopaminergic neurons and T-bars, mitochondria integrity. LRRK2WD40 flies displayed a spontaneous age-related impairment of climbing activity, and POM significantly and dose-dependently improved climbing performance both at PN 7 and PN 14. LRRK2WD40 fly motor disability was underpinned by a progressive loss of dopaminergic neurons in posterior clusters of the protocerebrum, which are involved in the control of locomotion, by a low number of T-bars density in the presynaptic bouton active zones. POM treatment fully rescued the cell loss in all posterior clusters at PN 7 and PN 14 and significantly increased the T-bars density. Moreover, several damaged mitochondria with dilated cristae were observed in LRRK2WD40 flies treated with vehicle but not following POM. This study demonstrates the neuroprotective activity of the immunomodulatory agent POM in a genetic model of PD. POM is an FDA-approved clinically available and well-tolerated drug used for the treatment of multiple myeloma. If further validated in mammalian models of PD, POM could rapidly be clinically tested in humans.

Effect of Pomalidomide on Activity of Myeloma Cell Line MM1.S and Expression of CRBN

To explore the effects of different concentration of pomalidomide on human multiple myeloma cell line MM1.S and the expression of CRBN. CCK-8 method was used for detecting inhibition effect of promalidomide on proliferation of MM1.S cells. Apoptosis rate of MM1.S cells was detected by flow cytometry with Annexin V-FITC/PI double staining. Real-time quantitative PCR was used to determine CRBN gene expression level. Western blot was used to detect the effect of pomalidomide on the protein expression of CRBN in MM1.S cells. Pomalidomide has an inhibitory effect on MM1.S cells with time-and dose-dependent manners. Pomalidomide induced apoptosis in MM1.S cells. When the concentration of pomalidomide was 0, 40 and 80 μmol/L, the expression of CRBN gene after the treatment of MM1.S cells for 72 hours was 1.487±0.340, 0.211±0.054 and 0.055±0.005, by using actin as internal refereme. Pomalidomide significantly reduced CRBN protein expression in MM1.S cells. Pomalidomide can inhibit the proliferation of MM1.S cells and promote its apoptosis. A certain concentration of pomalidomide can reduce the expression of CRBN gene and down-regulate its protein expression in MM1.S cells.

Four-Year Interim Analysis of Miroir, a French Multicenter, Non-Interventional Study of Pomalidomide in Relapsed/Refractory Multiple Myeloma

BACKGROUND Real-world data on the use of pomalidomide (POM) for the treatment (Tx) of relapsed/refractory multiple myeloma (RRMM) are limited. The MIROIR study was designed to evaluate POM Tx in routine clinical practice in France. Here, we present results from a prespecified 4-year interim analysis. METHODS MIROIR is a multicenter, observational, ambispective, non-interventional study of POM in routine clinical practice. Adult patients (pts) with MM who initiated POM Tx in France between October 1, 2014, and September 30, 2018, were included. All pts were required to be enrolled in the French IMNOVID® registry. Data were collected from medical records of consenting pts. Key exclusion criteria included previous treatment with POM or simultaneous participation in a clinical trial. The primary endpoint is progression-free survival (PFS) at 6 months. Key secondary endpoints include time to next Tx (TTNT), overall survival (OS), and safety. This study is ongoing; targeted enrollment is 3000 pts (ClinicalTrials.gov, NCT02902900). RESULTS A total of 2099 pts were included in this analysis (median follow-up: 23.3 months; data cutoff: February 1, 2019). Median age was 70.0 years, and 655 pts (31.2%) were aged ≥ 75 years; 1134 pts (54.0%) were male. Median time from start of first-line Tx to POM initiation was 51.4 months. Pts had received a median of 3 prior lines of therapy (range: 0-9), with 914 (43.5%), 644 (30.7%), 312 (14.9%) and 229 pts (10.9%) receiving ≤ 2, 3, 4, and ≥ 5 prior lines, respectively. From 2014 to 2016, the median number of prior lines of therapy before POM initiation was 3, and from 2016 to 2018, the median was 2. Nearly all pts received prior lenalidomide (LEN; 97.0%) and bortezomib (96.7%). POM was initiated at 4 mg/day in 1635 pts (77.9%) overall and in 1216 pts (84.2%) aged < 75 years and in 419 pts (64.0%) aged ≥ 75 years. Dexamethasone was prescribed at 20 mg/day and 40 mg/day in 507 (35.1%) and 732 pts (50.7%) aged < 75 years and in 405 (61.8%) and 62 pts (9.5%) aged ≥ 75 years. Overall, the 6-month PFS rate was 51.7% (95% CI, 49.4%-54.1%). Other key PFS data in pt subgroups are reported in the Table. In the overall population, median TTNT, 12-month OS rate, and median OS were 10.4 months (95% CI, 9.7-11.2), 70.6% (95% CI, 68.5-72.6), and 24.6 months (95% CI, 22.9-not reached), respectively. Among 1164 pts (55.5%) with ≥ 1 adverse event (AE), the most common AEs were neutropenia (290 pts; 24.9%), infections (263 pts; 22.6%), thrombocytopenia (99 pts; 8.5%), and asthenia (87 pts; 7.5%). POM dose was reduced due to an AE in 20.7% of pts; POM Tx was interrupted or discontinued due to an AE in 36.2% and 15.2% of pts, respectively. CONCLUSIONS The results of this interim analysis confirm the efficacy of POM reported in clinical trials and underscore its role in Tx of RRMM, including after LEN Tx. Median PFS in pts with ≤ 2 prior Tx lines was numerically longer than in pts who had more Tx lines, supporting earlier Tx with POM. PFS outcomes were similar regardless of the duration of LEN Tx (< or ≥ 6 months) before initiation of POM and whether pts had received LEN or another Tx as their most recent therapy. The latter finding suggests that POM can be used after relapse or resistance to LEN and that there is no need to replace an IMiD agent with another class of treatment. Disclosures Decaux: Celgene Corporation, Janssen, Takeda, Amgen: Honoraria. Macro:Celgene, Janssen, Amgen, Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial Support. Gourgou:Celgene: Employment, Equity Ownership. Lachenal:Celgene: Other: Scientific Comittee's. Stoppa:Celgene: Honoraria. Jaccard:Abbvie: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Perrot:jannsen: Honoraria, Membership on an entity's Board of Directors or advisory committees; takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding. Karlin:AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fohrer:Celgene: Consultancy, Honoraria. Leleu:Carsgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Merck: Honoraria; Oncopeptide: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria.

Updated Results from the German Mpnsg-0212 Combination Trial: Ruxolitinib Plus Pomalidomide in Myelofibrosis with Anemia

Updated Results from the German Mpnsg-0212 Combination Trial: Ruxolitinib Plus Pomalidomide in Myelofibrosis with Anemia

Identification of Novel Immune Cell Populations in Lenalidomide Refractory Relapsed Multiple Myeloma Patients Treated with Pomalidomide and Low Dose Dexamethasone

Identification of Novel Immune Cell Populations in Lenalidomide Refractory Relapsed Multiple Myeloma Patients Treated with Pomalidomide and Low Dose Dexamethasone

Translational and Clinical Evidence of a Differentiated Profile for the Novel CELMoD, Iberdomide (CC-220)

Translational and Clinical Evidence of a Differentiated Profile for the Novel CELMoD, Iberdomide (CC-220)

A Phase Ia/Ib Study Exploring the Synthetic Lethality of the Orally Administered Novel BTK Inhibitor, Dtrmwxhs-12 (DTRM-12), in Combination with Everolimus and Pomalidomide in Patients with Relapsed/Refractory CLL, DLBCL or Other B-Cell Lymphomas

A Phase Ia/Ib Study Exploring the Synthetic Lethality of the Orally Administered Novel BTK Inhibitor, Dtrmwxhs-12 (DTRM-12), in Combination with Everolimus and Pomalidomide in Patients with Relapsed/Refractory CLL, DLBCL or Other B-Cell Lymphomas

Favorable Progression-Free Survival Associated with Immune Bio-Markers Modulated By Pomalidomide in Relapsed/Refractory Multiple Myeloma: An Analysis of Phase III Study

We have previously shown that immune cells, including regulatory T cells, Th17 cells, myeloid-derived suppressor cells and NK cells are abnormal in multiple myeloma (MM). It is well demonstrated that immune-modulatory drugs like pomalidomide (POM) have shown impact on various immune sub-populations in pre-clinical studies. Relapsed/refractory (RR) MM (N=540) patients were randomized to be bortezomib and dexamethasone (Vd) with or without pomalidomide POM (Vd) in a large Phase III CC4047-MM007 (OPTIMISMM, NCT01734928) study, allowing for critical investigation into the impact of POM on immune cell-subset. We have analyzed 197 RRMM patients utilizing 366 peripheral blood samples collected at screening, day 8 of cycle 1 and day 8 of cycle 3 using 98 immune biomarker-panel with multi-color flow to identify changes with POM exposure in various sub-populations of B, T, & NK cells. The primary objective was to investigate association of PFS with the modulation of predictive and prognostic immune bio-markers by POM. The analyzed patient-treatment cohorts had identical characteristics as the total patient population and was balanced for the 2-treatment arms, overall patient characteristics and response. Among B-Cell-subpopulations, we observed significant up-regulation of B1b cells (CD19+CD43+) and down-regulation of regulatory B cells (Bregs, CD19+CD5+CD43-) by the PVd arm as compared with the Vd arm. A significant increase in MZB cells were observed in both arms. Patients with a higher proportion of either CD19+ B cells or Bregs at screening showed significantly favorable PFS (logrank p value < 0.05) in the PVd arm as compared with the VD arm, which indicates that these markers are predictive of PFS for PVd treatment. Moreover, patients with a higher proportion of either [naïve B cells (CD19+CD27-IgD+)] or [CD95+ B cells that display germinal center differentiation features (CD19+ CD185+) at cycle 1 day 8] showed significantly favorable PFS in PVd arm (logrank p value < 0.05); however, they were not prognostic with the Vd arm alone. This indicates that the early impact of Pom on these cell types may provide a prognostic bio-marker outcome following PVd therapy in B cell-compartment at cycle 1. Among T-Cell subpopulations, we observed that patients with higher proportion of CD4+ T cells at screening showed significantly favorable PFS in PVd arm, indicating a predictive marker. We observed significantly favorable PFS in PVd arm in both patients with a higher number of CD8 T cells expressing OX-40 at cycle 3 day 8 and patients with lower number of CD4 T cells or Tfh cells (CD4+CD185+) expressing PD-1 or regulatory T cells expressing (low CD127+ and high CD25+) HLA-DR at cycle 3 day 8, indicating prognostic markers. The studied markers were neither predictive nor prognostic for the Vd arm alone. The total proportion of NK cells were significantly elevated following the Pom-containing regimen as early as day 8 of cycle 1 and persisted at cycle 3 as compared to the Vd arm. Among NK cell-subpopulations, we observed that the patients with either a higher proportion of NK cells without expressing KIR molecules or a lower proportion of NKT cells expressing CD158b KIR molecule at screening had significantly superior PFS with in the PVd, which indicates that each is a predictive marker. Finally, we showed that patients with either a higher proportion of NK cells expressing activation marker NKG2D, or a lower number of CD158b expressing NK cells at cycle 3 had significantly improved PFS with the PVd arm but not with the Vd arm, which indicates the prognostic nature of these markers. In summary, this large randomized study identified specific immunophenotypes at screening and after exposure to pomalidomide combinations, allowing for the identification of predictive and prognostic markers for favorable PFS, respectively. Disclosures Biyukov: Celgene: Employment, Equity Ownership. Oriol:Celgene, Amgen, Takeda, Jansse: Consultancy, Speakers Bureau. Pierceall:Celgene Corporation: Employment, Equity Ownership. Richardson:Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Anderson:Janssen: Other: Advisory Board; Gilead Sciences: Other: Advisory Board; C4 Therapeutics: Other: Scientific founder ; Sanofi-Aventis: Other: Advisory Board; OncoPep: Other: Scientific founder . Thakurta:Celgene: Employment, Equity Ownership. Munshi:Oncopep: Consultancy; Adaptive: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Adaptive: Consultancy; Amgen: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Oncopep: Consultancy; Takeda: Consultancy.

Genetic and Transcript Changesin Cereblon in IMiD-Treated Myeloma Patients

Myeloma survival has been significantly improved by novel therapies over the past two decades. Immunomodulatory agents (IMiDs, Lenalidomide (LEN) and Pomalidomide (POM)) are a backbone of current treatment strategies. But myeloma (MM) remains incurable, because patients ultimately relapse. IMiD drug resistance mechanisms are multifactorial, and can be either dependent or independent of IMiDs binding to Cereblon (CRBN) (a component of an E3 ligase) in tumor and immune cells. A small series of relapsed patients demonstrated sub-clonal mutation rates of 12% in CRBN and 10% in other CRBN pathway genes (Kortum et al, Blood 2016), but the clinical implication of this observation is unknown. In contrast, baseline gene expression of CRBN was not associated with clinical outcome to POM-DEX therapy (Qian et al, Leukemia & Lymphoma 2018). An integrated assessment of the burden of different mechanisms of CRBN function loss, the selective pressure for their survival, and their effects on response to CRBN-modulating agents, is lacking. For patients that progress on IMiD-based therapies, there is a need to develop drugs that will overcome their resistance. To appropriately target the right novel agents to the right patients, resistance mechanisms must be understood. A deeper understanding of the mechanistic basis for IMiD-specific resistance mechanisms is critical for differentiating new Cereblon modulating agents (eg CELMoDs) from the IMiDs. Here, we present the largest comprehensive analysis of the burden of CRBN mutation or transcript variants in relapsed refractory myeloma (RRMM) patients. We analysed WGS and RNASeq data from 298 MM samples from 268 patients across 4 clinical trials (CC-4047-MM-010 (N=226), CC-4047-MM-013 (N=17), CC-220-MM-001 (N=45) and CC-122-ST-001MM2 (N=10), for whom outcome data were available. All patients had been exposed to LEN-based therapy and a subset (69/268) were also exposed to POM-based therapy. The overall incidence of single nucleotide variants in CRBN was 17/298 (5.7%). The incidence of at least monoalleleic deletion at the CRBN gene locus was 21/298 (5.5%). CRBN has different transcript isoforms (Gandhi et al, BJHaem 2014). As high levels of isoform ENST00000424814.5, with deletion of exon 10, was previously correlated with poorer survival (Neri et al, Blood 2016), we assessed incidence of a high ratio (>2) of exon 10-deleted CRBN transcript to full length CRBN transcript. 92 samples had sufficient purity (>90% tumor cells) for this analysis. 13/92 samples (14.1%) had a high exon10-deleted transcript ratio. Overall, 43/268 (16.0%) patients had genetic or transcript variants in CRBN. In contrast, 27/514 (5.2%) newly diagnosed myeloma (NDMM) patients from the Myeloma Genome Project had genetic or transcript variants in CBRN; 2/514 (0.4%) had CRBN mutations, 11/514 (2.1%) had CRBN gene deletion and 14/514 (2.7%) had a high exon10-deleted transcript ratio. Thus, there was an increase in CRBN variants from NDMM to RRMM. In patients exposed to LEN but not POM (219/268), there were 5 CRBN mutations, 14 monoallelic CRBN deletions and 13/92 patients with high exon10-deleted transcript ratio. In 69/268 patients exposed to POM (baseline from CC-220-MM-001 (N=35), CC-122-ST-001MM2 (N=10), or follow up samples from CC-4047-MM-010 (N=24)), there were 12 CRBN mutations in 8 patients (11.6%) and 7 CRBN deletions (10.1%), approximately double the incidence seen in the whole cohort. 3 CRBN deletions were homozygous, which was not observed in non-POM-exposed individuals. Sample purity was insufficient to measure transcript ratios. In summary, 16.0% of RRMM patients that received LEN or POM have genetic or transcript variants in CRBN, a higher proportion than in NDMM. The impact of these aberrations on CRBN function, especially related to binding of CRBN-modulating drugs, remains to be ascertained. Analysis of the correlation between CRBN variation and response to therapy, clinical outcomes, and the incidence and effect of mutation or copy loss of CRBN interactors (E3 Ligase members and regulators, CRBN substrates) is underway and will be presented. Disclosures Gooding: Celgene: Research Funding. Ansari-Pour:Celgene Corporation: Consultancy. Towfic:Celgene Corporation: Employment, Equity Ownership. Ortiz:Celgene Corporation: Employment, Equity Ownership. Rozelle:Celgene Corporation: Other: Contractor for Celgene. Zadorozhny:Celgene Corporation: Other: Contractor for Celgene. Amatangelo:Celgene Corporation: Employment, Equity Ownership. Flynt:Celgene Corporation: Employment, Equity Ownership. Tsai:Celgene Corporation: Employment, Equity Ownership. Neri:Celgene, Janssen: Consultancy, Honoraria, Research Funding. Bahlis:AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Vyas:Novartis: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Astellas: Speakers Bureau; Abbvie: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding. Thakurta:Celgene: Employment, Equity Ownership.

Results from Phase 1/2 Trial of Tagraxofusp in Combination with Pomalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma

Background: The bone marrow microenvironment of many multiple myeloma (MM) patients contains high levels of CD123-expressing plasmacytoid dendritic cells (pDCs). These pDCs have been shown to augment MM growth and contribute to drug resistance (Chauhan, et al., Cancer Cell, 2009). Tagraxofusp, a novel CD123 targeted therapy, has demonstrated high levels of anti-tumor activity in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive CD123+ malignancy of pDC origin. Tagraxofusp demonstrated potent in vitro and in vivo activity against MM cell lines and primary tumor samples via both a direct anti-MM effect and indirect pDC-targeting effect (Ray, et al., Leukemia, 2017), as well as demonstrating synergy in these systems when used in combination with traditional MM therapies including pomalidomide (POM). As such, targeting pDCs with tagraxofusp may offer a novel therapeutic approach in MM. Methods: This multicenter, single arm Phase 1/2 trial enrolled patients with relapsed or refractory (r/r) MM and tested two different doses of tagraxofusp (7 or 9 mcg/kg). Patients received tagraxofusp as a daily IV infusion for days 1-5 of a 28-day cycle as a single agent for the initial run-in cycle (cycle 0) and in combination with standard doses/administration of POM and dexamethasone (DEX) in cycles 1 and beyond. Objectives included evaluation of safety and tolerability, identification of the maximum tolerated or tested dose, and efficacy. Results: 9 patients with r/r MM received tagraxofusp (7 mcg/kg, n=7; 9 mcg/kg, n=2). 5 males, median age 65 years (range: 57-70), median 3 prior therapies (range 2-6). Median follow-up was 12 months (range: 7 - 19). The most common treatment-emergent AEs (TEAEs) were hypoalbuminemia 67% (6/9); chills, fatigue, insomnia, nausea and pyrexia each 56% (5/9); and dizziness, headache, hypophosphatemia, and thrombocytopenia each 44% (4/9). The most common grade 3 and 4 TEAEs were thrombocytopenia 44% (4/9) and neutropenia 33% (3/9). No grade 5 events reported. 5 patients treated with tagraxofusp and POM+DEX had a partial response (PR) after tumor evaluation. These patients demonstrated a rapid decrease in a set of myeloma-related laboratory values from pre-tagraxofusp treatment levels after the first combination cycle of tagraxofusp and POM+DEX. Additionally, these 5 patients demonstrated >50% decreases in peripheral blood pDC levels after both tagraxofusp monotherapy and combination therapy. Conclusions: Tagraxofusp was well-tolerated, with a predictable and manageable safety profile, when dosed in combination with POM+DEX in patients with r/r MM. Evidence of pDC suppression in peripheral blood and BM was observed in this patient population. 5 patients that received tagraxofusp and POM+DEX combination had PRs and decreases in pDC levels while on treatment with tagraxofusp. Given CD123 expression on pDCs in the tumor microenvironment and the potential synergy of tagraxofusp with certain MM agents including POM, tagraxofusp may offer a novel mechanism of action in MM. NCT02661022. Disclosures Richardson: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Zonder:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Chen:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Rupprecht:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Chauhan:C4 Therapeutics.: Equity Ownership; Stemline Therapeutics: Consultancy. Anderson:Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board; OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder .

Pomalidomide + Bortezomib + Low-Dose Dexamethasone after 1 Prior Line of Therapy in Patients with Lenalidomide-Pretreated Multiple Myeloma: Subanalysis of the Phase 3 Optimismm Trial By Patient Age and Prior Stem Cell Transplant

Pomalidomide + Bortezomib + Low-Dose Dexamethasone after 1 Prior Line of Therapy in Patients with Lenalidomide-Pretreated Multiple Myeloma: Subanalysis of the Phase 3 Optimismm Trial By Patient Age and Prior Stem Cell Transplant