Pomalidomide Research Articles

A Validated Chiral Chromatography Method for Enantiomeric Separation of Pomalidomide in Human Plasma.

In the present work, new chiral stationary phase high-performance liquid chromatography (CSP-HPLC) method was established and validated for the quantification of pomalidomide (PMD) enantiomers in human plasma. The chromatographic enantiomeric separation was achieved on a Daicel-CSP, Chiralpack IA 4.6 × 250mm, 5μm; because of its advantages of high degree of retention, high resolution capacity, better reproducibility, ability to produce lower back pressure and low degree of tailing. The mobile phase was maintained as methanol: glacial acetic acid (499.50ml:50μL). Ultraviolet wavelength for detection was 220nm. PMD enantiomer-I and enantiomer-II were separated at 8.83 and 15.34min, respectively. Limit of detection and limit of quantification for each enantiomer and the calibration curve of standard PMD was linear in range between 10-5,000ngmL-1. The method was validated according to The International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH(Q2R1)) specific guidelines. We found no interference peak with PMD chromatogram obtained. This is a simple, reliable and specific method for detection and quantification of enantiomer of PMD in human plasma sample.

Alliance A061202: ixazomib, pomalidomide, and dexamethasone for patients with lenalidomide-refractory MM in first relapse

AbstractOptimal therapy for the growing number of patients with lenalidomide (LEN)-refractory multiple myeloma in their first relapse remains poorly defined. We therefore undertook a randomized phase 2 study to evaluate the efficacy and safety of combining the oral proteasome inhibitor ixazomib (IXA) with pomalidomide (POM) and dexamethasone (DEX) in this patient population. The overall response rate (ORR) for POM-DEX was 43.6%, and for IXA-POM-DEX, it was 63.2%. The depth of response, measured by the attainment of at least a very good partial response, favored triplet therapy over doublet therapy (28.9% vs 5.1%; P = .0063). A preplanned interim analysis after 75% of the progression events had occurred demonstrated an improvement in progression-free survival (PFS) that favored IXA-POM-DEX and that crossed the predefined boundary of superiority, leading to release of the study results. With additional follow-up, the median PFS for POM-DEX was 7.5 months (95% confidence interval [CI], 4.8-13.6 months) vs 20.3 months for IXA-POM-DEX (95% CI, 7.7-26.0 months; hazard ratio, 0.437; upper 90% bound = 0.657). The ORR and median PFS for 26 of 30 eligible patients who crossed over from the doublet to the triplet therapy at disease progression was 23.1% and 5.6 months, respectively. Overall survival was similar between the 2 groups. More hematologic toxicities were seen with the triplet therapy, but nonhematologic adverse events were similar between the 2 arms. Our data support further testing of this all-oral triplet therapy in comparison with current standard triplet therapy in the context of phase 3 studies for patients with LEN-refractory disease at first relapse. This trial was registered at www.clinicaltrials.gov as #NCT02004275.

Exploring the binding mechanism of Pomalidomide drug with CT-DNA: Insights from multi-spectroscopic, molecular docking and simulation studies

Exploration of the interaction of a thalidomide analogue immunomodulatory and anti-angiogenic drug pomalidomide (POD) with calf thymus DNA (CT-DNA) was carried out using multi-spectroscopic (UV–Vis, fluorescence, and circular dichroism), molecular docking and metadynamics simulation studies in Tris–HCl buffer (pH 7.4). The results revealed that POD binds to the nucleic acid via groove binding mode. The proposed binding mode is strongly supported by competitive dye displacement assay using ethidium bromide (EB) and rhodamine B (RB) dyes, KI quenching studies and viscosity measurements. The thermodynamic parameters such as ∆Ho (60 kJ mol−1), ∆So (297 JK−1 mol−1) and ∆Go (-22 kJ mol−1) indicated that the POD/CT-DNA interaction is spontaneous and is stabilized predominantly by hydrophobic forces. The proposed groove binding mode of interaction of POD with CT-DNA was further confirmed by a computer-aided molecular docking studies and analysis of free energy surface contour derived from the molecular simulation study.

A Phase 2b Study of Selinexor in Combination with Carfilzomib, Daratumumab, or Pomalidomide in Patients with Multiple Myeloma Relapsing on Current Therapy

Background: Selinexor is an oral, selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1), leading to retention of tumor suppressor proteins and apoptosis in malignant cells. Preclinical studies suggest synergistic activity when selinexor is combined with other treatments for multiple myeloma (MM). We hypothesize the addition of selinexor can recapture response to patients relapsing on their current carfilzomib (CFZ), pomalidomide (POM) or daratumumab (DARA)-based regimens. Methods: This is an ongoing phase 2b, open-label, multicenter investigator-initiated study to evaluate the safety and efficacy of selinexor plus CFZ, POM, or DARA. MM patients with documented disease progression or refractory disease while on current treatment with any CFZ-containing regimen (Arm 1), any POM-containing regimen (Arm 2), or any DARA-containing regimen (Arm 3) were eligible for this study. Patients were assigned to the respective arm only if their most recent line of therapy contained the specific drug of interest. Arm 1 consists of selinexor 80 mg orally on D1, 8, 15; CFZ 56 mg/m 2 IV on D1, 8, 15; and dexamethasone (DEX) 40 mg or 20 mg if ≥75 years old on D1, 8, 15, 22. Arm 2 consists of selinexor 60 mg orally on D1, 8, 15; POM 4 mg orally on D1-21; and DEX 40 mg or 20 mg if ≥75 years old on D1, 8, 15, 22. Arm 3 consists of selinexor 100 mg orally on D1, 8, 15, 22; DARA 16 mg/kg IV or 1,800 mg SQ dosing as per standard of care; and DEX 40 mg or 20 mg if ≥75 years old on D1, 8, 15, 22. The primary endpoint is overall response rate (ORR), which includes patients who experience partial response (PR), very good partial response (VGPR), complete response (CR), or stringent CR (sCR), based on International Myeloma Working Group response criteria (Kumar 2016). Secondary endpoints include duration of response (DOR), clinical benefit rate (CBR = sCR + CR + VGPR + PR + stable disease [SD]), progression-free survival (PFS), and treatment-emergent adverse events (TEAEs). Results: At data cutoff (July 14, 2023), there were 23 patients enrolled, including 20 patients on trial, 2 screen failures, and 1 in screening. Of the 20 patients on trial, 1 patient was enrolled onto Arm 1, 9 patients onto Arm 2, and 10 patients onto Arm 3. The median age was 66 years (range 52-83), 30% with ISS stage III MM, 75% with high-risk cytogenetics, 90% refractory to the last LOT, 50% triple refractory, and 35% quadruple refractory. Fifteen unique patients had high-risk cytogenetics, which included 9 patients with 1q21 duplication, 7 with t(4;14), 2 with del(17p)/monosomy 17, 4 with TP53 mutation, and 1 with complex karyotype. In 18 patients evaluable for response, the ORR was 33% (6/18; PR, 6 [33%]) and the CBR was 89% (16/18; PR, 6 [33%]; SD, 10 [56%]); 2 patients withdrew consent before response evaluation. For Arm 2, the ORR was 29% (2/7; PR, 2 [29%]) and the CBR was 86% (6/7; PR, 2 [29%]; SD, 4 [57%]). For Arm 3, the ORR was 44% (4/9; PR, 4 [44%]) and the CBR was 100% (9/9; PR, 4 [44%]; SD, 5 [56%]). In the overall cohort, median DOR was 9.46 months (95% CI, 5.1-12.3), and median PFS was 5.98 months (95% CI, 3.9-NR) (Figure 1). There were 18/20 patients who experienced any grade TEAEs (Table 1). No treatment-related deaths occurred. The most common grade 3 TEAEs were neutropenia (25%), thrombocytopenia (15%), pneumonia (10%), and hyperglycemia (10%). One patient experienced a grade 4 TEAE of neutropenia. There were 3 unique patients who experienced SAEs related to study treatment, which included pneumonia (n=2), chest pain (n=1), sepsis (n=1), and lactic acidosis (n=1). Seventeen patients discontinued treatment due to disease progression (n=12) and withdrawal of consent (n=5). Two patients are deceased: one patient died during long-term follow-up unrelated to treatment of disease; and one patient was hospitalized for dehydration, anorexia, and hyponatremia after C1D8 of KCD then experienced progressive cytopenias upon discharge likely due to disease progression. Conclusions: Preliminary results suggest selinexor plus CFZ, POM, or DARA is safe and restores sensitivity to therapy in relapsed/refractory MM patients. In this population of heavily pretreated MM patients relapsing on their most recent line of therapy, the ORR of 33% and CBR 89% highlights the clinical potential and generally manageable side effect profile of selinexor as an add-on drug for patients with relapsed/refractory MM in combination with CFZ, POM, and DARA. Clinical trial information: NCT04661137.

A Phase II Multicenter Clinical Trial Assessing the Safety and Efficacy of Ixazomib, Pomalidomide and Dexamethasone Combination As Second or Third-Line Treatment for Triple-Class Exposed Patients with Relapsed and Refractory Multiple Myeloma (iPod-790 Trial)

Introduction: Despite significant improvement in the outcomes of early treatment lines in myeloma, most patients (Pts) invariably relapse. As triple and quadruple regimens are being introduced at the upfront setting, many Pts are either triple-class exposed or triple-class refractory (TCE/TCR) early in their disease course. Although novel immunotherapies are emerging with impressive efficacy among TCE/TCR myeloma Pts, their use is currently limited due to potential toxicities, costs and logistic constraints. We report the outcomes of the IPoD-790 clinical trial (NCT04790474), an all-oral regimen: ixazomib (IXA), pomalidomide (POM) and dexamethasone (DEX) (IPd) combination, in Pts with relapsed refractory multiple myeloma (RRMM) who progressed after bortezomib (BTZ), lenalidomide (LEN) and daratumumab (DARA) therapies. Methods: A phase 2, investigator initiated, open-label, single-arm, prospective, multicenter study evaluating the safety, tolerability and efficacy of IPd as a second or third-line combination treatment for TCE RRMM Pts. Pts receive IXA: 3 mg days (d) 1,4,8,11 of 21-d Cycles (Cy) 1-3; 4mg d 1,8,15 of 28-d Cy 4-24. POM 4mg: d 1-14 Cy 1-3; d 1-21 Cy 4-24. DEX 20mg: d 1,2,8,9,15,16 Cy 1-3; d 1,2,8,9,15,16,22,23 Cy 4-24. Treatment continues for 24 cycles, or until disease progression (PD) or unacceptable toxicity (the earliest of the three). After completion of 24 treatment cycles, Pts continue POM DEX as standard of care. The primary endpoint is progression free survival (PFS) according to IMWG criteria. Results: Fifty-five (out of the 60 Pts planned) were enrolled; we report data on 46 Pts who had their first dose between March 2021 and April 2023, further data will be presented at the meeting. The median age was 72 (range: 53-88); 18 (39%) were ≥75 years old; 59% were male, ISS was I/II/II for 48% / 25% and 28% respectively; 59% had high risk FISH cytogenetics (t(4:14), t(14:16), +1q21, del17p) with 14% double-hit. Nine percent had extramedullary disease at study enrollment. Exposure rates to BTZ, LEN and DARA were 100%, 98% and 96%, respectively. Forty-one percent had undergone autologous bone marrow transplantation. Refractoriness rates to BTZ, LEN and DARA were 57%, 91% and 65%, respectively. Thirty-seven percent were TCR. At data cutoff date of 15-Jun-2023, the median follow-up time was 10.4 [95% CI 7.6-13.2] months. Ninety-three percent of the Pts had at least one treatment emergent adverse event (TEAE) and 65% had a TEAE grade 3 or 4. Common (≥ 10%) TEAEs include neutropenia 35% (28% Gr 3 or 4), pneumonia 24% (17% Gr 3 or 4), thrombocytopenia 22% (15% Gr 3 or 4), back pain 22% (2% Gr 3 or 4), asthenia 20% (0% Gr 3 or 4), diarrhea 20% (0% Gr 3 or 4), peripheral edema 20% (2% Gr 3 or 4), COVID19 infection 15% (2% Gr 3 or 4 ), anemia 13% (2% Gr 3 or 4), acute kidney injury (AKI) 13% (7% Gr 3 or 4), rash 13% (0% Gr 3 or 4). At data cut-off date, 31 Pts (67%) discontinued the study treatment; 20 (43%) due to PD, 7 (15%) due to adverse events (including 3 patients with pneumonia, and 1 patient each with COVID19 infection, campylobacter gastroenteritis, upper gastrointestinal bleeding and AKI) and 4 (9%) died (2 cases of pneumonia, 1 COVID 19 infection and 1 cerebro-vascular accident). Overall response rate was 59% (27/46); 8 Pts (17%) achieved complete or very good partial response (CR/VGPR), 19 Pts (41%) achieved partial response (PR) and 12 Pts (30%) had stable disease (SD). The median PFS was 6.6 [95% CI 2.9 - 10.3] months (Figure 1a). Median duration of response (DOR) was 10.8 months. Median OS was not reached; 1-year overall survival was 81.6±6.7% (Figure 1a). One-year OS was significantly better for responders (89.3±7.3%) than non-responders (72.2±10.7%), p=0.015 ( figure 1b). Conclusions: IPd combination with a twice-weekly ixazomib induction provided an all-oral safe and efficacious therapy in triple-exposed RRMM Pts, most of whom were refractory to both DARA and LEN. Response rates and PFS are encouraging, compared to parenteral PI and IMiD combination regimens in TCE/TCR MM, with a favorable safety profile and convenience, especially among an elderly and frail population with relapsed myeloma.

Pomalidomide, Dexamethasone, and Daratumumab Versus Other Triplet Regimens in Patients with Relapsed or Refractory Multiple Myeloma: A Population-Adjusted Indirect Treatment Comparison

Introduction: Multiple myeloma (MM) is an incurable malignant plasma cell disorder in which most patients eventually relapse or become refractory to treatment. Lenalidomide (LEN) is typically administered as part of first-line regimens; however, patients who receive LEN usually relapse, necessitating improved options in later lines of therapy. The phase 2, non-randomized MM-014 trial (NCT01946477) demonstrated promising efficacy of pomalidomide (POM) plus dexamethasone and daratumumab (DPd) among patients with relapsed or refractory MM (RRMM), with an overall response rate of 77.7% and a median overall survival (OS) of 56.7 months at a median follow-up of 41.9 months. With the evolving treatment landscape of RRMM, however, there is limited head-to-head data comparing DPd to other standard of care therapies to inform clinical decision-making. Objective: To investigate the comparative efficacy of DPd versus non-POM-containing triplets in adult patients with RRMM using population-adjusted indirect comparison (PAIC) approaches. Methods: A PAIC was conducted using individual patient-level data of 112 adult patients with RRMM who were exposed to LEN (75.9% refractory to LEN) from cohort B of the MM-014 trial. Investigator-assessed OS was the primary endpoint of this analysis. A systematic literature review was performed to identify comparable interventional studies assessing the efficacy of non-POM-containing triplets for RRMM as well as potential prognostic variables (PVs). PVs verified by clinicians were selected for inclusion if significantly associated with OS (p < 0.1) in the MM-014 trial based on univariate Cox regression model. The suitability of these potential trials for PAIC was assessed by considering the comparability of study design, inclusion/exclusion criteria, patients' baseline characteristics, and outcomes. A retrospective analysis utilizing Flatiron electronic health record data from Jan 2011 to July 2022 was previously performed to evaluate the effect of LEN-refractory status on OS using multivariable Cox regression. Given the lack of a common comparator, unanchored PAIC was performed for OS using matching-adjusted indirect comparison (MAIC) and confirmatory simulated trial comparison (STC). A sensitivity analysis was conducted to explore the impact of LEN-refractory status as a PV. Results: Six trials were systematically identified as eligible comparators in initial screening including TOURMALINE-MM1, CANDOR, CASTOR, POLLUX, ASPIRE, and LEPUS. The analyses using Flatiron data showed that patients who were refractory to LEN had significantly shorter OS than those exposed to LEN but not refractory (Hazard ratio: 1.51; 95% CI: 1.17, 1.94), indicating the unsuitability to compare treatments based on studies with large variations in proportion of LEN-refractory patients. Four trials were excluded due to differences violating the transitivity assumption (0% LEN-refractory patients in TOURMALINE-MM1 and POLLUX; LEN-refractory status not reported in ASPIRE; only Chinese patients in LEPUS). The remaining two trials are phase 3 randomized controlled trials investigating carfilzomib plus dexamethasone and daratumumab (DKd) (CANDOR; NCT03158688; Usmani et al. Blood Adv. 2023; Epub ahead of print) and daratumumab plus bortezomib and dexamethasone (DVd) (CASTOR; NCT02136134; Sonneveld et al. J Clin Oncol. 2023; 41:1600-1609). In the base case MAIC adjusting for creatinine clearance, time from diagnosis, International Staging System score, and refractory to LEN, DPd was associated with numerical reduction in the risk of death compared to DKd and DVd (Table). In addition, the base case STC showed significant improvement of OS for DPd over DKd and DVd, confirming the findings from MAIC (Table). In the sensitivity analyses excluding LEN-refractory status, the effect estimates were substantially different from those in the base case analyses (>40% difference), demonstrating the importance of adjusting for LEN refractory status. Conclusions: In patients with RRMM, consistent OS benefit was found for DPd versus DKd and DVd regardless of the PAIC technique used. These findings support the use of DPd over DKd and DVd in treating patients with RRMM, especially given the oral route of administration of pomalidomide. This study also highlighted the importance of considering LEN refractory status when comparing efficacy of treatments for RRMM across trials.

Medical Writing Bias in Myeloma Clinical Research: A Comprehensive Analysis

Background Previous studies investigating associations between pharmaceutical funding and clinical trial results have found ties between pharmaceutical sponsorship and results favoring the sponsor's interests. There are no studies examining potential sponsorship bias within the field of multiple myeloma (MM). Addressing sponsorship bias is essential to ensure reliability, validity, and ethical conduct of clinical research in the field of MM. This study analyzes potential sponsorship bias in MM specifically regarding use of medical writers that are employees of or directly funded by pharmaceutical companies among published clinical research studies of drugs approved to treat MM from January 2000 - March 2023. Methods Clinical study papers from PubMed between January 2000 and March 2023 were analyzed if at least 1 of the 10 following drugs were evaluated: bortezomib (BORT), carfilzomib (CARF), daratumumab (DARA, elotuzumab (ELO), isatuximab (ISA), ixazomib (IXA), lenalidomide (LEN), panobinostat (PAN), pomalidomide (POM), and selinexor (SELI), and the manufacturer of the drug(s) sponsored the study (N=1466). Papers were considered to contain potential medical writing bias if the paper was written by employees of the manufacturer of the drug(s) or medical writers directly funded by the manufacturer. Papers were analyzed by year, drug, and journal in which it was published. Results From 2000 - March 2006, no potential writing bias occurred. In 2007, it first became apparent when 4% (2/53) of papers showed bias which has increased as follows: 2008 - 2012 [14% (41/300)], 2013 - 2017 [25% (100/405)], 2018-2022 [33% (171/521)], and increased to 44% (12/27) in 2023. We also analyzed writing bias according to the specific drugs from January 2000 - March 2023 with the following rates of potential bias: ISA 93% (26/28), IXA 77% (36/47), DARA 76% (63/83), ELO 71% (17/24), SELI 62% (8/13), POM 55% (27/49), PAN 50% (9/18), BORT 47% (47/100), LEN 46% (75/163) and CARF 32% (15/47). Potential writing bias was also determined according to the specific medical journal in which the paper was published from 2000 - March 2023. Blood and British Journal of Haematology have the highest number of potentially biased manuscripts at 42 and 30, respectively, representing 25% (42/142) and 21% (30/143) of the papers published, respectively. New England Journal of Medicine and Lancet have high percentages of potential writing bias at 33% (9/27) and 46% (6/13), respectively. Many journals have 100% (n=6) but these sources only had 1 paper meeting the study criteria. Conclusion Since 2000, we have observed an alarming increase in the rate of clinical research papers evaluating drugs approved to treat MM which have been written by pharmaceutical company employees or medical writers directly funded by them. Notably, nearly half (44%) of papers published this year showed potential writing bias. Rates varied greatly between different drugs with ISA, IXA and DARA showing the highest rates of writing bias whereas BORT, LEN and CARF showed the lowest rates. Specific journals including Blood and British Journal of Haematology both show high numbers of papers with potential writing bias; and, furthermore, a high percentage of papers published in high impact journals such as the New England Journal of Medicine and Lancet show this type of potential bias. This practice of allowing medical writing to be carried out by those with direct ties to the pharmaceutical company is likely to result in the publication of papers with results and conclusions regarding the efficacy and safety of drugs that are biased which compromises their scientific integrity and objectivity.

Quantification of Pomalidomide Using Conventional and Eco-Friendly Stability-Indicating HPTLC Assays: A Contrast of Validation Parameters.

High-performance thin-layer chromatographic (HPTLC) assays for pomalidomide (PMD) measurement are lacking in the published database. Furthermore, eco-friendly stability-indicating analytical assays for PMD measurement are also lacking in the published database. In order to detect PMD in commercial products more accurately and sustainably than the conventional normal-phase HPTLC (NP-HPTLC) assay, an effort was made to design and verify a sensitive and eco-friendly reversed-phase HPTLC (RP-HPTLC) assay. The silica gel 60 NP-18F254S and 60 RP-18F254S plates were used as the stationary phases for NP-HPTLC and RP-HPTLC methods, respectively. The solvent system for NP-HPTLC was chloroform-methanol (90:10 v/v). However, the solvent system for RP-HPTLC was ethanol-water (75:25 v/v). The greenness scores for both assays were measured by AGREE approach. PMD measurement was performed for both assays at 372 nm. In the 50-600 and 20-1000 ng/band ranges, the NP-HPTLC and RP-HPTLC methods were linear for PMD measurement. The RP-HPTLC assay was superior to the NP-HPTLC method for measuring PMD in terms of sensitivity, accuracy, precision, and robustness. The ability of both methods to identify PMD in the presence of its degradation products suggests that both methods have stability-indicating features. When employing the NP-HPTLC and RP-HPTLC assays, respectively, the assay for PMD in commercial capsules was 88.68 and 98.83%. The AGREE scores for NP-HPTLC and RP-HPTLC assays were calculated to be 0.44 and 0.82, respectively, suggesting an outstanding greenness characteristic of the RP-HPTLC method than the NP-HPTLC method. The RP-HPTLC method was found to be superior to the NP-HPTLC method based on these findings. Therefore, the RP-HPTLC method could be successfully applied for the determination of PMD in pharmaceutical products.

A phase IIb study of selinexor in combination with carfilzomib, daratumumab, or pomalidomide in patients with multiple myeloma relapsing on current therapy.

e20042 Background: Selinexor is an oral, selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1), leading to retention of tumor suppressor proteins and apoptosis in malignant cells. Preclinical studies suggest synergistic activity when selinexor is combined with other treatments for MM. We hypothesize the addition of selinexor can recapture response to patients relapsing or refractory on carfilzomib (CFZ), pomalidomide (POM) or daratumumab (DARA)-based regimens. Methods: This is an ongoing phase IIb, open-label, multicenter study to evaluate the safety and efficacy of selinexor plus CFZ, POM, or DARA in patients with MM. Patients were enrolled to each arm only if their disease was refractory to the specific drug of interest (CFZ for Arm 1, POM for Arm 2, and DARA for Arm 3). Arm 1 (n=1) consists of selinexor 80 mg orally on D1, 8, 15; CFZ 56 mg/m2 IV on D1, 8, 15; and dexamethasone (DEX) on D1, 8, 15, 22. Arm 2 (n=7) consists of selinexor 60 mg orally on D1, 8, 15; POM 4 mg orally on D1-21; and DEX on D1, 8, 15, 22. Arm 3 (n=7) consists of selinexor 100 mg orally on D1, 8, 15, 22; DARA 16 mg/kg IV or 1,800 mg SQ on D1, 8, 15, 22 for C1-2; D1 and 15 for C3-6; D1 for ≥C7; and DEX on D1, 8, 15, 22. The primary endpoint is ORR and secondary endpoints include PFS, OS, MRD negativity and TEAEs. Results: At data cutoff (Feb 6 2023), 15 patients were enrolled with a median age of 64 years (range 60-83), 27% with ISS stage III MM, 73% with high-risk cytogenetics, 93% refractory to the last LOT, 47% triple refractory, and 33% quadruple refractory (Table). The ORR was 33% (4/12; 4 PR) and the CBR was 92% (11/12; 7 SD); 3 patients are pending. The most common grade 3-4 TEAEs (n=34) were neutropenia (32%), hypophosphatemia (9%), pneumonia (6%), hyperglycemia (6%), and fatigue (6%). Ten patients discontinued treatment due to PD (n=5), withdrawal of consent (n=2), or TEAEs (n=3; fall, diarrhea, and RSV pneumonia), of whom 1 patient died while hospitalized for diarrhea and weakness. Conclusions: Preliminary results show selinexor plus CFZ, POM, or DARA is safe and restores sensitivity to therapy in relapsed/refractory MM patients. In this population of heavily pretreated MM patients, the ORR (33%) and CBR (92%) observed are higher compared to those seen with single-agent selinexor (ORR 4% and CBR 21%) (Chen C et al, Blood 2018). Clinical trial information: NCT04661137 . [Table: see text]

A multispectral study and computer simulation on the interaction of pomalidomide with human serum albumin

Pomalidomide (POM) has been discovered as a new molecular-glue-type degraders in recent years. It is a potent immunomodulatory drug and is used for the treatment of recrudescent and intractable multiple myeloma (MM). The interaction between POM and human serum albumin (HSA) was studied by multiple spectral techniques, molecular docking technique, and molecular dynamics simulation in this research. POM and HSA formed a complex with one binding stoichiometry. Site I was the binding site of POM to HSA and the binding constant was (6.180 ± 0.009) × 103 M−1 (293 K). Based on the thermodynamic results, the binding process was exothermic and spontaneous. Van der Waals forces and H-bonds were the chief driving forces. The conformational changes in HSA induced by POM were reflected in β-turn content increasing and α-helix content reducing. The results of computer simulation were consistent with that of the multiple spectral experiments. In addition, the results of molecular docking indicated π electrons in POM were also vital for the stability of HSA-POM complex. Molecular dynamics simulation showed that Leu198, Lys199 and Trp214 played a contributing role in the binding process, and the fluorescence of HSA quenched by POM might be attributed to the reduction in the accessible surface area values of Trp214. This research is aimed at better understanding the effects of molecular-glue-type degraders on human health, and it is helpful in clinical treatment of MM.

Abstract 6253: SP-3164, a novel molecular glue degrader with activity in preclinical models of multiple myeloma

Abstract Multiple myeloma (MM) makes up approximately 10% of all hematologic malignancies, with increasing incidence worldwide. Though treatment options for newly diagnosed patients have evolved in recent years, they are not curative, and relapse is common with 2,500-3,000 relapsed or refractory (R/R) MM US patients seeking novel treatments, annually. Cereblon (CRBN)-binding Ikaros and Aiolos (I/A) protein degraders (i.e., lenalidomide (LEN) and pomalidomide (POM)) have had great success in treating MM. However, due to the unstable chiral nature of the CRBN-binding moiety, common to these molecules, many exist as racemic mixtures (1:1 mixture of interconverting (R)- and (S)-enantiomers). A growing body of evidence suggests that the (S)- enantiomer is the active anticancer species, while the (R)-enantiomer is inactive and potentially results in undesired activity. The ability to stabilize the active (S)- enantiomer represents a potential strategy to improve therapeutic outcomes. We are developing SP-3164, the deuterium-stabilized (S)-enantiomer of avadomide (AVA), an I/A-degrading molecular glue which has been studied in over 400 patients, demonstrating safety and activity in hematologic diseases. Our in vitro data demonstrate that SP-3164 more potently and rapidly degrades the cancer-promoting transcription factors, I/A, compared to LEN, POM, and AVA, while the stabilized (R)-enantiomer, SP-3165, neither binds CRBN nor degrades I/A. In preliminary in vivo studies, SP-3164 elicited significant tumor growth inhibition (TGI). Here, we investigate the activity of SP-3164 in MM, compared to established treatment regimens. SP-3164’s potential to degrade Aiolos in MM.1S cells was compared to SP-3165, AVA, and POM. SP-3164 rapidly and robustly degraded Aiolos in a time- and dose-dependent manner, more potently than AVA and POM, while SP-3165 demonstrated minimal Aiolos degradation. To investigate the effect of SP-3164 on cell survival, we treated NCI-H929 cells with SP-3164 (0.1 µM, 1 µM, and 10 µM) and SP-3165 (1 µM) and assessed apoptosis by flow cytometry. SP-3164 induced dose-dependent early and late apoptosis after 72 hours, while SP-3165 showed no induction of apoptosis. SP-3164’s in vivo activity was assessed and compared to SP-3165, LEN, and POM in an NCI-H929 mouse xenograft model. SP-3164 showed significant TGI as a single agent while SP-3165 seemed to support tumor growth. LEN and POM demonstrated minimal TGI. When combined with dexamethasone (DEX), SP-3164 had improved TGI compared to the combination of POM+DEX. These preclinical data demonstrate that SP-3164 is a potent CRBN-binding molecular glue with the ability to rapidly degrade cancer-promoting transcription factors and induce apoptosis in vitro. In vivo, SP-3164 has superior single agent and combination activity compared to approved molecular glues. These data support the continued development as a novel therapy in MM. Citation Format: Aundrietta D. Duncan, Daniela Y. Santiesteban, Nadeem Q. Mirza, Steve Horrigan, Sheila DeWitt, Vincent Jacques, P. Leif Bergsagel. SP-3164, a novel molecular glue degrader with activity in preclinical models of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6253.

Lenalidomide in Multiple Myeloma: Review of Resistance Mechanisms, Current Treatment Strategies and Future Perspectives.

Multiple myeloma (MM) is the second most common hematologic malignancy, accounting for approximately 1% of all cancers. Despite the initial poor prognosis for MM patients, their life expectancy has improved significantly with the development of novel agents. Immunomodulatory drugs (IMiDs) are widely used in MM therapy. Their implementation has been a milestone in improving the clinical outcomes of patients. The first molecule belonging to the IMiDs was thalidomide. Subsequently, its novel derivatives, lenalidomide (LEN) and pomalidomide (POM), were implemented. Almost all MM patients are exposed to LEN, which is the most commonly used IMiD. Despite the potent anti-MM activity of LEN, some patients eventually relapse and become LEN-resistant. Drug resistance is one of the greatest challenges of modern oncology and has become the main cause of cancer treatment failures. The number of patients receiving LEN is increasing, hence the problem of LEN resistance has become a great obstacle for hematologists worldwide. In this review, we intended to shed more light on the pathophysiology of LEN resistance in MM, with particular emphasis on the molecular background. Moreover, we have briefly summarized strategies to overcome LEN resistance and we have outlined future directions.

Belantamab Mafodotin in Combination with Pomalidomide and Dexamethasone Demonstrates Durable Responses in Triple Class Exposed/Refractory Multiple Myeloma

Background: Belantamab mafodotin (belamaf) is a first-in-class antibody-drug conjugate (ADC) targeting B-cell maturation antigen (BCMA). Belamaf has shown clinically meaningful activity as a single agent in relapse/refractory multiple myeloma (RRMM). The Algonquin study demonstrated that the anti-myeloma activities of belamaf are significantly increased by the immunomodulatory drug pomalidomide (POM). The Algonquin study is a two part study designed to evaluate the safety and efficacy of different doses and schedules of belamaf in combination with POM and dexamethasone (DEX) (Bela-Pd) in patients (pts) with RRMM. Here we report updated safety and efficacy data for the subgroup of RRMM pts exposed or refractory to lenalidomide (LEN), a proteasome inhibitor (PI) and an anti-CD38 agent (triple class exposed). Methods: Eligibility criteria included > 1 prior lines of treatment (LoT), LEN and PI exposure and refractoriness to the last LoT. POM was administered at 4 mg days 21/28 days, DEX 40 mg (20 mg age > 75 years) weekly in conjunction with IV belamaf administered as a SINGLE dose of 1.92 mg/kg Q4W or 2.5 mg/kg Q4W, Q8W or Q12W, or SPLIT equally (2.5 or 3.4 mg/kg) on days 1 and 8 Q4W. Responses were assessed by International Myeloma Working Group (IMWG) criteria and adverse events (AEs) were graded by CTCAE criteria except for corneal findings which were also graded by the pre-specified keratopathy and visual acuity (KVA) scale. In Part 1 up to 12 pts were enrolled in each cohort to inform the recommended part 2 dose (RP2D). In part 2, 23 patients will be enrolled to provide 35 patients (inclusive of the 12 treated at the RP2D of 2.5 mg/kg Q8W in Part 1) for overall response determination. Results: At data cut-off (April 11, 2022), 54 triple class exposed pts had been enrolled in the following dose levels and schedules: 1.92 mg/kg Q4W (n=6), 2.5 mg/kg (SINGLE and SPLIT) Q4W (n=6), 2.5 mg/kg Q8W (n=26), 2.5 mg/kg Q12W (n=12), and 3.4 mg/kg SPLIT (n=4). The median age was 67.5 years (range 36-85) and median prior LoT was 3 (range 2-5). Prior therapies (exposed/refractory) included stem cell transplant (61.1%), PI (100%/79.6%), LEN (100%/92.6%), anti-CD38 (100%/100%) and 72.2% triple class refractory. The most frequent grade 1-2 AEs reported in all cohorts were keratopathy (an ophthalmologic finding) (68.6%), decreased best-corrected visual acuity (BCVA) (60.8%), fatigue (51.0%), thrombocytopenia (35.3%), and blurred vision (33.3%). Grade 3/4 AEs reported in >20% of pts across all cohorts, were keratopathy (54.9%), neutropenia (37.3%), thrombocytopenia (27.5%), and decreased BCVA (23.5%). Three patients discontinued treatment due to AEs (one G4 decreased visual acuity, one G3 elevated ALT, and one due to myelodysplastic syndrome) and three grade 5 AEs were observed (one from myeloma progression, one from lung infection, and one from myelodysplastic syndrome). At data cut-off, 50/54 patients were evaluable for response. Across all cohorts the ORR was 86.0% (60.0% > VGPR). Responses by dosing cohort are summarized in Table 1. At a median follow-up of 5.7 months, the median PFS (n=49 at a data-cut of March 28, 2022) was 15.6 months (95% CI: 12.9, NYR; across all cohorts). Conclusions: Patients who are triple class exposed/refractory remain challenging to treat and require therapies with novel mechanisms of action. In the recent LocoMMotion study, triple class exposed MM patients who prospectively received real-life standard of care (SOC) therapies demonstrated an overall response rate (ORR) of 29.8% and median PFS of 4.6 months. Thus, the combination of Bela-Pd represents an improvement over widely available SOC treatments for this poor prognosis patient population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase II Multicenter Clinical Trial Assessing the Safety and Efficacy of Ixazomib Pomalidomide Dexamethasone Combination As Second or Third-Line Treatment for Patients with Triple Exposed Relapsed and Refractory Multiple Myeloma: Prespecified Interim Analysis (IPoD-790 trial)

Introduction: Despite significant improvement in the outcomes of early treatment lines in myeloma, most patients (Pts) invariably relapse. As triple and quadruple regimens are being introduced at the upfront setting, many Pts are either triple-exposed or triple-refractory early in their disease course. We report here the outcomes of a pre-specified interim analysis of the IPoD-790 clinical trial (NCT04790474), an all oral ixazomib (IXA) pomalidomide (POM) dexamethasone (DEX) (IPd) combination, in Pts with relapsed refractory multiple myeloma (RRMM) previously treated with bortezomib (BTZ) lenalidomide (LEN) and daratumumab (DARA). Methods: A phase 2, investigator initiated, open-label, single-arm, prospective, multicenter study evaluating the safety, tolerability and efficacy of IPd as a second or third-line combination treatment for Pts with RRMM who progressed after receiving BTZ, LEN and DARA during the first and second treatment lines. IXA is administered twice-weekly during the first 3 cycles. Pts receive IXA: 3 mg days (d) 1, 4, 8, 11 of 21-d Cycles (Cy) 1-3; 4mg d 1, 8, 15 of 28-d Cy 4-24. POM 4mg: d 1-14 Cy 1-3; d 1-21 Cy 4-24. DEX 20mg: d 1,2,8,9,15,16 Cy 1-3; d 1,2,8,9,15,16, 22,23 Cy 4-24. Treatment continues until disease progression (PD) or unacceptable toxicity. After completion of 24 treatment cycles, Pts continue POM DEX as standard of care. The primary endpoint is progression free survival (PFS) according to IMWG criteria. Results: Twenty-two Pts (out of the 60 Pts planned) enrolled between February 2021-May 2022. The median age was 71 (range: 53-88), median time from Myeloma diagnosis to study enrollment was 3.7 years; 58% had high risk FISH cytogenetics (t(4:14), +1q21, del17p); 10% had extramedullary disease at study enrollment; 32%, 9%, 73% and 86% of the Pts were refractory to BTZ, cyclophosphamide, LEN and DARA, respectively. Forty-five percent had previously undergone an auto-transplant. At the interim analysis cutoff date of 28-Jun-2022, after a median follow-up of 5.8 months (mo) (95% CI 4.5-7.1), 13 Pts discontinued the study treatment due to disease progression (PD) (n=9, 41%), death (n=2, 9%, 1 each: COVID-19 and cerebrovascular accident) and withdrawal of consent (n=2, 9%). Eighty-six percent of the Pts had at least one treatment emergent adverse event (TEAE) and 59% had a TEAE grade ≥3. TEAE that occurred in ≥10% include neutropenia 27% (23% ≥Gr 3), thrombocytopenia 27% (14% ≥Gr 3), rash 23%, diarrhea 14%, dyspnea 14%, fatigue 14%, COVID-19 14% and pneumonia 14% (14% ≥Gr 3). No Pts discontinued therapy due to an AE. Overall response rate was 53% (10/19 of evaluable Pts); 2 (10%) complete or very good partial response (CR/VGPR); 8 (42%) partial response (PR); 6 (32%) stable disease; 3 (16%) PD. Median time to response was 0.7 (range: 0.4-6) mo. The median PFS and overall survival (OS) were 6.9 [95% CI 2.0-12.0] and not-reached (NR), respectively [Figure 1A]. Median PFS was 10.4 vs 2.2 mo among Pts who achieved at least a PR vs non-responsive Pts, respectively (p=0.005). [Figure 1B]. Conclusions: IPd combination with twice-weekly ixazomib provided an all-oral safe and efficacious therapy in triple-exposed RRMM Pts, most of whom were refractory to both DARA and LEN. Study enrollment is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Treatment Patterns of Patients Initiating Third-Line Therapy in Relapsed or Refractory Multiple Myeloma in Europe

Background: Despite advances, most patients with multiple myeloma (MM) eventually relapse and progress through multiple lines of therapy. To complement clinical trial data, real-world evidence on treatment patterns can provide valuable insights on clinical practice in different countries and help identify and address unmet medical needs. Here, we report real-world (RW) treatment use in patients from European data sets who initiated third-line (3L) treatment for relapsed or refractory (RR) MM. Methods: This retrospective, noninterventional analysis used claims data from the German AOK PLUS health insurance fund and Italian local health units (2012-2020) and applied an algorithm based on prescription and procedure codes. The algorithm defined the start of a new line of therapy as the introduction of a new agent not part of the prior line. Agents given within 30 days of start defined the regimen. Retreatment after >6 months of discontinuation were also considered a new line. Patients initiating 3L treatment from 2016 to 2020 (index date range) were identified. Baseline characteristics and treatment patterns were then reported. Results: Overall, 276 patients from Germany and 289 patients from Italy who met selection criteria were identified (Table). Patients in Germany and Italy had similar baseline characteristics in terms of sex, age, and time since diagnosis; 27% and 15% of patients, respectively, had prior stem cell transplant. Prior to 3L treatment, IMiD use was lower (56% vs 74%) and proteasome inhibitor (PI) use was higher (96% vs 52%) among patients in Germany vs those in Italy, respectively. At 3L, the proportion of double class-exposed patients in Germany was higher vs Italy (52% vs 33%). In Germany, common first-line (1L) regimens were bortezomib (BORT) + dexamethasone (DEX; Vd) (46%), melphalan (MEL) + prednisone (PRED) + BORT (14%), and Vd + cyclophosphamide (8%). The most common 2L treatment regimens were lenalidomide (LEN) + DEX (Rd; 30%), Vd (11%), and carfilzomib (CFZ) + Rd (8%). By 3L, 95% and 54% of patients had received prior BORT- and LEN-based regimens, respectively. In 3L, combinations were often based on LEN and/or CFZ with daratumumab (DARA) monotherapy and pomalidomide (POM) + DEX (Pd) also contributing about 4% each (Table). In Italy, common 1L regimens included MEL ± DEX ± PRED (22%), Vd (6%), and thalidomide (THAL) + DEX (5%). Rd (40%) and Vd (8%) were the most common 2L regimens in Italy; by 3L, 56% and 49% of patients had received prior LEN- and BORT-containing regimens, respectively. Overall, Pd was the second most common 3L treatment in Italy and its use was higher than in Germany (12% vs 4%), whereas 3L use was lower for regimens based on CFZ (10% vs 21%) and DARA (9% vs 29%). Patients in Italy also had higher 3L use of conventional therapies such as MEL compared with patients in Germany (15% vs 3%). Retreatment patterns in Germany and Italy showed that 60% and 82% of patients initiating 3L treatment, respectively, had prior exposure to the same agent class (IMiD, PI, monoclonal antibodies). Of 50 patients in Germany with BORT treatment in 3L, 47 (94%) also had prior BORT; of 135 patients with LEN treatment in 3L, 47 (35%) had prior LEN. Of 40 patients in Italy with BORT treatment in 3L, 31 (78%) had prior BORT; of 131 patients with LEN treatment in 3L, 82 (63%) had prior LEN. Additionally, of 13 patients in Italy that received prior THAL, all were retreated with THAL in 3L. Conclusions: This study of European claims datasets provides a perspective of RW clinical practice with a focus on patients initiating 3L treatment from 2016 to 2020 for comparison with the evolving treatment landscape for RRMM. LEN-based regimens were most commonly observed in 3L, with high proportions of CFZ- and POM-based regimens in Germany and Italy, respectively. This finding is likely the result of BORT- and LEN-based regimens being common in 1L and 2L, respectively, reflecting what was approved and/or used before and during 2016. Many 3L patients were retreated with the same agent class used in a prior line. BORT use in 3L was prominent for retreatment in Germany and Italy, which may reflect BORT's prior use in a fixed-duration regimen. Notably, retreatment with LEN in 3L was also prominent in Italy. Comparisons with more recent index groups could help elucidate treatment evolution over time. Additionally, it would be relevant to understand how European RW clinical practice compares with observations in the US setting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

IMiDs Synergize with EP300 Inhibition to Disrupt the Ikzf/MYC/IRF4 Axis in Multiple Myeloma

Multiple myeloma (MM) is a heterogeneous plasma cell malignancy for which current therapies eventually fail. In myeloma, endogenous and translocated superenhancers drive the expression of the lineage-defining transcription factor IRF4 and oncogene MYC, respectively - both considered "undruggable". Successful standard-of-care immunomodulatory imide drugs (IMiDs) degrade superenhancer-binding pioneer factors IKAROS and AIOLOS; however, depletion of IKAROS and AIOLOS does not always correlate with a successful IMiD response, and patients treated with IMiDs ultimately relapse. We show responses to the IMiD Pomalidomide (POM) are directly correlated with downregulation of IRF4 and MYC. In IMiD-resistant cells and tumors, IRF4 and MYC downregulation could be achieved with novel coactivator-targeting drugs including the BET inhibitor JQ1 and the CBP/EP300 inhibitor GNE-781, but these were toxic and lacked a therapeutic window in vivo. We show how POM combined with GNE781 synergize and downregulate MYC and IRF4 levels, killing myeloma cells in vitro and in vivo. However, resistance to this combination was induced by expression of the AP-1 factor BATF, which directly maintained IRF4 expression and myeloma cell survival. These results identify a potent therapeutic combination and a hereto unrealized mechanism of IMiD resistance in multiple myeloma.

Nanocrystals as an effective strategy to improve Pomalidomide bioavailability in rodent

Pomalidomide (POM) is an FDA-approved immunomodulatory imide drug (IMiDs) an it is effectively used in the treatment of multiple myeloma. IMiDs are analogs of the drug thalidomide and they have been repurposed for the treatment of several diseases such as psoriatic arthritis and Kaposi Sarcoma. In recent years, IMiDs have been also evaluated as a new treatment for neurological disorders with an inflammatory and neuroinflammatory component. POM draws particular interest for its potent anti-TNF-α activity at significantly lower concentrations than the parent compound thalidomide. However, POM’s low water solubility underpins its low gastrointestinal permeability resulting in irregular and poor absorption. The purpose of this work was to prepare a POM nanocrystal-based formulation that could efficiently improve POM’s plasma and brain concentration after intraperitoneal injection. POM nanocrystals prepared as a nanosuspension by the media milling method showed a mean diameter of 219 nm and a polydispersity index of 0.21. POM’s nanocrystal solubility value (22.97 µg/mL) in phosphate buffer was about 1.58 folds higher than the POM raw powder. Finally, in vivo studies conducted in adult Male Sprague-Dawley rats indicated that POM nanocrystal ensured higher and longer-lasting drug levels in plasma and brain when compared with POM coarse suspension.

P1055: CLINICAL AND GENETIC RESULTS OF THE PHASE IB/II TRIAL MPNSG-0212: RUXOLITINIB PLUS POMALIDOMIDE IN MYELOFIBROSIS WITH ANEMIA

Background: Ruxolitinib (RUX) alleviates disease-associated symptoms including splenomegaly in patients (pts) with myelofibrosis (MF). However, management of cytopenia remains challenging. Aims: As single-agent pomalidomide (POM) improved cytopenia in 14-29% of MF pts in our previous MPNSG-0109 trial, we sought to investigate the combination of RUX plus POM in MF pts with anemia (Hb <10 g/dL and/or RBC transfusion dependency [RBC-TD]). Methods: MPNSG-0212 is a multicenter, open-label, phase-Ib/II trial (NCT01644110) comprising 39 pts in cohort 1 (co1, recruited 2013-2017) and 52 pts in co2 (2017-2021). Co1 pts received RUX 10 mg BID plus POM 0.5 mg QD, while POM was intended to be increased in co2 to 1 and 2 mg QD after 3 and 6 28-day-cycles, respectively. Primary endpoint was response according to IWG-MRT and RBC-TI criteria at end of cycle 12 (EOC12). In addition, genomic landscape was characterized in all pts using targeted NGS of 269 candidate genes (Illumina NextSeq550). Results: Co1 and co2 pts had similar characteristics: median age was 71 years (range 49-86), median Hb level 8.6 g/dL (5.4-11.7), and median spleen size 17.5 cm (11.4-36); 30% were RBC-TD, 66% intermediate-2, and 25% high-risk according to DIPSS; mutations (muts) in JAK2, CALR, or MPL were identified in 57%, 23%, and 20%, respectively; 55% had ≥1 high-molecular risk (HMR) mut, with ASXL1 being the most common (41%), followed by SRSF2 (24%), EZH2 (10%) and IDH2 (9%). Of note, pts in co2 were more frequently pre-treated with RUX compared to co1 (44% vs 15%; p=.006). Median treatment time at data cut-off was 12 cycles in co1 (2-98) and co2 (3-46); 3 pts of co2 have not yet reached EOC12. In co1, 8/39 pts (21%) achieved response at EOC12: partial remission (PR, n=1), clinical improvement (CI, n=6), or RBC-TI (n=1); 18/39 pts (46%) were treated for >12 cycles due to response (n=8), clinical benefit (CB, n=5) defined as Hb increase ≥1 g/dL or >50% improvement of ≥1 quality of life (QoL) symptom according to MPN-SAF, or stable disease (SD, n=5). Median Hb level at EOC12 was 9.3 g/dL; 15/39 pts (38%) were on treatment for >30 cycles, and 3 pts remained on long-term treatment (cycle 76, 97, and 98). In 73% and 40% of pts in co2, POM dose was increased to 1 mg and 2 mg QD after cycle 3 and 6, respectively. 5/49 pts (10%) showed response at EOC12 (CI, n=3 and RBC-TI, n=2), while 14 additional pts (29%) had CB; median Hb level at EOC12 was 8.6 g/dL; 22/49 pts (45%) were treated for >12 cycles; 3 pts were still on treatment (cycle 21, 36, and 46). Targeted NGS did not reveal a distinct mutational pattern associated with treatment response. Median overall survival (OS) of co1 and co2 was 3.6 and 2.6 years, respectively (p=.66). Among all, CALR, but not JAK2 or MPL muts were associated with better OS (p=.04), whereas HMR muts were in trend prognostically adverse (p=.057). Pts with more than 3 muts had a worse median OS (1.2 vs 4 years, p=.002). Combination therapy was well tolerated in both cohorts. Most common grade 1/2 adverse events (AE) were dyspnea (28%) and fatigue (23%), while the most frequent grade 3 AE was worsening of anemia (32%) in the first weeks of combination treatment not limiting therapy. Summary/Conclusion: Treatment with RUX and POM was safe and feasible in our study of advanced MF with an adverse genetic profile. Almost half of co1 and co2 pts were treated >12 cycles due to clinical benefit of the combination therapy with a subset of 38% of pts in co1 receiving treatment for >30 cycles. Dose increase of POM in co2 did not result into better anemia response or improvement of OS. Authors FS and EJ contributed equally.

PB1996: TREATMENT PATHWAYS AT FIRST RELAPSE POST-ASCT IN MULTIPLE MYELOMA: IMPACT OF MAINTENANCE THERAPY ON TREATMENT OPTIONS

Background: The introduction of new agents and treatment combinations has led to significant improvements in outcomes for multiple myeloma (MM) patients. In particular, lenalidomide maintenance therapy (LenM) following autologous stem cell transplant (ASCT) in younger/fitter MM patients has now become standard given the survival benefits associated with it. However, most MM patients will relapse post-ASCT and many effective relapse regimens have a lenalidomide backbone (e.g. KRD: carfilzomib, lenalidomide, dexamethasone, DRD: daratumumab-RD, IRD: ixazomib-RD) making choice of regimen at first relapse increasingly difficult in patients progressing during LenM therapy. Real world data reflecting these choices is needed to inform treatment decisions and consensus guidelines. Aims: We carried out an audit with an aim to: 1. Evaluate treatment and outcomes in MM patients undergoing ASCT from 2010-2020 2. Assess the impact of LenM post-ASCT and therapy choice after relapse. Methods: We carried out a retrospective audit of all patients with MM attending an Irish hospital who underwent ASCT from 2010-2020. Data was collected by chart/electronic record review. Endpoints included no. of ASCT/year and type of induction/maintenance therapy, relapse rates post-ASCT and choice of post-relapse therapy. Results: 71 patients at our centre underwent ASCT for MM between 2010-2020 (24 female,47 male) with median age of 67 and most common isotype IgG Kappa (n=33). The most frequently used induction was cyclophosphamide(C), bortezomib(V) and dexamethasone(D) (>60%, VCD). Use of maintenance therapy increased markedly over this decade, with 0% receiving maintenance in 2010, 44% in 2014 and 83% in 2020. LenM was most common, >75% (n=28).Other maintenance therapies included bortezomib n=4, daratumumab (dara)n=3 and lenalidomide + bortezomib (RV) combination n=4. First relapse treatment data was available for 36 patients. Regimens included carfilzomib/dexamethasone (KD) n=16 +/- lenalidomide (KRD) n=1, pomalidomide (PD), n=1, ixazomib (ID) n=1, dara (n=3) and dara combinations, including daraVD, n=1, and daraPD, n=1. 26 patients did not receive maintenance containing lenalidomide and the majority of these patients received ASCT pre-2015. There were n=13 relapses in this group: n=4 received lenalidomide regimens (RVD/VCD) at relapse. KD n=4, dara n=1, and ID n=1 were also used. First relapse therapy for 17 patients who progressed during LenM included: KD(n=11) 64.7%, dara(n=2) 11.7%, pomalidomide(n=1) 5.8%, and RV(n=2) 11.7% and VCD(n=1) 5.8%. Overall, carfilzomib-based therapy (without lenalidomide) was the most commonly prescribed therapy on first relapse. We observed a clear increase in its use from 2015-2020, in parallel with increased use of LenM. We also noted reducing rates of lenalidomide-based relapse therapies in later years, correlating with increased LenM. Importantly, neither DRD or PVD combinations were reimbursed for prescription in Irish healthcare during the period of audit and are notable absences from the relapse treatment regimens used. Summary/Conclusion: This audit highlights the treatment pathway and outcomes for all patients with MM undergoing ASCT over 10 years in our centre. We have noted significant changes in choice of therapy upon relapse, with carfilzomib prescription rates increasing and lenalidomide-based regimen use decreasing. Our real world data provides direct insight into the effect of widespread LenM therapy on choice of agent upon relapse and highlights the need for consensus treatment guidelines to reflect this evolution in treatment for MM patients.

Phase II study of the combination of daratumumab, ixazomib, pomalidomide, and dexamethasone as salvage therapy in relapsed/refractory multiple myeloma: Stage 2 interim results.

8041 Background: The combination of daratumumab (Dara), pomalidomide (POM), and dexamethasone (dex) (DPd) has previously demonstrated deep and durable responses including high rates of minimal residual disease (MRD) negativity, in patients with relapsed/refractory (R/R) MM. Quadruplet regimens may further improve results. We report updated findings from a phase 2 multicenter trial of the addition of ixazomib to DPd (DIPd) in patients with early R/R MM. Methods: This is a prospective, multi-center, open-label, single arm phase II trial with a primary objective to evaluate the overall response rate (ORR), safety, and efficacy of DIPd. Secondary endpoints include progression-free survival (PFS), overall survival (OS), and MRD-negativity rate. A Simon’s optimal 2-stage design was used, with 14 subjects in stage 1 to assess response and 32 patients for stage 2. Eligible patients may not have had exposure Dara or ixazomib, may not have progressed on POM, and may have received ≥1 and ≤3 prior lines of therapy. The first six patients in the safety run-in received Dara 16mg/kg IV weekly x 8 doses, biweekly x 8 doses, then monthly, POM 4mg orally on days 1-21 of a 28-day cycle, ixazomib 4mg orally on days 1,8,15 every 28 days, and dex 20-40mg weekly. Grade 3-4 neutropenia was observed in 100% of patients, prompting dose reduction to ixazomib 3 mg and POM 3 mg by the DSMB. An amendment allowed subcutaneous Dara administration. MRD assessments are being performed by EuroFlow for patients in VGPR or suspected CR. Pharmacodynamic changes in patients’ tumor microenvironments were established by custom panel mass cytometry to include T-cell memory and activated subpopulations, B-cell content, NK-cell subpopulations as well as MDSCs, Tregs and T-exhaustive markers, monocytes and dendritic cells. Results: To date, 14 subjects have been treated in stage 1, and 18 patients in stage 2. Median age was 61.5 (range 41-87) years, 50% were female and 72% white. Median number of prior regimens was 1 (range 1-3), all patients were lenalidomide-exposed, and 47% (11/23) had high-risk cytogenetic features. The most common grade 3-4 treatment emergent adverse events included neutropenia (78%), infection (30%), leukopenia (11%), respiratory conditions (7%), psychiatric disturbance (4%), and thrombosis (4%). Median time on treatment was 4 months (1-29), with 11 patients remaining on DIPd and 5 deaths (4 due to progressive disease and 1 due to sepsis). ORR to date was 84% (16/19), and the best responses included: 5 (26%) sCR; 4 (21%) VGPR; 7 (37%) PR. After a median follow up of 12 months, the median OS was 39 months and PFS was 9.5 months. Conclusions: The quadruplet regimen DIPd is a well-tolerated combination that has shown early safety, efficacy, and ORR in early R/R myeloma, including patients with high-risk genetic abnormalities. Clinical trial information: NCT03590652.