Sonneveld, Pieter

Background:IBER is a novel cereblon E3 ligase modulator (CELMoD) with enhanced tumoricidal and immunostimulatory activities. Preclinically, IBER overcomes immunomodulatory drug (IMiD) resistance and has synergy with daratumumab (DARA), bortezomib (BORT), and dexamethasone (DEX).Aims:This phase 1b/2a multicenter, open‐label, dose‐escalation study (NCT02773030) was conducted to evaluate the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and preliminary efficacy of IBER in combination with DEX, in patients with relapsed/refractory multiple myeloma (RRMM).Methods:Eligible patients had RRMM and must have received ≥2 prior regimens including lenalidomide (LEN) and/or pomalidomide (POM), and a proteasome inhibitor (PI). All patients had progressed on or within 60 days of last MM therapy. Escalating doses of IBER were given on days 1–21, in combination with DEX 40 mg (20 mg in patients aged >75 years) on days 1, 8, 15, and 22, of each 28‐day cycle. Dose escalation was reviewed by a dose escalation committee.Results:As of January 2019, 58 patients had received IBER + DEX. Median age was 64.5 years (range 33–79), and median number of prior regimens was 5 (2–12). Prior therapies included autologous stem cell transplantation (79%), LEN (100%), POM (69%), PIs (100%), and DARA (66%). IBER dose ranged from 0.3 to 1.2 mg; MTD/RP2D was not reached. Median duration of therapy was 12+ weeks (range 4–109). Grade 3–4 adverse events (AEs) were reported in 41 (72%) patients and were not related to dose. Grade 3–4 neutropenia, thrombocytopenia, neuropathy, and fatigue occurred in 26%, 11%, 2%, and 0% patients, respectively. Three patients discontinued treatment due to AEs. Clinical activity occurred early and was observed across all dose levels (Table 1); 20 of 51 patients remain on treatment (2–27+ cycles).Summary/Conclusion:IBER + DEX showed favorable efficacy and safety in heavily pretreated patients with RRMM who failed multiple prior therapies. This study is ongoing, including combinations of IBER with DARA or BORT.image

Background:Iberdomide (IBER) is a novel cereblon (CRBN) E3 ligase modulatory compound (CELMoD) that is being investigated as monotherapy, in combination with dexamethasone (DEX), and in combination with DEX and daratumumab or bortezomib in a phase 1b/2a dose‐escalation study in relapsed/refractory multiple myeloma (RRMM). IBER modulates CRBN, which induces ubiquitination of Aiolos, Ikaros and ZFP91, increases their proteasome‐dependent degradation, and thereby inhibits myeloma cell growth. IBER binds more potently to CRBN and is more efficient at degrading Aiolos and Ikaros than the immunomodulatory agents (IMiDs) lenalidomide (LEN) and pomalidomide (POM) and it can overcome IMiD drug resistance in pre‐clinical models.Aims:To determine if IBER is pharmacodynamically (PD) active in multiple myeloma patients refractory to POM and/or LEN, and to establish pharmacokinetic (PK)/PD and PD/dose relationships.Methods:As of Jan 11, 2019, 83 patients received IBER as monotherapy or in combination with DEX; 61 (74%) were LEN refractory and 47 (57%) were POM refractory. Longitudinal immunohistochemistry (IHC) data on CRBN, Aiolos, Ikaros and ZFP91 expression was obtained from bone marrow samples from 14 patients dosed with 0.3–0.9 mg IBER daily ± DEX. PD analysis of immune activity by TruCulture® (n = 45) and by peripheral blood flow cytometry (n = 60) was completed on a subset of patients dosed up to 1.0 mg IBER ± DEX. A population PK approach was used to estimate exposure (area under the concentration curve over the 24 hr dosing interval [AUCτ]) on 59 patients dosed up to 1.0 mg IBER ± DEX.Results:IBER AUCτ increased in a dose‐proportional manner in RRMM patients over the dose range 0.3–1.0 mg (22.4–65.31 ng∗hr/mL, respectively). In patient biopsies analyzed to date, CRBN expression was observed in all tumors by IHC at baseline and did not significantly change while on‐treatment. Furthermore, no significant decrease in baseline CRBN expression was observed in patients refractory to POM. In MM cells, significant decreases in Aiolos (median 37% decrease, P < 0.001), Ikaros (median 12% decrease, P = 0.006), and ZFP91 (median 47% decrease, P < 0.001) protein expression were observed on‐treatment across all dose levels; these decreases were unrelated to levels of CRBN expression at screening or prior LEN or POM refractoriness. In TruCulture® samples, dose‐dependent increases were observed in IL‐2 and IFN‐γ, with median increases of 78% and 66%, respectively, 5 hours post 0.9 mg dose of IBER. A dose‐ and exposure‐dependent decrease in B‐cells was detected (median 74% decrease at cycle 2 day 15, IBER 0.9 mg). These observations are consistent with the proposed IBER mechanism of action. Immunoprofiling showed significant increases in total and proliferating NK cells in RRMM patients treated with IBER, and a dose‐dependent increase in proliferating, activated, and effector memory T‐cells. These trends were consistent in RRMM patients treated with IBER monotherapy and in combination with DEX.Summary/Conclusion:These translational analyses from IBER treated RRMM patients indicate it is pharmacodynamically active at the lowest dose (0.3 mg) and exhibits dose‐ and exposure‐dependent immunostimulatory activity, supporting further dose‐escalation beyond 1.0 mg, which is currently ongoing. These results also suggest that prior refractoriness to LEN or POM is not associated with significant loss of CRBN or IBER PD activity, supporting continued investigation of IBER in RRMM patients refractory to IMiD drugs.

Background:Patients (pts) with multiple myeloma associated with high cytogenetic risk abnormalities have poor outcomes. In CASTOR, D‐Vd prolonged progression‐free survival (PFS) vs bortezomib and dexamethasone (Vd) alone, and exhibited a manageable safety profile in pts with RRMM. We conducted a subgroup analysis of D‐Vd vs Vd in CASTOR, based on cytogenetic risk.Aims:The purpose of this analysis was to determine the efficacy and safety of D‐Vd in CASTOR based on cytogenetic risk status.Methods:Eligible pts received ≥1 prior line of therapy. Cytogenetic risk was based on a combined analysis of next‐generation sequencing (NGS) and fluorescence in situ hybridization (FISH)/karyotype testing. High‐risk pts had t(4;14), t(14;16), or del17p abnormalities. Standard (std)‐risk pts were confirmed negative for all 3 abnormalities. Minimal residual disease (MRD; 10–5) was assessed via NGS using clonoSEQ® assay V2.0.Results:In CASTOR (D‐Vd, n = 251; Vd, n = 247), high‐risk was confirmed in 26.7% and 25.9% of pts in the D‐Vd and Vd groups, respectively. At a median follow up of 40.0 months (mo), D‐Vd prolonged PFS vs Vd in pts with high‐ (median 13.4 vs 7.2 mo; HR, 0.40 [95% CI, 0.24–0.65]; P = 0.0002) or std‐risk (median 18.4 vs 6.8 mo; HR, 0.28 [95% CI, 0.20–0.37]; P <0.0001). Higher ORR was seen with D‐Vd vs Vd (high risk: 84.8% vs 60.0%; P = 0.0226; std risk: 85.4% vs 65.0%; P <0.0001), including deep responses of ≥CR (high risk: 33.3% vs 8.3%; std risk: 29.9% vs 10.2%) and ≥VGPR (high risk: 65.2% vs 35.0%; P = 0.0049; std risk: 64.3% vs 28.0%; P <0.0001). Higher rates of MRD negativity (high risk: 17.9% vs 0%; P = 0.0003; std risk: 13.3% vs 2.4%; P = 0.0003), and sustained MRD negativity for ≥6 mo (high risk: 16.4% vs 0%; P = 0.0006; std risk: 6.1% vs 1.8%; P = 0.0859) and ≥12 mo (high risk: 7.5% vs 0%; P = 0.0581; std risk: 1.8% vs 0%; P = 0.2477) were seen with D‐Vd vs Vd. D‐Vd significantly prolonged PFS vs Vd in pts with one prior line of therapy only (high risk: median 20.1 vs 8.4 mo; HR, 0.30 [95% CI, 0.14–0.64]; P = 0.0012; std risk: median 32.6 vs 7.9 mo; HR, 0.18 [95% CI, 0.11–0.29]; P <0.0001; Figure). Additionally, D‐Vd significantly prolonged PFS2 (high risk: median 27.9 vs 18.6 mo; HR, 0.59 [95% CI, 0.37–0.94]; P = 0.0258; std risk: median 40.1 vs 21.6 mo; HR, 0.43 [95% CI, 0.32–0.59]; P <0.0001) regardless of cytogenetic risk status.Additional data including safety analyses will be presented.Summary/Conclusion:Adding daratumumab to Vd demonstrates significant efficacy in pts with high‐risk RRMM including PFS2. Among high‐risk RRMM pts, MRD negativity was only achieved with D‐Vd. These findings support use of D‐Vd for high‐risk RRMM. NCT02136134image

8006 Background: In 2 randomized phase 3 trials of RRMM patients (pts), DRd (POLLUX) or DVd (CASTOR) significantly improved PFS and deepened responses compared with Rd or Vd alone, respectively. The novel mechanism of action of daratumumab (D) may improve the poor prognosis associated with high-risk cytogenetic abnormalities in RRMM. Therefore, we examined the efficacy of DRd and DVd among RRMM pts with standard (std) or high cytogenetic risk status. Methods: Bone marrow aspirates were collected at screening and assessed centrally via next generation sequencing (NGS). Pts with high-risk cytogenetics included those who had ≥1 of the following abnormalities: t(4;14), t(14;16), or del17p; std-risk pts were defined as those confirmed negative for these abnormalities. Efficacy analyses included PFS and ORR. Results: Samples from 311/569 pts in POLLUX and 353/498 pts in CASTOR were assessed via NGS. In POLLUX, the median duration of follow-up was 17.3 months. Significantly longer median PFS and numerically higher ORR were observed with DRd vs Rd among high-risk patients, and significant improvements in these outcomes were observed in std-risk patients (Table). In CASTOR, the median duration of follow-up was 13.0 months. Significantly longer median PFS and higher ORR were observed with DVd vs Vd among both high- and std-risk pts (Table). Concordance rates for t(4;14), t(14;16), and del17p were high (88%-98%) between NGS and FISH. Updated data, including subgroup analyses, will be presented. Conclusions: In RRMM pts, the addition of D to standard-of-care regimens improved outcomes regardless of cytogenetic risk status. Targeting CD38 by combining D with Rd or Vd appears to improve the poor outcomes associated with high-risk cytogenetic status. See table. Clinical trial information: NCT02136134 and NCT02076009. [Table: see text]

Key Points Using the largest set of patients with newly diagnosed myeloma, we identified 63 mutated driver genes. We identified oncogenic dependencies, particularly relating to primary translocations, indicating a nonrandom accumulation of genetic hits.

LBA4 Background: Daratumumab (D), a human anti-CD38 IgGκ mAb, induces deep and durable responses with a favorable safety profile in RRMM pts. We report a pre-specified interim analysis of the first randomized controlled study of D (CASTOR; NCT02136134). Methods: Pts with ≥1 prior line of therapy were randomized (1:1) to 8 cycles (q3w) of bortezomib (V)/dexamethasone (d) (V: 1.3 mg/m2sc on Days 1, 4, 8, 11; d: 20 mg po on Days 1, 2, 4, 5, 8, 9, 11, 12) ± D (16 mg/kg iv qw in Cycles 1-3, Day 1 of Cycles 4-8, then q4w until progression). Primary endpoint was PFS. Results: 498 pts (DVd, 251; Vd, 247) were randomized. Baseline demographics and disease characteristics were well balanced. Pts received a median of 2 prior lines of therapy (range 1-10). 66% received prior V; 76% received prior IMiD; 48% received prior PI and IMiD; 33% were IMiD-refractory; 32% were refractory to last line of prior therapy. With median follow-up of 7.4 months, D significantly improved median PFS (61% reduction in risk of progression) and TTP for DVd vs Vd (Table). D significantly increased ORR (83% vs 63%, P <0.0001), and doubled rates of ≥VGPR (59% vs 29%, P <0.0001), and ≥CR (19% vs 9%, P= 0.0012) for DVd vs Vd, respectively; median duration of response was NR vs 7.9 months, respectively. Most common (>25%) AEs (DVd/Vd) were thrombocytopenia (59%/44%), peripheral sensory neuropathy (47%/ 38%), diarrhea (32%/22%) and anemia (26%/31%). Most common grade 3/4 AEs (>10%) were thrombocytopenia (45%/33%), anemia (14%/16%), neutropenia (13%/4%). 7%/9% of pts discontinued due to a TEAE. D-associated infusion-related reactions (45% of pts) mostly occurred during the first infusion; most were grade 1/2 (grade 3/4, 9%/0%). Conclusions: D significantly improved PFS, TTP, and ORR in combination with Vd vs Vd alone. DVd doubled both VGPR and sCR/CR rates vs Vd alone. Safety of DVd is consistent with the known safety profile of D and Vd. The addition of D to Vd should be considered a new standard of care for RRMM pts currently receiving Vd alone. Clinical trial information: NCT02136134. [Table: see text]

AbstractThe International Myeloma Working Group consensus updates the definition for high-risk (HR) multiple myeloma based on cytogenetics Several cytogenetic abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20), nonhyperdiploidy, and gain(1q) were identified that confer poor prognosis. The prognosis of patients showing these abnormalities may vary with the choice of therapy. Treatment strategies have shown promise for HR cytogenetic diseases, such as proteasome inhibition in combination with lenalidomide/pomalidomide, double autologous stem cell transplant plus bortezomib, or combination of immunotherapy with lenalidomide or pomalidomide. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. Based on data available today, bortezomib and carfilzomib treatment appear to improve complete response, progression-free survival, and overall survival in t(4;14) and del(17/17p), whereas lenalidomide may be associated with improved progression-free survival in t(4;14) and del(17/17p). Patients with multiple adverse cytogenetic abnormalities do not benefit from these agents. FISH data are implemented in the revised International Staging System for risk stratification.