ASH 2018 Abstracts 589, 599, and 1993

Michael Kauffman, MD, PhD,  CEO of Karyopharm Therapeutics Inc. discusses ASH 2018 abstract 589 and 1993:

598 – Results of the Pivotal STORM Study (Part 2) in Penta-Refractory Multiple Myeloma (MM): Deep and Durable Responses with Oral Selinexor Plus Low Dose Dexamethasone in Patients with Penta-Refractory MM (View Abstract)

599 – Deep and Durable Responses with Selinexor, Daratumumab, and Dexamethasome (SDd) in Patients with Multiple Myeloma (MM) Previously Exposed to Proteasome Inhibitors and Immunomodulatory Drugs: Results of Phase 1b Study of SDd (View Abstract)

1993 – Selinexor Plus Pomalidomide and Low Dose Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma (View Abstract)

 

Introduction: Selinexor is a novel, oral Selective Inhibitor of Nuclear Export (SINE) compound that blocks exportin 1 (XPO1). Selinexor treatment results in nuclear accumulation and activation of tumor suppressor proteins, inhibition of NF-kB, and translational suppression of several oncoprotein mRNAs (e.g., c-myc, cyclin D).Multiple myeloma (MM) remains incurable, and most patients (pts) eventually progress through standard drug classes of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), anti-CD38 mAbs and others. The increased use of combinations in MM treatment, (PIs/IMiDs/mAbs), has led to a growing number of pts with penta-refractory MM (pts that have been treated with bortezomib (bort), carfilzomib (carfil), lenalidomide (len), pomalidomide (pom) and daratumumab (dara)). Active novel therapies with different mechanisms of actions are needed to address this unmet medical need. Part 1 of STORM enrolled pts with both quad- (bort, carfil, len, pom, treated MM) or penta-refractory MM and demonstrated an overall response rate (ORR) of 21% (Vogl et al, JCO 2018). Based on these findings, the Pivotal Part 2 of STORM was initiated, enrolling an additional cohort of 122 patients with penta-refractory MM.

Methods: Pts with penta-refractory MM were treated with 80 mg selinexor plus 20 mg dexamethasone (Sd) twice weekly. Pts must have received an alkylator, bort, carfil, len, pom and dara, and had MM refractory to ≥1 PI, ≥1 IMiD, dara, a glucocorticoid, and their last therapy. Pts must have a total ANC ≥1000 mm3,platelets ≥50k/mm3(or ≥75k if marrow plasma cells <50%), and creatinine clearance ≥20 mL/min. The primary endpoint was ORR. Secondary endpoints: duration of response (DOR), clinical benefit rate (CBR), progression free survival (PFS), and overall survival (OS). Efficacy was assessed by an Independent Review Committee (IRC) based on IMWG criteria. OS was also compared to a cohort of pts with PI, IMiD, dara refractory MM from the Flatiron Health Analytic Database (FHAD), (ref: ASH 2018 abs ID: 116493),who met all the inclusion criteria for STORM.

Results: As of 1-Jun-2018, 122 pts (71 M/ 51 F) were enrolled in 38 sites (US and EU). Pt characteristics were [medians (range)]: age 65 yrs (40-85); 7 (3 – 18) prior treatment regimens, 6.6 yrs (<1 – 23.4) from initial MM diagnosis.65 pts (53%) had high risk cytogenetics, 86 pts (70%) had prior dara in combination, 102 pts (84%) had prior stem cell transplantation, 2 pts had prior CAR-T therapy. All pts enrolled with progressive disease (PD), 72% of pts had increases (3% – 792%) in MM markers from screening to C1D1 (median 11 days). Frequently reported Sd treatment related adverse events (AEs) included (all grades, grades 3/4): thrombocytopenia (67%, 53%), nausea (67%, 10%), fatigue (68%, 21%), anorexia (50%, 2%), anemia (46%, 28%), and weight loss (46%, 0%). Eight pts remain on study and 114 pts discontinued treatment (most commonly for PD). There were 4 deaths on treatment: sepsis, respiratory failure, pulmonary embolism, and an unrelated, unspecified cardiac event. IRC determined ORR (≥PR) was 26.2%, with 6.5% ≥ very good partial response, including 2 stringent complete responses (sCRs; MRD negative at 1:10-6and at 1:10-4sensitivity). Both pts who relapsed after CAR-T achieved PRs. The CBR (≥minimal response, [MR]) was 39.3%, and 79% of pts achieved ≥stable disease (SD). Responses typically occurred within the first month. Medians: DOR 4.4 months (mo) (range <1 – 10 mo), PFS 3.7 mo, and OS 8.0 mo. Pts with ≥MR had significantly longer OS than pts with PD/NE (median not reached vs 1.9 mo, p=<0.0001). Compared to the FHAD cohort, STORM cohort had longer OS (Figure 1, HR 0.41, p=0.0001).

Conclusions: Results of the pivotal STORM Part 2 in penta (PI, IMiD, dara)-refractory MM demonstrated that oral selinexor plus low-dose dexamethasone (Sd) was highly active with an ORR of 26.2%. Importantly, responses were rapid and deep with 2 patients achieving sCRs (both MRD negative) in these heavily pre-treated penta-refractory MM pts (median 7 prior regimens, 53% high risk). AEs are a function of dose/schedule/disease severity and can be managed with dose modifications and supportive care. No major organ toxicity was observed and AEs were typically transient and reversible. Sd is an all-oral, first in class mechanism with novel MOA and represents a potential therapeutic option to the growing number of pts with penta-refractory MM who have exhausted approved therapies.

Figure1

Introduction– Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1). Selinexor with low dose dexamethasone (Sd) or in with protesome inhibitors (PIs) or immunomodulatory drugs (IMiDs), has shown anti-MM activity in patients (pts) with relapsed or refractory MM. Daratumumab (Dara), an anti-CD38 mAb, is approved for the treatment of heavily pretreated MM is limited by short PFS and an ORR of ~21% in quad-refractory MM. Selinexor in combiniation with dara have shown preclinical synergistic killing of MM cells.

Methods– Pts were eligible if they had received ≥ 3 prior lines of anti-myeloma therapy, including a PI and an IMiD. Selinexor was dose-escalated in 2 concurrent cohorts: once-weekly (QW, at 100 mg) or twice-weekly (BIW, at 60 mg). Dara was 16 mg/kg IV (recommended schedule) and dexamethasone (dex) was 40 mg QW or 20 mg BIW. The objectives were to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, tolerability and preliminary efficacy of the combination of this SDd combination in pts with PI/IMiD refractory MM

Results– As of Jul 20th2018, 25 pts (11 males / 14 females) have been enrolled. Three pts have been enrolled into the 60 mg BIW and 22 pts in the 100 mg QW cohorts. Pts have a median age of 68 years and a median of 3 (range, 2 – 10) prior treatment regimens. Common SDd treatment related adverse events included (all grades, grades 3/4): thrombocytopenia (58%, 42%), leukopenia (54%, 38%), anemia (46%, 29%), nausea (50%, 0%) and fatigue (46%, 8%). Two dose limiting toxicities (DLTs) were reported in the 60 mg BIW cohort: G3 thrombocytopenia and G2 fatigue requiring dose reduction in selinexor to 100 mg QW. In the 100 mg QW escalation cohort, 6 pts enrolled, 5 evaluable, with no DLTs. This cohort was expanded and enrollment is ongoing. A total of 21 pts were evaluable for response. In 19 dara-naïve pts, the ORR was 74% (5 VGPR, 9 PR, 2 MR, 2 SD, 1 PD), including 3 unconfirmed PRs, 1 unconfirmed MR. In the 2 pts with dara refractory MM, there was one PD and one SD. The longest duration of therapy is 13 months. Based on tolerability and efficacy, the RP2D of SDd is selinexor 100 mg, daratumumab 16 mg/kg and dex 40 mg, administered QW.

Conclusions– Selinexor 100 mg QW can be combined safely with dara (per approved dosing) and dex. The preliminary ORR of 74% with SDd in patients with PI/IMiD refractory MM who are dara naïve is promising and compares favorably to 21% ORR of Dara and Sd in quad refractory myeloma. This once weekly regimen is well tolerated with no major organ toxicities to date. Data from the full phase 1 dose expansion will be presented.

Introduction– The nuclear export protein exportin 1 (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO1. Selinexor forces nuclear retention and reactivation of cell cycle regulators such as p53, IkB, and Rb. Pomalidomide/dexamethasone (Pd) is approved in relapsed/refractory MM (RRMM)with an overall response rate (ORR) of 30% and progression-free survival (PFS) rate of <4 months in patients (pts) having received a prior proteasome inhibitor (PI) and IMiD. Strategies to improve the ORR and PFS are needed. In murine MM models, the combination of selinexor with IMiDs shows synergistic anti-MM activity and good tolerability.

Methods– Pts with RRMM who received ≥ 2 prior therapies including lenalidomide (len) and a PI were enrolled. Selinexor was evaluated in 2 different dosing schedules of once-weekly (QW, 60 or 80 mg) or twice-weekly (BIW, 60 or 80 mg), with pomalidomide (pom)3 or 4 mg PO daily, and dexamethasone (dex) 20 mg BIW or 40 mg QW. The primary objectives were to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, and preliminary efficacy of the combination of selinexor, pomalidomide, and low dose dex (SPd) in pts with RRMM.

Results– As of July 20th2018, 34 pts (16 male / 18 female) have been enrolled. The median age is 61 years and patients received a median of 4 (range, 2 – 9) prior treatment regimens. Thirty-two patients were IMiD refractory (21 len, 11 pom/len). Six dose limiting toxicities (DLTs) were observed: G3 fatigue (60 mg BIW, pom 4 mg), G3 febrile neutropenia (FN) (60 mg BIW, pom 3 mg), G3 FN and G4 neutropenia (80 mg QW, pom 4), G3 thrombocytopenia (80 mg QW, pom 3 mg) and 4 missed doses in Cycle 1 due to symptomatic hyponatremia (80 mg BIW, pom 4 mg). Enrollment on selinexor 80 mg QW, pom 3 mg is ongoing. Common SPd treatment related adverse events included (all grades, grades 3/4): neutropenia (62%, 56%), thrombocytopenia (59%, 32%), anemia (53%, 29%), anorexia (56%, 0%), fatigue (50%, 9%), nausea (47%, 0% ). Thirty pts were evaluable for response, which is outlined in Table 1. Median PFS is 10.3 months with a median follow up of 9.4 months.

Conclusions– Enrollment is ongoing to evaluate once weekly selinexor in combination with Pd , (SPd). This all-oral SPd combination has clinical activity with an ORR 55% in pom-naive pts with heavily pretreated MM compared to previously published data of 30% ORR for Pd alone. Similarly, the PFS on SPd is 10.3 months vs. <4 months for Pd alone. No unexpected adverse events were noted. Phase 1 dose escalation of the combination of SPd is ongoing to define the optimal RP2D.

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Education Conference Coverage ASH 2018 Conference Coverage ASH 2018 Abstract 598