Jakubowiak, Andrzej

8504 Background: CFZ is a novel proteasome inhibitor of the epoxyketone class that exhibits a high level of proteasome selectivityand demonstrates antitumor activity in bortezomib (BTZ)-resistant MM pts in phase I studies. Methods: PX-171–003-A0 was an open-label, multicenter study that enrolled MM pts who relapsed from >2 prior therapies, failed BTZ and at least 1 immunomodulatory agent [thalidomide (THAL) or lenalidomide (LEN)], and were refractory to last treatment [progressing on or within 60 d of last therapy or <25% response to last therapy]. Pts received CFZ 20 mg/m2 IV d 1, 2, 8, 9, 15 and 16 every 28 d for up to 12 cycles (C). Clinical benefit response (CBR) was defined as MR or better. Results: 46 pts were enrolled, including 78% with progression on or within 60 d of last therapy and 22% with no response to last therapy. 39 pts completed at least 1 C of CFZ, had measurable M-protein, and were evaluable for response. Median prior therapies was 5 (range 2–15). 100% of pts received prior BTZ, 91% prior THAL, 89% prior LEN, and 83% prior stem cell transplant (SCT) and all had failed combinations including anthracyclines (80%) and/or alkylating agents (94%). Pts received a median of 3 C (range 1–12); 13 pts completed ≥6 C. CBR was 26% (10/39 eval pts), including 5 pts achieving PR and 5 pts achieving MR. 5 BTZ-refractory pts achieved MR or PR. Median TTP was 6.2 mo, the median DOR for the MR + PR was 7.4 mo. 8/10 pts achieved response during C1. 16 additional pts achieved SD for at least 6 wks. The most common adverse events were fatigue, anemia, thrombocytopenia, nausea, upper respiratory infection, increased creatinine and diarrhea. Peripheral neuropathy occured in < 10% of pts with 1 Gr 3 in a pt with pre-existing Gr 2. Conclusions: Single-agent CFZ achieved a TTP of > 6 mo in relapsed and refractory MM pts who failed available therapies. 26% of patients had at least an MR and median duration of >7 mo with this steroid- and anthracycline-sparing regimen. CFZ toxicities were manageable and importantly, exacerbation of pre-existing PN was rare. The study has been expanded to enroll an additional 250 pts in this unmet medical need population at an escalated dose, and treatment has been extended beyond a year. [Table: see text]

Background:Venetoclax (Ven) is a highly selective, potent, oral BCL‐2 inhibitor that induces apoptosis in malignant cells dependent on BCL‐2 for survival. Proteasome inhibitors (PIs) and dexamethasone (d) were shown to increase BCL‐2 dependence in multiple myeloma (MM) cells, and preclinical studies showed enhanced inhibition of MM tumor growth with Ven+PI compared to either alone. Moreover, d has been shown to indirectly promote BCL‐2 dependency in MM cells. Clinical trials have since demonstrated efficacy of Ven in combination with the PI bortezomib in patients (pts) with relapsed/refractory MM (RRMM).Aims:We report interim data for Ven combined with second‐generation PI carfilzomib (K) and d in pts with RRMM.Methods:In this ongoing Phase 2 study (NCT02899052), pts with RRMM (1–3 prior lines of therapy) and no prior K exposure received VenKd on 28‐day cycles in 4 dose‐finding and 1 expansion cohort: Ven 400 mg/day + K 27 mg/m2 Day 1, 2, 8, 9, 15, 16 + d 40 mg Day 1, 8, 15, 22 (Cohort 1); same regimen but with Ven 800 mg/day (Cohort 2); Ven 800 mg/day + K 70 mg/m2 Day 1, 8, 15 + d 40 mg Day 1, 8, 15, 22 (Cohort 3/expansion cohort); or Ven 800 mg + K 56 mg/m2 Day 1, 2, 8, 9, 15, 16 + d 40 mg Day 1, 2, 8, 9, 15, 16, 22, 23 (Cohort 4). Treatment continued until progressive disease or unacceptable toxicity.Results:As of the clinical data cut‐off of 1 Feb 2019, 43 pts were enrolled. Median age was 67 (range, 37–79), 26 (62%) pts had ISS II/III disease, and 8 (19%) were t (11;14)+. Median number of prior lines of therapy was 2 (range, 1–3). Forty (93%) pts received prior PI (49% refractory), 33 (77%) received prior immunomodulatory drug (IMiD, 61% refractory), and 33 (77%) received prior PI+IMiD (33% double refractory).All pts had at least 1 adverse event (AE). The most common AEs of any grade were diarrhea (65%), nausea (49%), fatigue (47%), cough (35%), insomnia, dyspnea, vomiting, upper respiratory infection (33% each), lymphopenia (28%), thrombocytopenia, and dyspepsia (26% each). Thirty‐six (84%) pts had a Grade 3/4 AE, the most common being lymphopenia (23%), pneumonia, hypertension (16% each), and hypophosphatemia (12%).The overall response rate (ORR) was 79%, complete response or better (≥CR) rate was 40%, and very good partial response or better (≥VGPR) rate was 64% for all pts (Table). Median follow‐up for 42 pts was 10.4 months (95% CI = 8.0–13.8); 15 pts had progression‐free survival (PFS) events, with median PFS yet to be achieved. Baseline bone marrow core biopsy samples from 25 pts were evaluated for BCL‐2 expression by immunohistochemistry, with high expression (≥50% of tumor cells with moderate or higher cytoplasmic staining) seen in 23 (92%) samples. Pts with high BCL‐2 expression had response rates similar to the overall study population. Other correlative biomarker analyses are ongoing.Summary/Conclusion:The combination of VenKd was found to be tolerable with no new safety signals. VenKd demonstrates promising efficacy in pts with RRMM. The study remains ongoing with an additional 60 pts with RRMM enrolling to assess efficacy and safety in a larger group of pts with similar eligibility (Cohort 6) and t (11;14)+ pts (Cohort 7).image

SummarySelinexor, an oral Selective Inhibitor of Nuclear Export, targets Exportin 1 (XPO1, also termed CRM1). Non‐clinical studies support combining selinexor with proteasome inhibitors (PIs) and corticosteroids to overcome resistance in relapsed/refractory multiple myeloma (RRMM). We conducted a phase I dose‐escalation trial of twice‐weekly selinexor in combination with carfilzomib and dexamethasone (SKd) to determine maximum tolerated dose in patients with RRMM (N = 21), with an expansion cohort to assess activity in carfilzomib‐refractory disease and identify a recommended phase II dose (RP2D). During dose escalation, there was one dose‐limiting toxicity (cardiac failure). The RP2D of twice‐weekly SKd was selinexor 60 mg, carfilzomib 20/27 mg/m2 and dexamethasone 20 mg. The most common grade 3/4 treatment‐emergent adverse events included thrombocytopenia (71%), anaemia (33%), lymphopenia (33%), neutropenia (33%) and infections (24%). Rates of ≥minimal response, ≥partial response and very good partial response were 71%, 48% and 14%, respectively; similar response outcomes were observed for dual‐class refractory (PI and immunomodulatory drug)/quad‐exposed (carfilzomib, bortezomib, lenalidomide and pomalidomide) patients (n = 17), and patients refractory to carfilzomib in last line of therapy (n = 13). Median progression‐free survival was 3·7 months, and overall survival was 22·4 months in the overall population. SKd was tolerable and re‐established disease control in RRMM patients, including carfilzomib‐refractory patients.Registered at ClinicalTrials.gov (NCT02199665)

Key Points Pomalidomide plus low-dose dexamethasone significantly improved PFS vs pomalidomide alone in relapsed and refractory multiple myeloma. Pomalidomide plus low-dose dexamethasone is an important new treatment option for RRMM patients who have received multiple prior therapies.