Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma

Abstract Selinexor is an oral inhibitor of the nuclear export protein exportin 1. Preclinical studies demonstrated synergistic antimyeloma activity between selinexor and proteasome inhibitors (PI) through suppression of NF-κB signaling and nuclear retention of tumor suppressor proteins. We tested selinexor in combination with low-dose bortezomib and dexamethasone (SVd) for the treatment of relapsed or refractory multiple myeloma (MM). The primary objectives of this study were to determine the safety profile, overall response rate (ORR), and a recommended phase 2 dose (RP2D) of SVd. We enrolled 42 patients to receive selinexor (60, 80, or 100 mg orally) plus bortezomib (1.3 mg/m2 subcutaneously) and dexamethasone (20 mg orally) once or twice weekly in 21- or 35-day cycles. Patients had a median of 3 (range 1-11) prior lines of therapy, and 50% were refractory to a PI. Treatment-related grade 3 or 4 adverse events reported in ≥10% of patients were thrombocytopenia (45%), neutropenia (24%), fatigue (14%), and anemia (12%). Incidence (4 patients, 10%) and grade (≤2) of peripheral neuropathy were low. The ORR for the entire population was 63%: 84% ORR for PI nonrefractory and 43% for PI-refractory patients. The median progression-free survival for all patients was 9.0 months; 17.8 months for PI nonrefractory, and 6.1 months for PI refractory. SVd treatment produced high response rates in patients with relapsed or refractory MM, including borezomib-refractory MM, with no unexpected side effects. The RP2D is selinexor (100 mg once weekly), bortezomib (1.3 mg/m2 once weekly for 4 weeks), and dexamethasone (40 mg once weekly) per 35-day cycle. This trial was registered at www.clinicaltrials.gov as #NCT02343042.

Download Full-text

Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiple myeloma patients

British Journal of Cancer ◽

10.1038/s41416-021-01608-2 ◽

2021 ◽

Author(s):

Cristina Gasparetto ◽

Gary J. Schiller ◽

Sascha A. Tuchman ◽

Natalie S. Callander ◽

Muhamed Baljevic ◽

...

Keyword(s):

Multiple Myeloma ◽

Nuclear Export ◽

Overall Response Rate ◽

Response Rate ◽

Proteasome Inhibitors ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Free Survival ◽

Grade 3 ◽

Dose Modifications

Abstract Background Proteasome inhibitors (PIs), including carfilzomib, potentiate the activity of selinexor, a novel, first-in-class, oral selective inhibitor of nuclear export (SINE) compound, in preclinical models of multiple myeloma (MM). Methods The safety, efficacy, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of selinexor (80 or 100 mg) + carfilzomib (56 or 70 mg/m2) + dexamethasone (40 mg) (XKd) once weekly (QW) was evaluated in patients with relapsed refractory MM (RRMM) not refractory to carfilzomib. Results Thirty-two patients, median prior therapies 4 (range, 1–8), were enrolled. MM was triple-class refractory in 38% of patients and 53% of patients had high-risk cytogenetics del(17p), t(4;14), t(14;16) and/or gain 1q. Common treatment-related adverse events (all/Grade 3) were thrombocytopenia 72%/47% (G3 and G4), nausea 72%/6%, anaemia 53%/19% and fatigue 53%/9%, all expected and manageable with supportive care and dose modifications. MTD and RP2D were identified as selinexor 80 mg, carfilzomib 56 mg/m2, and dexamethasone 40 mg, all QW. The overall response rate was 78% including 14 (44%) ≥ very good partial responses. Median progression-free survival was 15 months. Conclusions Weekly XKd is highly effective and well-tolerated. These data support further investigation of XKd in patients with MM.

Download Full-text

Biomodulatory therapy approach with lenalidomide in combination with pioglitazone, dexamethasone, and metronomic low-dose chemotherapy with treosulfan in patients with relapsed/refractory multiple myeloma > second-line.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.8037 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 8037-8037

Author(s):

Daniel Heudobler ◽

Tanja Elger ◽

Stephanie Mayer ◽

Christina Hart ◽

Martin Vogelhuber ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Low Dose ◽

Metronomic Chemotherapy ◽

Progression Free Survival ◽

Hematologic Toxicity ◽

Open Label ◽

Refractory Multiple Myeloma ◽

Cell Transplants ◽

Grade 3

8037 Background: Nowadays, therapy for relapsed or refractory multiple myeloma (rrMM) usually consists of multi-targeted combination regimens for achieving complete remission. In this context, resistance resembles a therapeutic challenge that may be overcome by novel biomodulatory therapies communicatively reprogramming dysregulated cellular and intercellular homeostasis in neoplasia. Methods: The present, prospective phase II, one-arm, one-stage multi-center, open label trial, following phase I, focused on reprogramming myeloma and adjacent stroma cells in order to control rrMM beyond > 2nd-line treatment and following lenalidomide resistance in prior line. Adults with rrMM were eligible for receiving continuously, oral, daily dexamethasone 1mg, pioglitazone 45mg, low-dose treosulfan as metronomic chemotherapy ( 250mg bid) and lenalidomide 15mg, respectively, until disease progression. Results: Thirty-nine patients (mean time since diagnosis, 5.7 years; 66.7% with age > 60 years) had received a median of 5.5 (range 2 to 10) prior treatments. 89.5% of the patients were refractory to last therapy (all IMiD resistant), and 48.7% had received autologous stem-cell transplants. The overall response rate (CR, VGPR) was 17.9%. Eighteen patients (46.2%) had partial response or better; ten patients (25.6%) had stable disease. The disease control rate (DCR) was 71.8%. Time-to-progression was not significantly different between IMiD refractory patients and those relapsing following prior IMiD therapy or between high-risk versus non-high-risk cytogenetics. The median progression-free survival (PFS) and overall survival was 5.6 months (95% confidence interval [CI], 3.8 to 8.5) and 17.6 months (95% [CI], 14.9 to 39.2), respectively. The major AE (NCI-CTCAE grade) with grade ≥ 3 and relation to study drugs was hematologic toxicity (N = 31, 67.4%). Due to scheduled dose reductions, this was associated with only 7 (15.2%) grade ≥ 3 infections. Conclusions: The favorable safety profile, encouraging efficacy and equivalent median PFS between biomodulatory and modern targeted therapy in a historic comparison reveal a proof of concept of combined biomodulatory therapy in patients with heavily pretreated and IMiD-resistant rrMM, which should be further evaluated. Clinical trial information: NCT001010243.

Download Full-text

Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma

Blood ◽

10.1182/blood-2008-12-196238 ◽

2009 ◽

Vol 114 (4) ◽

pp. 772-778 ◽

Cited By ~ 110

Author(s):

Paul Richardson ◽

Sundar Jagannath ◽

Mohamad Hussein ◽

James Berenson ◽

Seema Singhal ◽

...

Keyword(s):

Multiple Myeloma ◽

Single Agent ◽

Progression Free Survival ◽

Prior Treatment ◽

Once Daily ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Treatment Regimens ◽

Common Grade ◽

Grade 3

Abstract Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351.

Download Full-text

Phase I-II Trial of Oral Cyclophosphamide, Prednisone and Lenalidomide (Revlimid®) (CPR) for the Treatment of Patients with Relapsed and Refractory Multiple Myeloma.

Blood ◽

10.1182/blood.v112.11.1723.1723 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1723-1723

Author(s):

Donna E. Reece ◽

Esther Masih-Khan ◽

Arooj Khan ◽

Peter Anglin ◽

Christine Chen ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Dose Level ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Oral Cyclophosphamide ◽

Varicella Zoster ◽

Refractory Multiple Myeloma ◽

Grade 3 ◽

Dose Levels

Abstract Oral cyclophosphamide and prednisone is a convenient regimen in relapsed and refractory multiple myeloma (MM), with a partial response (PR) rate of 40% and median progression-free survival of 19 months in our retrospective analysis of patients in first or second relapse after autologous stem cell transplantation (ASCT) (Trieu Y, et al, Mayo Clin Proc2005; 80: 1582). We sought to enhance the efficacy of this regimen by adding oral lenalidomide (Revlimid®), a potent anti-myeloma agent, in a phase I-II trial. The CPR regimen consisted of cyclophosphamide on days 1, 8 and 15, lenalidomide on days 1–21, and prednisone 100 mg every other day in a 28-day cycle. ASA 81 mg/day was given to all patients (pts) as prophylaxis for DVT. Three dose levels were evaluated using a 3 by 3 dose escalation design. Between 11/2007–07/2008, 15 pts with relapsed/refractory MM were entered onto study. Median age was 60 (45–78) years and 60% were male. Immunoglobulin subtype was IgGκ:λ in 10:1; IgA κ:λ in 2:1 and κ light chain in 1. Median number of prior regimens was 2 (1–3) and 14 had undergone previous ASCT, including double transplants in 2 pts. Prior therapy also included thalidomide in 3 (20%) and bortezomib in 6 (40%). FISH cytogenetics were available in 9, but none had 13q deletion, t(4;14) or p53 deletion. At the time of protocol entry, median β2-microglobulin level was 222 (92–325) nm/L, albumin 38 (35–46) g/L, creatinine 78 (50–100) μmol/L, platelet count 230 (93–318) x 109/L and ANC 2.5 (1.9–9.0) x 109/L. Protocol treatment is summarized in Table 1. Dose level N Cyclophosphamide dose (mg/m2) Lenalidomide dose (mg) Prednisone dose (mg) Median # cycles given 1 3 150 15 100 9 2 3 150 25 100 6 3 6 300 25 100 4 3 (expanded) 3 300 25 100 1 Dose limiting toxicity was not observed during cycle 1 at any of the dose levels and the maximum tolerated dose of this regimen has not yet been reached at the highest dose level planned; all pts remain on active therapy. Grade 3/4 thrombocytopenia was seen in 1 pt (cohort 2) and neutropenia in 4 pts (1 in cohort 1, 1 in cohort 2 and 2 in cohort 3) and were managed with dose reduction and/or growth factor support. No episodes of febrile neutropenia occurred in any pt. Only 1 pt experienced varicella zoster; routine antiviral prophylaxis was not used. Other grade 3/4 non-hematologic toxicities were uncommon and included abdominal pain/bacteremia in 1 pt in cohort 1, hypokalemia in 1 pt in cohort 2, and DVT in 1 pt in cohort 3. Mild grade 1/2 constipation (47%), muscle cramps (33%) and fatigue (33%) were also noted. To date, best response includes the following: dose level 1 (1 near complete remission [nCR], 2 PR); dose level 2 (3 PR); dose level 3 (4 PR, 2 minimal response [MR]); expanded cohort 3 (1 MR, 2 too early). We conclude: 1) the combination of full doses of the agents in CPR can be given in a 28-day cycle with minimal toxicity; 2) the overall response rate (nCR + PR + MR) in 13 evaluable pts to date is 87%; 3) no pts have progressed in this preliminary analysis; 4) longer follow-up is required to assess the long-term efficacy of this regimen.

Download Full-text

Elotuzumab in Combination With Lenalidomide and Low-Dose Dexamethasone in Relapsed or Refractory Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2011.37.2649 ◽

2012 ◽

Vol 30 (16) ◽

pp. 1953-1959 ◽

Cited By ~ 206

Author(s):

Sagar Lonial ◽

Ravi Vij ◽

Jean-Luc Harousseau ◽

Thierry Facon ◽

Philippe Moreau ◽

...

Keyword(s):

Multiple Myeloma ◽

Disease Progression ◽

Low Dose ◽

Infusion Reaction ◽

Weekly Dose ◽

Refractory Multiple Myeloma ◽

Subsequent Cycle ◽

Clinical Responses ◽

Grade 3

Purpose This phase I study evaluated elotuzumab, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma (MM). Patients and Methods Three cohorts were enrolled and treated with elotuzumab (5.0, 10, or 20 mg/kg intravenously) on days 1, 8, 15, and 22 of a 28-day cycle in the first two cycles, and days 1 and 15 of each subsequent cycle; lenalidomide 25 mg orally [PO] on days 1 to 21; and dexamethasone 40 mg PO weekly. Dose-limiting toxicities (DLTs) were assessed during cycle 1 of each cohort, and clinical responses were evaluated during each cycle. The first five patients received up to six cycles of therapy; subsequent patients were treated until disease progression. Results Twenty-nine patients with advanced MM and a median of three prior MM therapies were enrolled; 28 patients were treated, three each in the 5.0-mg/kg and 10-mg/kg cohorts and 22 in the 20-mg/kg cohort. No DLTs were observed up to the maximum proposed dose of 20 mg/kg. The most frequent grade 3 to 4 toxicities were neutropenia (36%) and thrombocytopenia (21%). Two patients experienced a serious infusion reaction (one grade 4 anaphylactic reaction and one grade 3 stridor) during the first treatment cycle. Objective responses were obtained in 82% (23 of 28) of treated patients. After a median of 16.4 months follow-up, the median time to progression was not reached for patients in the 20-mg/kg cohort who were treated until disease progression. Conclusion The combination of elotuzumab, lenalidomide, and low-dose dexamethasone was generally well tolerated and showed encouraging response rates in patients with relapsed or refractory MM.

Download Full-text

Efficacy of Once-Weekly Bortezomib with Daratumumab for Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-111908 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1958-1958

Author(s):

Natalia Gut ◽

Filiz Yucebay ◽

Jessica Dempsey ◽

Junan Li ◽

Don M. Benson

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Hematologic Malignancy ◽

Small Sample Size ◽

Single Agent ◽

Proteasome Inhibitors ◽

Progression Free Survival ◽

Small Sample ◽

Weekly Schedule ◽

Refractory Multiple Myeloma

Abstract Background Multiple Myeloma (MM) is an essentially incurable hematologic malignancy with the goals of therapy being disease control, improved quality of life, and prolonged survival.1,2 Despite improved survival with proteasome inhibitors and immunomodulatory agents, outcomes for patients with refractory disease, resistant to these classes of therapy, are poor. Daratumumab, an anti-CD38 antibody, is a commonly utilized therapy for relapsed/refractory multiple myeloma (RRMM) as a single agent based on the SIRIUS study which resulted in adequate response and acceptable safety profiles.3,4 Currently, it is approved in various combinations including with bortezomib. The approval of daratumumab in combination with bortezomib days 1, 4, 8, and 11 of a 21-day cycle was based on the CASTOR study which resulted in high response rates and acceptable safety profiles.5With the addition of bortezomib, additional toxicities in this RRMM setting may be a concern.6 Previous studies of bortezomib in RRMM patients have demonstrated that once-weekly bortezomib is equally as efficacious and better tolerated than the standard twice-weekly schedule, with a lower incidence of peripheral neuropathy and myelosuppression.8,9 However, there are currently no published reports of combining once-weekly bortezomib with daratumumab for patients with RRMM. Methods The present study sought to evaluate the progression-free survival (PFS) of daratumumab administered with once-weekly bortezomib for patients with RRMM. Secondary objectives included evaluation of overall survival (OS), overall response rate (ORR), time to response (TTR), and toxicity of once-weekly bortezomib with daratumumab. Eighteen patients were identified in an Institutional Review Board (IRB)-approved retrospective review of our institutional experience with daratumumab and once-weekly bortezomib. The median age of patients was 65 years (range 47 - 76, Table 1). Ten patients (55.6%) had three or more prior lines of therapy. Twelve patients (66.7%) had previous autologous stem cell transplantation. Sixteen patients (88.9%) had prior proteasome inhibitor (PI) therapy. Thirteen patients (72.2%) had disease refractory to their last line of therapy. Results The median PFS was 3.5 months. Median OS was not reached and TTR were undetermined due to the small sample size. The ORR was 33.3%, with 6 out of 18 patients experiencing an objective partial response or better (Table 2). Of those that responded, 4 patients (66.7%) remained on therapy at the time of data collection.The side effect profile was more tolerable, with less thrombocytopenia (27.8% all grade) and peripheral neuropathy (33.3% all grade) than previously reported (Table 3). Conclusions Daratumumab monotherapy was approved in heavily pretreated RRMM based on the SIRIUS trial showing promising efficacy and a favorable safety profile.4 The median PFS was 3.7 months compared to our PFS of 3.5 months. The combination of daratumumab with bortezomib administered twice weekly was approved based results from the CASTOR trial showing superiority of daratumumab in combination with bortezomib and dexamethasone over bortezomib and dexamethasone.5 As depicted in Table 2, our ORR of 33.3% is similar to the ORR of 29.2% in the SIRIUS trial, however differs greatly from 82.9% in the CASTOR trial. While the present work is retrospective and hypothesis-generating, our results suggest that further prospective inquiry is necessary to determine the additional efficacy of adding once-weekly bortezomib to daratumumab. Disclosures Dempsey: Heron Therapeutics: Honoraria; TESARO: Honoraria.

Download Full-text

Selective Inhibition of Nuclear Export With Oral Selinexor for Treatment of Relapsed or Refractory Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2017.75.5207 ◽

2018 ◽

Vol 36 (9) ◽

pp. 859-866 ◽

Cited By ~ 60

Author(s):

Dan T. Vogl ◽

David Dingli ◽

Robert Frank Cornell ◽

Carol Ann Huff ◽

Sundar Jagannath ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Nuclear Export ◽

Selective Inhibition ◽

Refractory Disease ◽

Nuclear Retention ◽

Common Grade ◽

Duration Of Response ◽

Heavily Pretreated ◽

Grade 3

Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

Download Full-text

Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

Blood ◽

10.1182/blood.2019000722 ◽

2019 ◽

Vol 134 (5) ◽

pp. 421-431 ◽

Cited By ~ 43

Author(s):

Ajai Chari ◽

Joaquín Martinez-Lopez ◽

María-Victoria Mateos ◽

Joan Bladé ◽

Lotfi Benboubker ◽

...

Keyword(s):

Multiple Myeloma ◽

Treatment Options ◽

Progression Free Survival ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Common Grade ◽

Frontline Treatment ◽

Phase 1B ◽

Immunomodulatory Drug ◽

Grade 3

Abstract Patients with relapsed or refractory multiple myeloma (RRMM) have limited treatment options and poor survival outcomes. The increasing adoption of lenalidomide-based therapy for frontline treatment of multiple myeloma has resulted in a need for effective regimens for lenalidomide-refractory patients. This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory drug; lenalidomide-refractory patients were eligible. Carfilzomib- and daratumumab-naïve patients (n = 85) received carfilzomib weekly on days 1, 8, and 15 of each 28-day cycle (20 mg/m2 initial dose, escalated to 70 mg/m2 thereafter) and dexamethasone (40 mg/wk). Of these, 10 patients received the first daratumumab dose as a single infusion (16 mg/kg, day 1 cycle 1), and 75 patients received a split first dose (8 mg/kg, days 1-2 cycle 1). Subsequent dosing was per the approved schedule for daratumumab. Patients received a median of 2 (range, 1-4) prior lines of therapy; 60% were lenalidomide refractory. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (31%), lymphopenia (24%), anemia (21%), and neutropenia (21%). Infusion-related reactions were observed in 60% and 43% of single and split first-dose patients, respectively. Overall response rate was 84% (79% in lenalidomide-refractory patients). Median progression-free survival (PFS) was not reached; 12-month PFS rates were 74% for all treated patients and 65% for lenalidomide-refractory patients. D-Kd was well tolerated with low neutropenia rates, and it demonstrated deep responses and encouraging PFS, including in patients refractory to lenalidomide. The trial was registered at www.clinicaltrials.gov as #NCT01998971.

Download Full-text

Once weekly selinexor, carfilzomib, and dexamethasone (SKd) in patients with relapsed/refractory multiple myeloma (MM).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.8530 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 8530-8530 ◽

Cited By ~ 4

Author(s):

Cristina Gasparetto ◽

Brea Lipe ◽

Sascha Tuchman ◽

Natalie Scott Callander ◽

Suzanne Lentzsch ◽

...

Keyword(s):

Weight Loss ◽

Nuclear Export ◽

Progression Free Survival ◽

Median Number ◽

Maximum Tolerated Dose ◽

Nuclear Retention ◽

Prior Therapy ◽

Previously Treated ◽

Phase 1B ◽

Grade 3

8530 Background: Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks exportin 1 (XPO1), forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was approved by the FDA, based on data from the STORM study wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients (pts) with refractory MM. We hypothesize that once weekly (QW) SKd may be an active well tolerated regimen and evaluated this combination in a dose escalation/expansion study. Methods: STOMP is a phase 1b/2 study evaluating various doses and enrolled pts with carfilzomib naive relapsed MM. Oral selinexor was dosed QW at 80 or 100 mg. Carfilzomib was dosed QW (on days 1, 8 and 15 of 28-day cycle) at 56 mg/m2 or 70 mg/m2. Dexamethasone was dosed at 40 mg QW. The primary objectives of the study are to assess the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), as well as explore the efficacy and safety of SKd. Results: As of January 2020, 18 pts were enrolled. Median age was 71 years (range: 50-76). Median number of prior regimens was 4 (range: 1-8). All pts (n = 18) were previously treated with bortezomib and lenalidomide, and 50% and 56% pts were refractory to bortezomib and lenalidomide respectively. Nine (50%) pts received prior pomalidomide treatment and 8 (44%) pts were refractory. Eleven (61%) pts received prior daratumumab treatment and 9 (50%) were refractory. The MTD was selinexor 80 mg QW, carfilzomib 56 mg/m2 QW and dexamethasone 40 mg QW. The ORR and CBR were 72% and 79% respectively with 4 complete responses, 7 very good partial responses, 2 partial responses, and 1 minimal response. Stable disease was observed in 3 pts. With a median follow-up period of 4.7 (1.8-16.3) months, median progression-free survival has not been reached. Common treatment-related adverse events (total, Grade ≥3) were thrombocytopenia (83.3%, 66.7%), nausea (66.7%, 0%), anemia (55.6%, 11.1%), fatigue (50%, 11.1%), anorexia (44%, 5.6%), weight loss (44%, 0%), and neutropenia (33.3%, 11.1%). Conclusions: Once weekly SKd demonstrated an encouraging ORR of 72% in pts with a median of 4 lines of prior therapy. The majority of responses are deep and predominantly CR and VGPR. The combination is well tolerated with no new safety signal, no Grade ≥3 nausea, vomiting, diarrhea, weight loss or anorexia. The side effects are a function of the dose and schedule and can be managed with dose modification and supportive care. Enrolment is ongoing and supports a phase 3 study of SKd. Clinical trial information: NCT02343042 .

Download Full-text

Pomalidomide, dexamethasone, and daratumumab in relapsed refractory multiple myeloma after lenalidomide treatment

Leukemia ◽

10.1038/s41375-020-0813-1 ◽

2020 ◽

Vol 34 (12) ◽

pp. 3286-3297 ◽

Cited By ~ 5

Author(s):

David S. Siegel ◽

Gary J. Schiller ◽

Christy Samaras ◽

Michael Sebag ◽

Jesus Berdeja ◽

...

Keyword(s):

Multiple Myeloma ◽

Progression Free Survival ◽

Free Survival ◽

Safety And Efficacy ◽

Refractory Multiple Myeloma ◽

Secondary Endpoints ◽

Pretreated Patients ◽

Grade 3 ◽

Treatment Emergent Adverse Event

AbstractPatients with multiple myeloma who have relapsed after or become refractory to lenalidomide in early treatment lines represent a clinically important population in need of effective therapies. The safety and efficacy of pomalidomide, low-dose dexamethasone, and daratumumab was evaluated in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM) after one to two prior treatment lines in the phase 2 MM-014 study. Patients received pomalidomide 4 mg daily from days 1–21 and dexamethasone 40 mg weekly (28-day cycles). Daratumumab 16 mg/kg was administered per label. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. Per protocol, all patients (N = 112) had received lenalidomide in their most recent prior regimen (75.0% lenalidomide refractory). ORR was 77.7% (76.2% in lenalidomide-refractory patients); median follow-up was 17.2 months. Median PFS was not reached (1-year PFS rate 75.1%). The most common hematologic grade 3/4 treatment-emergent adverse event was neutropenia (62.5%). Grade 3/4 infections were reported in 31.3% of patients, including 13.4% with grade 3/4 pneumonia. These results demonstrate the safety and efficacy of pomalidomide-based therapy as early as second line in patients with RRMM, even immediately after lenalidomide failure, indicating that switching from the immunomodulatory agent class is not necessary.

Download Full-text