Overall survival of patients with triple‐class refractory multiple myeloma treated with selinexor plus dexamethasone vs standard of care in <scp>MAMMOTH</scp>
Authors: Robert Cornell, Parameswaran Hari, Shijie Tang, Noa Biran, Natalie Callander, Ajai Chari, Saurabh Chhabra, Mark A. Fiala, Zhubin Gahvari, Ujjawal Gandhi, Kelly Godby, Ridhi Gupta, Sundar Jagannath, Megan Jagosky, Yubin Kang, Ankit Kansagra, Michael Kauffman, Saranya Kodali, Shaji K. Kumar, Arjun Lakshman, Michaela Liedtke, Sagar Lonial, Xiwen Ma, Ehsan Malek, Joshua Mansour, Elizabeth F. McGehee, Amarendra Neppalli, Barry Paul, Paul Richardson, Emma C. Scott, Sharon Shacham, Jatin Shah, David S. Siegel, Elvira Umyarova, Saad Z. Usmani, William Varnado, Ravi Vij, Luciano Costa
Journal: American Journal of Hematology (2020)

To the Editor: Multiple myeloma (MM) is the second most common hematologic malignancy worldwide, with an estimated annual incidence of 1.5-6.8 per 100 000 population. Proteasome inhibitors (PI) and immunomodulatory agents (IMiDs) have advanced the management of MM by improving the depth and duration of response. However, when patients become refractory to both drug classes, outcomes are poor, with median overall survival (OS) of 9 months in patients refractory to bortezomib and an IMiD.1 Anti-CD38 and anti-SLAMF7 antibodies have further advanced the field; despite this, most patients develop MM refractory to available therapies and have a particularly poor prognosis, with survival measured in months.2 Patients who receive multiple lines of treatment, including the five major agents lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab, are classed as penta-treated. The use of three-drug and four-drug combinations in the early treatment of MM means that there are also an increasing population of patients who become triple-class refractory (TCR; refractory to IMiDs, PIs, monoclonal antibodies [mAbs]) early in treatment. These patients require novel therapies in the face of clonal diversity and multi-refractoriness.3 There is currently no clear consensus on the optimal treatment sequence for patients with relapsed and/or refractory MM (RRMM), nor a standard of care for patients with penta-treated TCR MM. As a first-in-class oral selective inhibitor of nuclear export (SINE), selinexor targets exportin 1, which is overexpressed in MM cells.3, 4 Inhibition of exportin 1 restores nuclear retention and functional activation of MM tumor suppressor proteins, inhibition of NF-kB signaling, and induction of translational suppression of several oncoprotein mRNAs.4 The efficacy of selinexor in combination with low-dose dexamethasone (sel-dex) was demonstrated in the pivotal Phase 2b Selinexor Treatment of Refractory Myeloma (STORM) Part two study (NCT02336815). In 122 patients with penta-treated/TCR-MM treated with sel-dex, the overall response rate (ORR) was 26% and overall survival (OS) was 8.6 months.3 Based on these results, selinexor was approved in the US for the treatment of patients with MM refractory to at least two PIs, at least two IMiDs, and an anti-CD38 mAb. The retrospective Monoclonal Antibodies in Multiple Myeloma: Outcomes after THerapy failure (MAMMOTH) study was designed to investigate the natural history and outcomes of patients with RRMM after they became refractory to anti-CD38 mAbs, including a subset of patients who were TCR; these patients were treated in academic centers, but did not receive sel-dex.5 In the present analysis, the MAMMOTH dataset was used to generate a cohort of patients similar to those in STORM to compare OS and ORR with contemporary care vs that achieved with sel-dex. The study design and patient criteria for STORM and MAMMOTH have been described previously.3, 5 Eligible patients in STORM were treated with selinexor 80 mg plus dexamethasone 20 mg twice weekly (days 1 and 3) until disease progression. Patients continued to be followed for OS after discontinuation of therapy. To align with the patient population from STORM, patients from MAMMOTH were included in this analysis if, after being penta-treated and becoming TCR, they received subsequent MM-directed therapy other than sel-dex. Study data were collected between January 2017 and June 2018. For both studies, OS was calculated from the time of initiation of next line of therapy after penta-treated/TCR status was reached until death or last follow-up. The OS was compared in STORM vs MAMMOTH utilizing Cox regression analysis and adjusted for covariates potentially influencing the outcome. The analysis included 64 of the 122 patients from STORM, who received sel-dex as first line of therapy after their MM first became penta-treated/TCR. Fifty-eight patients from STORM received therapy after their MM became penta-treated and TCR and before enrollment in STORM and were excluded from this analysis. From the MAMMOTH dataset, we extracted 128 of the 275 patients who met the inclusion criteria (Figure S1). The two cohorts were similar in terms of patient age, presence of high-risk cytogenetic abnormalities, and number of prior treatment regimens (Table S1). Patients in STORM had longer time between MM diagnosis and post-penta-treated/TCR therapy, reflecting a less aggressive disease, with a higher proportion refractory to carfilzomib as well as to all three treatments of carfilzomib, pomalidomide, and daratumumab. After their MM became penta-treated/TCR, the most common therapies administered to patients in MAMMOTH were pomalidomide-based (36.8%) and traditional chemotherapy (33.6%; Table S1). In an indirect comparison, patients in STORM had better OS than patients in MAMMOTH; median (95% confidence interval [CI]): 10.4 (7.9-not evaluable) vs 6.9 (5.3-8.6) months; P = .043 (Figure 1). In multivariate analysis, patients in STORM had a lower risk of death compared with patients in MAMMOTH [adjusted hazard ratio HR = 0.55:95% CI: 0.36-0.86; P = .009]. Covariates significantly associated with a shorter OS were refractoriness to carfilzomib, and high-risk cytogenetics (Table S2). The ORR to the first therapy after attaining penta-treated/TCR MM status was 32.8% (21/64 patients) in STORM compared with 25.0% (32/128 patients) in MAMMOTH (P = .078, Figure S2). In patients with a high cytogenetic risk (including p53 abnormalities, del 17p, t[4;14], t[14;16], del 13), the ORR was 21.9% (7/32 patients) in STORM and 24.6% (16/65 patients) in MAMMOTH (P = .96). For patients refractory to carfilzomib, pomalidomide, and daratumumab, the ORR was 33.3% (20/60 patients) and 26.0% (27/104 patients) in STORM and MAMMOTH, respectively (P = .40, Figure S2). In this analysis, patients first treated with sel-dex after developing penta-treated/TCR-MM in STORM had longer OS compared with retreatment strategies with conventional care at academic centers in MAMMOTH. The conventional retreatment strategies in MAMMOTH after reaching penta-treated/TCR status were agents that patients had previously received; in many cases, their disease was documented to be refractory to these agents. This likely reflects the reuse of these agents combined with other agents as part of alternative regimens. As a first-in-class SINE targeting exportin 1, the use of sel-dex in STORM represents a non-cross-resistant therapy with a novel mechanism of action. The increasing incidence of patients developing multi-refractory MM associated with early exposure to several classes of therapy, including newer agents such as daratumumab and other mAbs,1, 5 highlights the importance of placing patients on a suitable treatment early in the course of their MM. A similar analysis comparing outcomes of patients from STORM treated with sel-dex as the next line of therapy after developing penta-treated/TCR-MM (n = 64) with a comparable population of real-world patients treated with available therapy (other than sel-dex), in a largely community-based setting from the Flatiron Health Analytic Database (FHAD; n = 37) showed a median OS of 10.4 vs 5.2 months in STORM vs FHAD, respectively; adjusted HR: 0.49 (P = .024).6 These results are comparable to the present analysis. The similarity of results strengthen the confidence that the analysis reflects a true effect of a novel, anti-MM mechanism on OS, akin to those reported for therapies approved in the past. Possible reasons for the improved OS in the context of PFS observed with sel-dex is the use of supportive care to optimize responses, the short half-life of selinexor and reversal of treatment-emergent toxicities upon ceasing treatment. This allows patients with disease progression on sel-dex to move onto alternative treatment regimens, possibly in the context of a clinical trial. Furthermore, the ORR of 32.8% with sel-dex compared with 25.0% achieved with multi-agent combination retreatments supports the use of novel therapies. Patient heterogeneity arising from the retrospective nature of MAMMOTH may have some impact on the present analysis, despite adjustment by Cox regression.5 Although largely comparable, this retrospective analysis does not capture the effect of unmeasured confounding factors. Furthermore, potential referral bias in MM patients enrolled in academic centers with myeloma specialists, applicable to both data sets, may not be generalizable to outcomes in community settings, particularly as most patients with MM in the US receive four or more different lines of therapy.5 Additionally, the MAMMOTH data set may have contained patients ineligible for participation in clinical trials, suggesting an overall more fragile patient population. The relatively small sample size from STORM included in the analysis could limit the study findings, however this also underpins the need for further exploration of treatment options and combinations for these patients. The genomic and immunologic complexity of RRMM means that combination strategies are clearly preferred to optimize efficacy and tolerability. The ongoing Selinexor and Backbone Treatments of Multiple Myeloma Patients (STOMP) study has demonstrated encouraging efficacy and safety with once-weekly sel-dex in combination with common backbone therapy agents such as pomalidomide, lenalidomide, daratumumab, bortezomib, or carfilzomib. Indeed, early data from STOMP in patients who have progressed even after receiving fludarabine-cyclophosphamide conditioned chimeric antigen receptor T-cell therapy highlights the novel, non-cross resistant mechanism of action of selinexor and the need for further studies in RRMM patients refractory to anti-B-cell maturation antigen therapies. The improved OS and ORR achieved with sel-dex, compared with multi-agent combination retreatments, supports introduction of therapies with novel, non-cross reactive and potentially synergistic mechanisms, as opposed to recycling previously utilized treatments in patients with penta-treated/TCR-MM. A particular benefit observed in patients refractory to carfilzomib and those with high-risk cytogenetics, may guide patient selection for future studies with selinexor. We would like to especially thank all the patients who participated in the studies, and their families. The STORM study (NCT02336815) and the present analysis were funded by Karyopharm Therapeutics, Newton, Massachusetts. The MAMMOTH study was not commercially funded. The authors also acknowledge Liz Anfield, Prime Global, Knutsford, UK, for medical writing support, under the direction of the authors, which was funded by Karyopharm Therapeutics in accordance with Good Publications Practice (GPP3) guidelines. Development of this manuscript was supported by Karyopharm Therapeutics. R.C. reports honoraria from Karyopharm Therapeutics, Takeda, Janssen, Sanofi, and GlaxoSmithKline; P.H. reports honoraria from Bristol Myers Squibb, Takeda, Amgen, GlaxoSmithKline, Janssen, Karyopharm Therapeutics, Sanofi, and Pharmacyclics; S.T., J.S., M.K., and X.M. report being employed by and owning stock in Karyopharm Therapeutics; N.B. reports honoraria and speakers' bureau participation for Celgene, Amgen, Janssen, and Takeda; consulting or advisory role fees and reimbursement of travel, accommodations, or other expenses from Celgene, Amgen, and Takeda; and research funding from Merck and Amgen; N.C. reports research support from Cellectar; A.C. reports receiving grant support and consulting fees from Millennium/Takeda; grant support, advisory board fees, and consulting fees from Celgene, Novartis Pharmaceuticals, Amgen, and Janssen; consulting fees from Bristol Myers Squibb; advisory board fees from Sanofi and Oncopeptides; grant support from Pharmacyclics; and grant support and advisory board fees from Seattle Genetics; S.C. reports receiving honorarium from Takeda Pharmaceuticals; S.J. reports receiving advisory board fees and consulting fees from Bristol Myers Squibb, Janssen Pharmaceuticals, and Merck; Y.K. reports receiving advisory board fees from Takeda and grant support from InCyte; A.K. reports receiving advisory board fees from Celgene, Janssen, Karyopharm Therapeutics, Takeda, Pfizer and Pharmacyclics; S.K.K. reports receiving advisory board fees from AbbVie, Celgene, Janssen, Takeda Pharmaceuticals, Adaptive Biotechnologies, Kite Pharma, MedImmune/AstraZeneca; receiving research funding from AbbVie, Celgene, Janssen, Merck, Novartis, Roche, Sanofi, Takeda Pharmaceuticals, Kite Pharma and MedImmune/AstraZeneca; and is a member of the Independent Review Committee for Oncopeptides; M.L. reports receiving personal fees from Amgen, Celgene, Pfizer, Takeda, and Janssen; S.L. reports receiving advisory board fees from AbbVie, Amgen, Celgene, Takeda, Janssen Oncology, Juno Therapeutics, Novartis, Merck, Bristol Myers Squibb, and GlaxoSmithKline; and receiving research funding from Bristol Myers Squibb, Celgene, and Takeda; E.M. reports receiving advisory board and speaker fees from Takeda, Sanofi, Amgen and Celgene; speaker fees from Janssen; research funding from Medpacto Inc. and Cumberland; A.N. reports receiving advisory board fees from Amgen; B.P. reports receiving honoraria from Celgene; consulting fees from Amgen and Janssen; P.R. reports receiving grant support and honoraria from Oncopeptides, Celgene, and Takeda; grant support from Bristol Myers Squibb; and honoraria from Amgen, Janssen, and Karyopharm Therapeutics; E.S. reports being employed by GlaxoSmithKline; S.S. reports being employed by and owning stock in Karyopharm Therapeutics, holding patents (8 999 996, 9 079 865, 9 714 226, PCT/US12/048319, and I574957) on hydrazide-containing nuclear transport modulators and uses, and holding pending patents (PCT/US12/048319, 499/2012, PI20102724, and 012000928) on hydrazide-containing nuclear transport modulators and uses; D.S. reports receiving honoraria and consulting or advisory role fees for Celgene, Amgen, Merck, Janssen, Bristol Myers Squibb, Takeda, and Karyopharm Therapeutics; speakers' bureau participation for Celgene, Amgen, Merck, Janssen, Bristol Myers Squibb, and Takeda; and research funding from Celgene; S.U. reports receiving consulting fees from Abbvie, Amgen Inc, Bristol Myers Squibb, Celgene, EdoPharma, GlaxoSmithKline, Janssen, Merck, Sanofi, Seattle Genetics, Skyline Dx, Takeda, and TeneoBio; and research funding from Amgen, Array Biopharma, Bristol Myers Squibb, Celgene, Janssen, Merck, Pharmacyclics, Prothena, Sanofi, Seattle Genetics, Skyline Dx, and Takeda; R.V. reports receiving advisory board fees from Bristol Myers Squibb, Takeda, Janssen, Karyopharm Therapeutics, Securabio, and Genentech; and research funding from Bristol Myers Squibb and Takeda; L.C. reports research funding from Amgen and Janssen; and honoraria from Karyopharm Therapeutics, Celgene, Amgen, Janssen, and Sanofi. M.F., Z.G., U.G., K.G., R.G., M.J., S.K., A.L., J.M., E.F.M., E.U., and W.V. declare no conflict of interest. R.C., M.F., E.S., L.C., J.S., P.H., S.T. and P.R. contributed to study design. R.C., L.C., N.C., S.C., M.F., Z.G., Y.K., S.K., A.L., E.S., B.P., W.V., U.G., R.V., A.C., A.K., E.M., J.M., P.H., P.R., S.U., S.T., K.G., E.F.M., A.M., E.U., M.J., M.L., N.B. and R.G. were involved in data collection. R.C., S.C., M.F., E.S., L.C., S.J., R.V., W.V., A.C., A.K., J.S., P.H., P.R., S.U., S.T., X.M., D.S. and R.G. analyzed and interpreted the data. All authors critically reviewed the manuscript, approved the final version, and accept responsibility for the overall work. The data that support the findings of this study are available from the corresponding author upon reasonable request. Figure S1. Study flow Figure S2. Overall response rate: overall and in patients with high-risk cytogenetics or refractory to carfilzomib, pomalidomide and daratumumab Table S1. Baseline characteristics of patients with MM first treated with sel-dex (STORM) or other MM-directed therapy (MAMMOTH) after becoming penta-treated/TCR Table S2. Multivariate analysis for risk of death Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.