Elderly and frail patients with multiple myeloma (MM) are more vulnerable to the toxicity of combination therapies, often resulting in treatment modifications and suboptimal outcomes. The phase 3 BOSTON study showed that once-weekly selinexor and bortezomib with low-dose dexamethasone (XVd) improved PFS and ORR compared with standard twice-weekly bortezomib and moderate-dose dexamethasone (Vd) in patients with previously treated MM. This is a retrospective subgroup analysis of the multicenter, prospective, randomized BOSTON trial. Post hoc analyses were performed to compare XVd versus Vd safety and efficacy according to age and frailty status (<65 and ≥65 years, nonfrail and frail). Patients ≥65 years with XVd had higher ORR (OR 1.77, p = .024), ≥VGPR (OR, 1.68, p = .027), PFS (HR 0.55, p = .002), and improved OS (HR 0.63, p = .030), compared with Vd. In frail patients, XVd was associated with a trend towards better PFS (HR 0.69, p = .08) and OS (HR 0.62, p = .062). Significant improvements were also observed in patients <65 (ORR and TTNT) and nonfrail patients (PFS, ORR, ≥VGPR, and TTNT). Patients treated with XVd had a lower incidence of grade ≥ 2 peripheral neuropathy in ≥65 year-old (22% vs. 37%; p = .0060) and frail patients (15% vs. 44%; p = .0002). Grade ≥3 TEAEs were not observed more often in older compared to younger patients, nor in frail compared to nonfrail patients. XVd is safe and effective in patients <65 and ≥65 and in nonfrail and frail patients with previously treated MM.

Alexandra Hospital School of Medicine National and Kapodistrian University of Athens Athens Greece

Baylor University Medical Center Dallas Texas USA

Charles University and General Hospital Prague Czech Republic

CHU Lille Service des Maladies du Sang F 59000 Lille France

City Clinical Hospital 40 Moscow Russian Federation

City Clinical Hospital No 4 of Dnipro City Council Dnipro Ukraine

Cross Cancer Institute University of Alberta Edmonton Alberta Canada

Dana Farber Cancer Institute Boston Massachusetts USA

Department of Hemato oncology University Hospital Ostrava University of Ostrava Ostrava Czech Republic

Department of Hematology Cherkassy Regional Oncological Center Cherkassy Ukraine

Department of Hematology CHU la Miletrie and Inserm CIC 1402 Poitiers France

General Hospital Evangelismos Athens Greece

Hospital Universitario de Salamanca Salamanca Spain

Institute of Blood Pathology and Transfusion Medicine of National Academy of Medical Sciences of Ukraine Lviv Ukraine

Karyopharm Therapeutics Inc Newton Massachusetts USA

Kings College Hospital NHS Foundation Trust London UK

Medical University of Silesia Katowice Poland

National and Kapodistrian University of Athens School of Medicine Athens Greece

National Cancer Institute Ukraine Kiev Ukraine

Nil Ratan Sircar Medical College and Hospital Kolkata India

Norton Cancer Institute Louisville Kentucky USA

Seràgnoli Institute of Hematology Bologna University School of Medicine Bologna Italy

Simmons Comprehensive Cancer Center UT Southwestern Medical Center Dallas Texas USA

State Cancer Institute Indira Gandhi Institute of Medical Sciences Patna India

The Hugh and Josseline Langmuir Centre for Myeloma Research Imperial College London London UK

Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York New York USA

University Hospital Brno Brno Czech Republic

University Hospital Hotel Dieu Nantes France

University Hospitals of Leicester NHS Trust Leicester UK

University of Calgary Charbonneau Cancer Research Institute Calgary Alberta Canada

University of Maryland Greenebaum Comprehensive Cancer Center Baltimore Maryland USA

University of Melbourne St Vincent's Hospital Melbourne Victoria Australia

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Swan D, Lynch K, Gurney M, O'Dwyer M. Current and emerging immunotherapeutic approaches to the treatment of multiple myeloma. Ther Adv Hematol. 2019;10:204062071985417. https://doi.org/10.1177/2040620719854171.

Issa ME, Sedigheh Takhsha F, Sekhar Chirumamilla C, Perez-Novo C, Vanden Berghe W, Cuendet M. Epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma. 2017. https://doi.org/10.1186/s13148-017-0319-5.

van Andel H, Kocemba KA, Spaargaren M, Pals ST. Aberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options. Leukemia. 2019;33(5):1063-1075. https://doi.org/10.1038/s41375-019-0404-1.

Gandhi UH, Senapedis W, Baloglu E, et al. Clinical implications of targeting XPO1-mediated nuclear export in multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018;18(5):335-345. https://doi.org/10.1016/j.clml.2018.03.003.

Jakubowiak AJ, Jasielec JK, Rosenbaum CA, et al. Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma. Br J Haematol. 2019;186(4):549-560. https://doi.org/10.1111/bjh.15969.

Michels TC, Petersen KE. Multiple myeloma: diagnosis and treatment. Am Family Phys. 2017;95:373-383.

Rajkumar SV. Multiple myeloma: 2018 update on diagnosis, risk-stratification, and management. Am J Hematol. 2018;93(8):1091-1110. https://doi.org/10.1002/ajh.25117.

Kint N, Delforge M. Concise review treatment of multiple myeloma in the very elderly: how do novel agents fit in? J Geriatr Oncol. 2016;7(5):383-389. https://doi.org/10.1016/j.jgo.2016.08.001.

Myeloma - cancer stat facts. https://seer.cancer.gov/statfacts/html/mulmy.html. Accessed January 28, 2020.

Pawlyn C, Cairns D, Kaiser M, et al. The relative importance of factors predicting outcome for myeloma patients at different ages: results from 3894 patients in the myeloma XI trial. Leukemia. 2020;34(2):604-612. https://doi.org/10.1038/s41375-019-0595-5.

Costa LJ, Brill IK, Omel J, Godby K, Kumar SK, Brown EE. Recent trends in multiple myeloma incidence and survival by age, race, and ethnicity in the United States. Blood Adv. 2017;1(4):282-287. https://doi.org/10.1182/bloodadvances.2016002493.

Cook G, Larocca A, Facon T, Zweegman S, Engelhardt M. Defining the vulnerable patient with myeloma-a frailty position paper of the European Myeloma Network. Leukemia. 2020;34(9):2285-2294. https://doi.org/10.1038/s41375-020-0918-6.

Bringhen S, Mateos MV, Zweegman S, et al. Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials. Haematologica. 2013;98(6):980-987. https://doi.org/10.3324/haematol.2012.075051.

Zanwar S, Abeykoon JP, Kapoor P. Challenges and strategies in the management of multiple myeloma in the elderly population. Curr Hematol Malig Rep. 2019;14(2):70-82. https://doi.org/10.1007/s11899-019-00500-4.

Auner HW, Szydlo R, Hoek J, et al. Trends in autologous hematopoietic cell transplantation for multiple myeloma in Europe: increased use and improved outcomes in elderly patients in recent years. Bone Marrow Transplant. 2015;50(2):209-215. https://doi.org/10.1038/bmt.2014.255.

Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an international myeloma working group report. Blood. 2015;125(13):2068-2074. https://doi.org/10.1182/blood-2014-12-615187.

Camus V, Miloudi H, Taly A, Sola B, Jardin F. XPO1 in B cell hematological malignancies: from recurrent somatic mutations to targeted therapy. J Hematol Oncol. 2017;10(1):47-57. https://doi.org/10.1186/s13045-017-0412-4.

Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727-738. https://doi.org/10.1056/NEJMoa1903455.

Gavriatopoulou M, Chari A, Chen C, et al. Integrated safety profile of selinexor in multiple myeloma: experience from 437 patients enrolled in clinical trials. Leukemia. 2020;34:2430-2440. https://doi.org/10.1038/s41375-020-0756-6.

Zhu ZC, Liu JW, Yang C, Zhao M, Xiong ZQ. XPO1 inhibitor KPT-330 synergizes with Bcl-xL inhibitor to induce cancer cell apoptosis by perturbing rRNA processing and Mcl-1 protein synthesis. Cell Death Dis. 2019;10(6):1-14. https://doi.org/10.1038/s41419-019-1627-9.

Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511-e522. https://doi.org/10.1016/S2352-3026(20)30120-4.

Bahlis NJ, Sutherland H, White D, et al. Selinexor plus low-dose bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma. Blood. 2018;132(24):2546-2554. https://doi.org/10.1182/blood-2018-06-858852.

Grosicki S, Simonova M, Picka I, et al. Once-weekly selinexor, bortezomib, and dexamethasone versus twice-weekly bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label phase 3 trial. Lancet. 2020;396:1563-1573.

Engelhardt M, Ihorst G, Duque-Afonso J, et al. Structured assessment of frailty in multiple myeloma as a paradigm of individualized treatment algorithms in cancer patients at advanced age. Haematologica. 2020;105(5):1183-1188. https://doi.org/10.3324/haematol.2019.242958.

Cook G, Larocca A, Facon T, Zweegman S, Engelhardt M. Perspective multiple myeloma gammopathies defining the vulnerable patient with myeloma-a frailty position paper of the European myeloma network. Leukemia. 2020;34:2285-2294. https://doi.org/10.1038/s41375-020-0918-6.

Engelhardt M, Domm AS, Dold SM, et al. A concise revised myeloma comorbidity index as a valid prognostic instrument in a large cohort of 801 multiple myeloma patients. Haematologica. 2017;102(5):910-921. https://doi.org/10.3324/haematol.2016.162693.

Milani P, Vincent Rajkumar S, Merlini G, et al. N-terminal fragment of the type-B natriuretic peptide (NT-proBNP) contributes to a simple new frailty score in patients with newly diagnosed multiple myeloma. Am J Hematol. 2016;91(11):1129-1134. https://doi.org/10.1002/ajh.24532.

Dold SM, Möller M-D, Ihorst G, et al. Validation of the revised myeloma comorbidity index and other comorbidity scores in a multicenter German study group multiple myeloma trial. Haematologica. 2021; 106(3):875-880. https://doi.org/10.3324/haematol.2020.254235.

Offidani M, Corvatta L, Polloni C, et al. Assessment of vulnerability measures and their effect on survival in a real-life population of multiple myeloma patients registered at Marche region multiple myeloma registry. Clin Lymphoma Myeloma Leuk. 2012;12(6):423-432. https://doi.org/10.1016/j.clml.2012.06.008.

Cook G, Royle KL, Pawlyn C, et al. A clinical prediction model for outcome and therapy delivery in transplant-ineligible patients with myeloma (UKmyeloma research alliance risk profile): a development and validation study. Lancet Haematol. 2019;6(3):e154-e166. https://doi.org/10.1016/S2352-3026(18)30220-5.

Facon T, Dimopoulos MA, Meuleman N, et al. A simplified frailty scale predicts outcomes in transplant-ineligible patients with newly diagnosed multiple myeloma treated in the FIRST (MM-020) trial. Leukemia. 2020;34(1):224-233. https://doi.org/10.1038/s41375-019-0539-0.

Stege CAM, van der Holt B, Dinmohamed AG, et al. Validation of the FIRST simplified frailty scale using the ECOG performance status instead of patient-reported activities. Leukemia. 2020;34(7):1964-1966. https://doi.org/10.1038/s41375-020-0713-4.

Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-e346. https://doi.org/10.1016/S1470-2045(16)30206-6.

Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020;396(10262):1563-1573. https://doi.org/10.1016/S0140-6736(20)32292-3.

Durie BGM, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527. https://doi.org/10.1016/S0140-6736(16)31594-X.

Kumar S, Jacobus SJ, Cohen AD, et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM): results of ENDURANCE (E1A11) phase III trial. J Clin Oncol. 2020;38(18_suppl):LBA3. https://doi.org/10.1200/jco.2020.38.18_suppl.lba3.

Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331. https://doi.org/10.1056/nejmoa1607751.

Usmani SZ, Nahi H, Mateos MV, et al. Subcutaneous delivery of daratumumab in relapsed or refractory multiple myeloma. Blood. 2019;134(8):668-677. https://doi.org/10.1182/blood.2019000667.

Mateos MV, Nahi H, Legiec W, et al. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020;7(5):e370-e380. https://doi.org/10.1016/S2352-3026(20)30070-3.

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