Sustained Response to Selinexor-Based Therapy for Triple-Class Refractory Multiple Myeloma with Early Relapse After Allogeneic Stem Cell Transplantation
Daniel Sherbenou, Margaret Stalker, Peter Forsberg, Tomer Martin Mark
Clinical Practice Points
• Selinexor may be active even in the dire situation of early relapse after allogeneic stem cell transplantation.
• Selinexor retains activity in patients who are protea- some, immunomodulatory drug, and daratumumab refractory.
• Selinexor has the potential to be combined effectively with multiple standard anti-myeloma agents, including carfilzomib.
Keywords: Carfilzomib, Sine, Daratumumab, Elotuzumab, Pomalidomide
Introduction
The number of treatment options for multiple myeloma (MM) has grown over the past decades, with the advent of novel agents such as proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies.1 Despite the recent increase in the number and classes of new effective therapies, such as antibody– drug conjugates, allogeneic stem cell transplantation (SCT) remains an important option for relapsed disease and has been considered a potentially curative therapy.2 Although the use and timing of allogeneic stem cell transplant in MM are still debated,3 data regard- ing therapeutic options for patients who progress after allogeneic SCT remain lacking.4,5 Here, we present a case in which a patient with heavily pretreated myeloma had an extended response to selinexor in combination with carfilzomib and dexamethasone after his disease progressed after allogeneic SCT.
Case Report
History of Present Illness
A 57-year-old man was referred for IgG kappa myeloma management after experiencing progressive back pain over the prior 3 months. Magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (FDG) positron emission tomogra- phy/computed tomography (PET/CT) showed numerous large FDGFDG-avid lytic lesions throughout the cervical and thoracic spine, a severe pathologic compression fracture of T1, and epidu- ral tumors at the T1 and T9 vertebrae. No suspicious sites of extramedullary disease were present. For initial management, he underwent C7-T1 tumor resection and C7-T4 fixation. He also had multilevel laminectomies and instrumented fixation. Marrow sampling at the time of surgery revealed a plasma cell infiltrate.
Diagnostic bone marrow biopsy revealed a hypercellular marrow with 60% to 70% kappa-restricted plasmacytosis. Laboratory studies revealed a white blood cell count of 2.5 × 109/L, hemoglobin of 8.0 g/dL, and platelets of 226 × 109/L. IgG was 2465 mg/dL, IgA was 13 mg/dL, and IgM was 28 mg/dL; free kappa and lambda light chains were 48.1 and 0.7 mg/dL, respec- tively, with a ratio of 69.1. Serum protein electrophoresis with immunofixation revealed a M-spike of 1.5 g/dL, isotype IgG kappa. Beta-2 microglobulin was 8.1 mg/L, albumin was 3.5 g/dL, lactate dehydrogenase was 186 U/L, calcium was 11.6 mg/dL, and serum creatinine was 1.41 mg/dL, with an estimated creatinine clearance of 57 mL/min. Karyotype analysis identified an abnormal hyper- diploid clone, accounting for three of 20 analyzed cells with a 51- 52, XY, add(1)(p12), −2,+3,+5,+7, add(8)(p11.2), +9, +add(11) (q23), add(12)(p11.2), +15[cp3]/46,XY[17] karyotype. Fluorescence in situ hybridization assay showed a gain of 11q23 in 52.5% of selected cells, but they were negative for abnormalities of CDKN2C, CKS1B, TP53, 13q14, and other IGH rearrangements. The patient was staged as International Staging System (ISS) 3, revised ISS (R- ISS) 2.
Past Medical History
The patient’s past medical history included hyperlipidemia, depression, sleep apnea, and benign thyroid nodule.
Past Surgical History
The patient’s past surgical history included inguinal hernia repair.
Course of Treatment
The patient was started on weekly cyclophosphamide, borte- zomib, and dexamethasone as initial treatment. After 4 months of therapy, he had achieved partial response with a M-spike of 0.2 g/dL and normalization of free light chains. Bone marrow biopsy showed low-level persistent plasma cell myeloma with 5% kappa- restricted plasma cells, and autologous stem cell transplant (ASCT) was performed using melphalan 200 mg/m2 conditioning. The M- spike remained unchanged at day +100 at 0.2 g/dL. Coincidentally, 2 months after the ASCT the patient was diagnosed with multifo- cal papillary thyroid carcinoma, requiring total thyroidectomy and I131 therapy. The extent of disease work-up at the time also revealed cerebellum and vermis lesions, which were also surgically excised, with pathology revealing pilocytic astrocytoma.
Due to these complications after the ASCT, maintenance therapy was delayed, and bortezomib 1.3 mg/m2 dosed subcutaneously every 2 weeks was initiated 8 months after SCT. However, the disease progressed biochemically after only 1 month on mainte- nance. Over the next 33 months, the patient was treated with six additional lines of therapy, including PIs, IMiDs, daratu- mumab, and elotuzumab, combined with other chemotherapy agents (Table 1, Figure 1). During the course of salvage therapy, the patient’s myeloma became oligosecretory, and serial imaging with either PET/CT or MRI was used approximately every 2 months to assess response. The patient eventually developed triple-class refrac- tory disease after developing new bone lesions while on daratu- mumab, pomalidomide, and dexamethasone treatment approxi- mately 3 years after initial diagnosis. With limited treatments avail- able, the decision to pursue allogeneic transplant was made, and the patient underwent autologous SCT with carmustine, etopo- side, cytarabine, and melphalan (BEAM) conditioning, followed by a matched sibling donor reduced-intensity allogeneic SCT with fludarabine and total body irradiation (3 Gy) conditioning. No acute graft-versus-host disease (GVHD) was seen.
Unfortunately, 3 months after the allogeneic SCT, progression was noted on PET/CT with several new bone lesions, and repeat marrow sampling showed 36% clonal plasma cell involvement. Chimerism at the time of marrow sampling showed 100% donor CD33, CD56, and CD3 cells. The patient was started on his ninth line of therapy with selinexor 80 mg twice weekly, carfilzomib 56 mg/m2 weekly, and dexamethasone 40 mg once weekly (SKd) in a 28-day cycle. The patient also underwent radiation to address FDG activity seen in the hard palate and pterygopalatine fossa during cycle 1 of SKd. Results of an FDG PET performed after one cycle of therapy showed decreased FDG avidity in multiple lower extremity and iliac osseous lesions (Figure 1). The course of therapy was complicated by infection with mycoplasma pneumonia, for which SKd was held for 1 week, and he recovered uneventfully following a course of levofloxacin. One month after mycoplasma pneumonia infection, he was diagnosed with respiratory syncy- tial virus pneumonia and recovered with a course of ribavirin and levofloxacin while SKd was continued uninterrupted. Due to neutropenia and thrombocytopenia, selinexor dosing was changed from 80 mg twice weekly to 100 mg once weekly starting with cycle 4 of therapy, which is consistent with dosing currently being evalu- ated in an ongoing phase II study of SKd for relapsed/refractory multiple myeloma (RRMM).6 Repeat PET/CT imaging performed at cycles 3 and 5 have continued to be negative for recurrence of active myeloma. MRI imaging of the spine and skull at cycle 7 has also indicated ongoing response to SKd treatment.
Carfilzomib was adjusted to 27 mg/m2 on only day 1 start- ing with cycle 10 due to transfusion-dependent thrombocytope- nia, fatigue, diarrhea, and dysgeusia. PET/CT continued to be negative at cycle 11. Cycle 12 was delayed 1 week after a hospitaliza- tion for hypotension and dizziness at physical therapy that resolved with intravenous fluids. Tacrolimus was started for grade 1 chronic GVHD of the mouth, eyes, skin, and liver during cycle 13, and a percutaneous endoscopic gastrostomy tube was placed for weight loss. PET/CT was stable and bone marrow biopsy was negative at cycle 13. Cycle 14 was delayed for 1 month because the patient was admitted for hypotension secondary to Clostridioides difficile colitis, treated with vancomycin; hypoxia secondary to suspected pneumonia, for which he was started on Levaquin; and supraven- tricular tachycardia with a heart rate in the 150s requiring adeno- sine. Selinexor and carfilzomib were continued to be held until after the next scheduled PET/CT at the start of cycle 15.
The scan for cycle 15 showed signs of disease progression with a lytic lesion on the left posterior iliac bone, posterior aspect of right superior ribs, and multiple opacities in the bilateral lungs all showing increased FDG avidity. His labs at the time showed a detectable but unquantifiable M-spike, a new result from the previous cycle. The patient was started on the next line of therapy with isatuximab and pomalidomide.
Discussion
Therapy decisions for myeloma patients who progress after allogeneic SCT are challenging given the frailty of the patient, number of therapies and combinations available, unique comorbidi- ties such as GVHD, and the lack of data regarding salvage therapies in this patient population. Prior to allogeneic SCT, the patient had received eight prior lines of therapy, including ASCT, with a best response of very good partial remission for 6 months to the combi- nation of daratumumab, pomalidomide, and dexamethasone. By the time of the allogeneic transplant, the patient had proven refrac- tory to two immunomodulatory agents, two proteasome inhibitors, anti-CD38 and anti-SLAMF7 antibody therapies, and high-dose melphalan, as well as other alkylating agents. This left the patient with very limited remaining treatment options. Additionally, due to his non-secretory disease and prior history of both papillary thyroid cancer and pilocytic astrocytoma, he was unfortunately excluded from available clinical trials. He underwent a tandem autologous– allogeneic SCT and had quick disease progression within 100 days. Despite this dire circumstance, this patient achieved exceptional benefit from selinexor-based treatment after this early relapse from post-allogeneic SCT as described above.
Selinexor is a selective inhibitor of nuclear export that has been evaluated in patients with triple-class refractory disease, demonstrat- ing a 26% response rate when used in combination with dexametha- sone in this heavily pretreated population.7 Our patient had a rapid response to the combination of selinexor, carfilzomib, and dexam- ethasone, despite previously demonstrating acquired resistance to both of the latter agents. This is consistent with the rapid responses thus far reported in clinical trials.7,8 Of responders to selinexor and dexamethasone, 10% or more have had a duration of response lasting greater than 10 months.7 The Selinexor and Backbone Treat- ments of Multiple Myeloma Patients (STOMP) study of selinexor combined with multiple standard anti-myeloma agents showed that selinexor in combination with pomalidomide and dexamethasone for the treatment of RRMM had a 58% overall response rate and a progression-free survival (PFS) of 12.3 months.9 A subgroup of the STOMP trial studied selinexor in combination with daratumumab and dexamethasone in patients with RRMM and found a 73% response rate and median PFS of 12.5 months.10 When combined with carfilzomib (Kyprolis), SKd was reported at the 2020 Ameri- can Society of Hematology conference to have an overall response rate of 75%. Longer term data are pending regarding duration of response; however, median PFS had not been reached after 4.4 months of follow up.11 Treatment with SKd was relatively well toler- ated in the patient presented in this case report without exacerba- tion of severe bortezomib-induced preexisting peripheral neuropa- thy. He had persistent cytopenias, with a manageable but increased need for platelet transfusion support while on SKd that improved with dose reduction of both the selinexor and carfilzomib. The patient course was also complicated by multiple infections, which is not unusual in the RRMM patient population due to persis- tent immunosuppressive treatment, hypogammaglobulinemia, post- transplant status, and other comorbidities.
Few studies have been performed in the myeloma patient population that relapses after allogeneic SCT. Two small studies showed high rates of response to lenalidomide,12,13 as did two small studies of bortezomib (one with T-lymphocyte infusions).14,15 A retrospec- tive analysis of 126 patients who relapsed after allogeneic SCT showed that many patients responded to both PIs and IMiDs in this setting; however, most patients had just two prior lines of therapy, and only 36% had refractory disease prior to SCT.4 A caveat remains on the use of lenalidomide in that its use has been shown to trigger high rates of acute GVHD when used in the maintenance setting after allogeneic SCT.16-18 If chimerism remains mixed at the time of MM relapse, acute GVHD in addition to the MM itself would be a potential complication of IMiD therapy in this salvage setting. Based on the experience in the case above, it appears that selinexor does not exacerbate acute GVHD risk, but chronic GVHD may still develop; however, more corroborative data are needed. With the widespread use of PIs and IMiDs in almost every line of therapy, the addition of selinexor may prove to benefit patients with high-risk disease, such as with early MM relapse after allogeneic SCT, and should be explored in future prospective clinical trials.
Conclusion
Selinexor in combination with carfilzomib and dexamethasone for myeloma that has relapsed after allogeneic SCT resulted in a rapid and durable response in a heavily pretreated patient with RRMM. The activity of selinexor warrants consideration and further study in the post-allogeneic SCT setting.
References
1. Mikhael J. Treatment options for triple-class refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2020;20:1–7.
2. Passweg JR, Baldomero H, Bader P, et al. Impact of drug development on the use of stem cell transplantation: a report by the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2017;52:191–196.
3. Giralt S, Garderet L, Durie B, et al. American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplan- tation in Patients with Relapsed Multiple Myeloma. Biol Blood Marrow Transplant. 2015;21:2039–2051.
4. López-Corral L, Caballero-Velázquez T, López-Godino O, et al. Response to novel drugs before and after allogeneic stem cell transplantation in patients with relapsed multiple myeloma. Biol Blood Marrow Transplant. 2019;25:1703–1712.
5. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: multiple myeloma. Available at: https://www.nccn.org/professionals/ physician_gls/pdf/myeloma.pdf. Accessed: January 4, 2020.
6. Gasparetto C, Lentzsch S, Schiller G, et al. A phase 1b/2 study of selinexor, carfilzomib, and dexamethasone (SKD) in relapsed/refractory multiple myeloma (RRMM): PS1414. HemaSphere. 2019;3:650.
7. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381:727–738.
8. Vogl DT, Dingli D, Cornell RF, et al. Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36:859–866.
9. Chen C, Bahlis N, Gasparetto C, et al. Selinexor in combination with pomalido- mide and dexamethasone (SPd) for treatment of patients with relapsed refractory multiple myeloma (RRMM). Blood. 2020;136:18–19.
10. Gasparetto C, Lentzsch S, Schiller G, et al. Selinexor, daratumumab, and dexam- ethasone in patients with relapsed or refractory multiple myeloma. eJHaem. 2021;2:56–65.
11. Gasparetto C, Lipe B, Tuchman SA, et al. Selinexor in combination with carfilzomib and dexamethasone, all once weekly (SKd), for patients with relapsed/refractory multiple myeloma. Blood. 2020;136:14–15.
12. Bensinger WI, Green DJ, Burwick N, Becker PS. A prospective study of lenalido- mide monotherapy for relapse after allo-SCT for multiple myeloma. Bone Marrow Transplant. 2014;49:492–495.
13. Coman T, Bachy E, Michallet M, et al. Lenalidomide as salvage treatment for multiple myeloma relapsing after allogeneic hematopoietic stem cell transplanta- tion: a report from the French Society of Bone Marrow and Cellular Therapy. Haematologica. 2013;98:776–783.
14. El-Cheikh J, Michallet M, Nagler A, et al. High response rate and improved graft-versus-host disease following bortezomib as salvage therapy after reduced intensity conditioning allogeneic stem cell transplantation for multiple myeloma. Haematologica. 2008;93:455–458.
15. Montefusco V, Spina F, Patriarca F, et al. Bortezomib plus dexamethasone followed by escalating donor lymphocyte infusions for patients with multiple myeloma relapsing or progressing after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19:424–428.
16. Alsina M, Becker PS, Zhong X, et al. Lenalidomide maintenance for high-risk multiple myeloma after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2014;20:1183–1189.
17. Kneppers E, van der Holt B, Kersten MJ, et al. Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: results of the HOVON 76 Trial. Blood. 2011;118:2413–2419.
18. Sockel K, Bornhaeuser M, Mischak-Weissinger E, et al. Lenalidomide maintenance after allogeneic HSCT seems to trigger acute graft-versus-host disease in patients with high-risk myelodysplastic syndromes or acute myeloid leukemia and del(5q): results of the LENAMAINT trial. Haematologica. 2012;97:e34–e35.