Posted: Monday, April 6, 2020
Significant advancements in the diagnosis, monitoring, and treatment of multiple myeloma over the past 2 decades have transformed the course of the disease and improved survival.1,2 Although still incurable, multiple myeloma has been transformed, in many cases, from swiftly fatal to a potentially manageable and chronic disease. However, for patients with multiple myeloma that is refractory to multiple agents, treatment options are limited.
The prognosis for patients with triple-class refractory multiple myeloma—defined as disease refractory to proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies—is poor. Patients with daratumumab-refractory myeloma have a median overall survival of 1.7 to 3.0 months.3-5
There is a subset of patients who are heavily pretreated, triple-class–refractory, and penta-exposed (ie, previously treated with bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab). The introduction of the novel agent selinexor has provided an active therapeutic alternative for such patients, who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.6
Selinexor is a selective inhibitor of nuclear export (SINE) that gains access to cells and targets the mechanisms that move molecules out of the cell nucleus. SINE targets exportin 1, a molecule that chaperones the nuclear export of more than 250 proteins. Among those compounds exported by exportin 1 are the tumor suppressor proteins—which suppress tumor growth—mRNAs that lead to the production of oncoproteins and the glucocorticoid receptor. When selinexor is present, these targets accumulate in the cell nucleus, leading to apoptosis and cell death.7,8
Initial Approval of Selinexor
In July 2019, the U.S. Food and Drug Administration (FDA) granted accelerated approval to selinexor in combination with dexamethasone in patients with heavily pretreated multiple myeloma who had received at least four prior therapies and whose disease was refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.9 The decision to grant the accelerated approval was based on the objective response rate achieved in the STORM trial (ClinicalTrials.gov identifier NCT02336815).10 In this single-arm, phase IIb study, 122 patients with triple-class–refractory and penta-exposed myeloma received oral selinexor at 80 mg plus dexamethasone at 20 mg, both twice weekly. A partial response or better was observed in 26% of patients with myeloma refractory to currently available therapies; the median duration of response was 4.4 months.
According to Ajai Chari, MD, Professor of Medicine at the Tisch Cancer Institute and Icahn School of Medicine at Mount Sinai in New York and lead author of the published STORM trial results, most patients treated with selinexor have rapidly progressing disease. “Between the day of signing consent and the day of beginning treatment in the STORM trial, a median of 12 days, there was a 22% increase in paraprotein levels. Therefore, many of these patients do not have the luxury to wait the 4 to 6 weeks of the manufacturing period required for chimeric antigen receptor (CAR) T-cell therapy, which is also demonstrating impressive results in a heavily treated population.”
Starting Treatment at Higher Doses
Success with selinexor therapy begins with the dosing strategy, Dr. Chari told JNCCN 360. “I tell patients that treatment with selinexor is like jumping a car over a ramp. You must accelerate, jump off, land, and then adjust the speed as necessary.” When selinexor and dexamethasone are given without a third agent—as was done in the STORM trial—higher doses are necessary to control the disease, based on initial phase I studies.
Once you have controlled the disease in this highly refractory population, you can reduce the dose and initiate a maintenance strategy.
“Once you have controlled the disease in this highly refractory population, you can reduce the dose and initiate a maintenance strategy,” explained Dr. Chari. Patients must be thoroughly educated about what to expect before starting treatment. “We explain to patients that this is a drug with side effects, but we will provide aggressive supportive care and closely monitor them every step of the way.”
Another critical component of successful therapy is minimizing treatment interruptions. “Our goal in myeloma therapy is to keep patients on therapy,” said Sarah J. Ramirez, PA-C, of the Cancer Center at Froedtert Hospital and the Medical College of Wisconsin, Milwaukee. “A fatal flaw of myeloma treatment is being too quick to discontinue therapy when patients have side effects.” Selinexor has a very short half-life of 6 to 8 hours.7 “If you hold the drug, the toxicity clears very quickly,” explained Dr. Chari. “Therefore, selinexor can be held until the patient improves and then restarted at a lower dose instead of discontinuing therapy.”
Dr. Chari pointed out that response rates in STORM trial patients treated at Mount Sinai—about one-quarter of study participants—were higher than the overall study population. According to his data, the response rate in these patients was 54%, compared with 26% in the intention-to-treat population. Progression-free survival was 5.3 versus 3.7 months, and overall survival was significantly longer in study patients at Mount Sinai compared with the overall population: 15.6 versus 8.6 months, respectively.
“Due to our institution’s informed consenting method, our outstanding nursing care, and our algorithm for aggressive supportive care, just two patients (7%) at Mount Sinai discontinued therapy due to adverse events compared with 37.2% of the overall study patients,” Dr. Chari told JNCCN 360. “We believe this proactive approach effectively decreased treatment discontinuation for adverse events and instead allowed patients to remain on therapy and benefit with better response rates, progression-free survival, and overall survival.”
Two patients in the STORM trial whose disease progressed after CAR T-cell therapy had a response to therapy with selinexor and dexamethasone. In a recently published case study, seven patients whose disease progressed through CAR T-cell therapy—an even more difficult-to-treat population—demonstrated responses with selinexor-containing regimens.11 Considering that the fludarabine/cyclophosphamide conditioning regimens for CAR T-cell therapy can result in T-cell elimination for up to 1 year, it is impressive that some of these patients had deeper responses and a longer remission duration with selinexor-containing regimens than they did with the CAR T-cell therapy,” said Dr. Chari.
Single Agents Versus Combinations
There are two categories of drugs that have been approved for multiple myeloma in the past few years: those with single-agent activity with or without dexamethasone (such as carfilzomib, pomalidomide, and daratumumab) and those approved solely in triplet combinations (including ixazomib, elotuzumab, and panobinostat). “The STORM trial demonstrated that selinexor fits into the first category,” explained Dr. Chari. “However, no one is using carfilzomib, pomalidomide, or daratumumab with steroids alone. The reality is that triplets are required in heavily pretreated patients. Adding a third drug typically doubles the response and progression-free survival.”
The reality is that triplets are required in heavily pretreated patients.
Although using the combination of selinexor with other agents is currently off label, both Ms. Ramirez and Dr. Chari stressed that, in their respective clinical practices, it is given with at least one other drug in addition to dexamethasone. “We always combine selinexor with another agent,” explained Ms. Ramirez. “Selinexor plus carfilzomib is our preferred combination. The rationale is that even if a patient’s disease has not responded to all available options, selinexor will still have a synergistic effect with drugs that they have previously received due to its unique mechanism.” The dose of selinexor should be lower when given as part of triplet therapy, potentially decreasing the incidence of severe treatment-related adverse events. [Editor’s Note: The NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma do not currently include selinexor plus any other agent except dexamethasone.12]
The approval of triplet-based selinexor combinations may be on the horizon. Initial data from the multiarm STOMP study have demonstrated activity with selinexor plus dexamethasone in combination with several backbone agents, including bortezomib,13 lenalidomide,10 pomalidomide,10 and carfilzomib (NCT02343042).14 In addition, data from the BOSTON trial were recently released (NCT03110562).
“Due to dosing and toxicity concerns with selinexor, the FDA wanted to see proof from a confirmatory phase III study,” explained Dr. Chari. “However, the BOSTON study had a completely different patient population than STORM, with just one to three prior lines of therapy, and the dosing and schedule are different.” Bortezomib and dexamethasone were given once weekly, in combination with selinexor at 100 mg once weekly versus twice weekly in the control arm. The median progression-free survival was 13.9 versus 9.5 months (hazard ratio = 0.70, P = .0066) respectively.15
Managing Side Effects: Supportive Interventions
When beginning treatment with selinexor, proactive gastrointestinal supportive care is crucial. “We are very aggressive with antiemetics upfront, ensuring that patients have an antiemetic from every category in their armamentarium,” explained Ms. Ramirez. “We must be proactive because weight loss can happen very quickly.” Additionally, “We regularly check a comprehensive metabolic panel to monitor for electrolyte abnormalities, which may result from vomiting.”
We are very aggressive with antiemetics upfront.
At Mount Sinai, Dr. Chari said they have developed a three-drug cocktail for nausea—ondansetron, rolapitant, and olanzapine—to be given to all patients starting selinexor. “We prefer rolapitant over the other available neurokinin-1 receptor antagonist, aprepitant, because the latter can inhibit the metabolism of dexamethasone via the CYP pathway.” Intravenous fluids are also frequently used to mitigate dehydration. For patients with hyponatremia, salt tablets are administered if hydration is not adequate.
Other common side effects include fatigue and hematologic issues. “For the rare patient who doesn’t respond to dose reduction and is still fatigued, we will give methylphenidate,” said Dr. Chari. He explained that selinexor can reduce platelet counts by decreasing thrombopoietin signaling, leading to thrombocytopenia. “If you must hold the dose of selinexor for a platelet drop and/or are giving selinexor only once weekly, the interval between selinexor doses is a good time to administer romiplostim, off label, based on preclinical data.16 This can accelerate the platelet count recovery and keep the patient on schedule.”
Dr. Chari emphasized the importance of educating patients before treatment begins. “Patients must know that aggressive multiagent regimens will have adverse effects and that holding or reducing the dose of selinexor will optimize the risk/benefit profile,” he explained. “Nothing is more rewarding to a patient than having a response to treatment. They will be much more willing to work through a side effect with a dose change or therapy hold if they understand what to expect.”
Nothing is more rewarding to a patient than having a response to treatment.
Selinexor in the Community Setting
According to Ms. Ramirez, frequent face-to-face interaction with patients is important for clinicians giving selinexor in a community-based practice, especially when initiating therapy. “I would make sure that the patient is seen with great frequency that first month,” she told JNCCN 360. “Patients with myeloma tend to be elderly and often underreport side effects.” In the institutional setting, “I have the luxury of a wonderful nursing staff sitting one floor below me. They can quickly let me know if a patient isn’t doing well,” explained Ms. Ramirez. “It helps to have a nurse or physician assistant interacting with a patient every week for the first month of treatment.”
Dr. Chari recommends that community oncologists consider forming a partnership with an academic institution that has more experience with selinexor in multiple myeloma. “In this case, I see patients in more of a consultative fashion,” he commented. For the first cycle, patients will come to Mount Sinai to have labs checked, to receive optimized supportive care, to obtain antiemetics, etc. “We are guiding the patient through the first cycle, and once the first cycle is complete, the local oncologist can take over,” noted Dr. Chari.
Ajai Chari, MD, has served as a consultant for Amgen, Bristol-Myers Squibb, Celgene, Millennium/Takeda, Janssen, and Karyopharm; and served on the scientific advisory boards for Amgen, Celgene, Millennium/Takeda, Janssen, Karyopharm, Sanofi, and Seattle Genetics.
Sarah J. Ramirez, PA-C, reported no conflicts of interest.
- Kazandjian D. Multiple myeloma epidemiology and survival: A unique malignancy. Semin Oncol 2016;43:676–681.
- Nijhof IS, van de Donk NWCJ, Zweegman S, et al. Current and new therapeutic strategies for relapsed and refractory multiple myeloma: An update. Drugs 2018;78:19–37.
- Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia 2019;33:2266–2275.
- Cornell RF, Gandhi UH, Lakshman A, et al. Subsequent treatment outcomes of multiple myeloma refractory to CD38-monoclonal antibody therapy. Blood 2018;132(suppl 1):2015.
- Pick M, Vainstein V, Goldschmidt N, et al. Daratumumab resistance is frequent in advanced-stage multiple myeloma patients irrespective of CD38 expression and is related to dismal prognosis. Eur J Haematol 2018;100:494–501.
- Usmani S, Ahmadi T, Ng Y, et al. Analysis of real‐world data on overall survival in multiple myeloma patients with ≥3 prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or double refractory to a PI and an IMiD. Oncologist 2016;21:1355–1361.
- Karyopharm Therapeutics. Selinexor (Xpovio) prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212306s000lbl.pdf. Accessed March 20, 2020.
- Gandhi UH, Senapedis W, Baloglu E, et al. Clinical implications of targeting XPO1-mediated nuclear export in multiple myeloma. Clin Lymphoma Myeloma Leuk 2018;18:335–345.
- U.S. Food & Drug Administration. FDA grants accelerated approval to selinexor for multiple myeloma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-selinexor-multiple-myeloma. Accessed March 20, 2020.
- 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.
- Chari A, Vogl DT, Jagannath S, et al. Selinexor-based regimens for the treatment of myeloma refractory to chimeric antigen receptor T cell therapy. Br J Haematol. March 2, 2020. [E-pub ahead of print]
- Kumar SK, Callander NS, Baljevic M, et al. NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. Version 3.2020. Accessed April 1, 2020. To view the most recent version, visit NCCN.org.
- 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;132:2546–2554.
- Gasparetto C, Schiller GJ, Callander NS, et al. A phase 1b/2 study of selinexor, carfilzomib, and dexamethasone in relapsed/refractory multiple myeloma. Blood 2019;134(suppl 1):3157.
- Karyopharm Therapeutics: Karyopharm announces phase 3 BOSTON study meets primary endpoint with significant increase in progression-free survival in patients with multiple myeloma following one to three prior lines of therapy. Available at https://investors.karyopharm.com/news-releases/news-release-details/karyopharm-announces-phase-3-boston-study-meets-primary-endpoint. Accessed March 20, 2020.
- Machlus KR, Wu SK, Vijey P, et al. Selinexor-induced thrombocytopenia results from inhibition of thrombopoietin signaling in early megakaryopoiesis. Blood 2017;130:1132–1143.