Forsberg Explains How Selinexor Fits Into Sequencing Therapies in R/R Multiple Myeloma

Peter Forsberg, MD

Associate Professor, Medicine- Hematology

University of Colorado Hospital

University of Colorado Cancer Center

Aurora, CA

Targeted Oncology^TM: What data support the use of selinexor in this patient?

FORSBERG: The largest registration trial that was per-formed to evaluate selinexor was a combination phase 3 study called the BOSTON trial [NCT03110562], with selinexor, bortezomib, and dexamethasone [XVd]. This was in patients with 1 to 3 prior lines of therapy, so earlier relapse. The initial approval of selinexor was [for] patients who were pentarefractory or heavily exposed to prior therapies, and they used a different dosing of selinexor.

Selinexor was initially approved at an 80-mg twice-weekly dosing structure with the STORM trial [NCT02336815] and then subsequently other combination studies.^1,2 Dosing is now 100 mg weekly [in the BOSTON trial], so not the twice-weekly dosing, and that does have an impact on the severity of some of the adverse effects [AEs].

Often, [physicians] may use even further reduce doses to try to target manageable AEs and harness the efficacy that comes along with it. This trial enrolled 402 patients; the median age [was in] the late 60s, with a good portion who were over 65 years old. [Patients] were [randomly assigned] to weekly XVd vs twice weekly Vd, so a more dose-intense bortezomib regimen [in the Vd arm] that probably impacts the efficacy to a degree, but certainly some of the AEs that were seen, including neuropathy. The slightly different dosing structure in terms of cycle length was primarily built around response rate and progression-free survival [PFS].³

The baseline characteristics were not uncommon ones [and were] seen in the earlier relapsed setting, although there was a substantial percentage of patients with proteasome inhibitor previously, [which is] a decent number with stem cell transplant [and] a modest but not inconsequential number with prior daratumumab.³

So, [there were] some different characteristics from some of the patients that we may sometimes see in the relapsed setting, but it was a positive study. With the selinexor combination, the median PFS was [approximately] 14 months vs 9.5 months with Vd [HR, 0.70; 95% CI, 0.53-0.93; P = .0075].

What did the subgroup analyses show for the selinexor combination?

In the subgroup analyses, the selinexor-based combination showed consistent benefit across a variety of different subgroups. There is some reasonable consideration that patients treated with prior daratumumab were in a slightly more challenging scenario than some other relapsed settings. The impact prior daratumumab has shown in certain trials is that it [modifies] the effectiveness of future therapy a little more than other prior exposures, like lenalidomide. Patients with del(17p) in the high-risk cytogenetic category had a substantial shift toward benefitting with selinexor inclusion. One can tell themselves a story about why patients with del(17p) may particularly benefit from selinexor, which inhibits the export of certain proteins from the nucleus, possibly including tumor suppressors. There is some rationale for why these patients may benefit preferentially, although that’s mostly theoretical, but it does seem to show some specific benefit in that population.³

One must take the analysis for what it is, which is a population that included all sorts of patients who were enrolled. Essentially, patients who received the selinexor combination had a higher overall response rate [ORR] of 76% vs 62% in the Vd arm, then essentially a longer duration of response at 20 months vs [approximately] 12 months for the Vd arm.³

There were benefits across different groups. One of the important groups to focus on within any of these trials in the real world is the high-risk cytogenetics group. We don’t have many studies that have been performed specifically to evaluate high-risk groups, so we’re sort of stuck with subgroup and subset analyses. Essentially, there was a trend toward significant improvement in benefit for selinexor-treated patients with high-risk cytogenetics, with an improvement in PFS of [approximately] 4 months.

One is always going to see better outcomes in the standard-risk patients, but you want to see at least a similar benefit in the high-risk patients, ideally, and then an improvement in ORR. Both arms had comparable response rates.⁴ A slightly more exploratory analysis of patients with renal impairment did show benefit, especially across patients with reduced the glomerular filtration rate [GFRs]. In patients with the lowest renal function, there were fewer durable responses across the board, but still, the trend was toward benefit with selinexor treatment in those groups, as well [Table⁵].

How do the AEs impact the use of selinexor in this patient population?

With the conversation around selinexor, we can’t help but discuss some of the AEs, because anticipating, managing, and discussing them with your patient before you choose which therapy to use must include those characteristics. The most common treatment-emergent AEs with selinexor in comparison [with] bortezomib and dexamethasone included thrombocytopenia and anemia, so the myelosuppression with a predominance of thrombocytopenia [is notable].

Some of the issues that may come from selinexor crossing the blood-brain barrier more actively and causing direct neurologic AEs include fatigue, nausea, and sometimes reduced energy levels. These AEs are in part dose related, so using the once-weekly dose and having some flexibility with starting dose or dose adjustment can substantially impact them. Nausea is one of the most common ones, [which] requires a robust approach to minimize. [However], most nausea symptoms occur during the first month, then many patients improve in the subsequent cycles.

A lot of us think of getting through the first month of selinexor as a bit of a process, but once we do, it often gets more manageable moving forward. Dose modifications were common, with 89% of patients on the selinexor arm vs 76% on the Vd arm—so high rates in both arms. But the reasons were a little different and were more related to neuropathy with bortezomib vs related to things like fatigue, nausea, and thrombocytopenia with selinexor.³

If you use selinexor, what steps and supportive care do you routinely perform to help with tolerability?

For monitoring, it’s routine or consistent that during the first cycle, one wants to watch complete blood counts [CBCs] closely. So, often—even if they’re on an all-oral combination with pomalidomide [Pomalyst] or something like that—if you’re not using the BOSTON trial data but other phase 2 data with other combinations, you should still have [patients] come in routinely for CBC monitoring and standard blood chemistries, specifically sodium. Hyponatremia is another issue that can emerge, especially in patients who are not eating and drinking as much; they may need some fluid support or some counseling regarding taking it. Get a gauge of volume status, changes in nutritional baseline, and be proactive about any dosing adjustment.⁶

What impact do selinexor dose reductions have on toxicity profile and clinical outcomes?

Selinexor is not the only drug [in which] the initial dosing may not be the optimal long-term dosing that’s used in practice in appropriate patient population types. [However], there were certainly more issues in a dose-dependent fashion, especially with that 80-mg biweekly from the initial STORM trial.

The most used dose in clinical practice is the 80-mg once-weekly dose, which is the dose level after the first reduction [in] the BOSTON trial. One can use 100 mg if it’s a robust patient, or 80 mg or even 60 mg if it’s a patient in whom you’re worried more about the potential for AEs. You can always adjust the dose up or down. Certainly, AEs do occur in a dose-dependent manner to a degree; fatigue, nausea, and myelosuppression are affected by the dose.^3,6

The PFS was longer in patients who had dose reduction. Now, [we don’t know] whether that’s because they stayed on the dose longer and got dose reductions or they were able to stay on the drug longer because they got dose reductions. But essentially, patients who had reductions didn’t do worse. If anything, they had a trend toward doing better.⁷ It didn’t seem like it stole from the effectiveness of the agent. You can interpret the data how you do, but I think [they] support the validity of being flexible with dosing.

How can data from the selinexor trials be summarized and applied in clinical practice?

All these agents are useful. The nature of the myeloma universe is that even though we have complexity, we have a lot of options, [and] there’s utility to all of them in the right setting in the right patients and used the right way. There’s certainly no right answer in the world of myeloma combinations, except for specific scenarios in the upfront or maybe even second-line setting. Beyond that, there’s a lot of diversity in terms of what’s the right fit for different patients and how we tap into these different agents that have potential use.

One of the good things about selinexor is that it [has] a growing body of data with a variety of different partners. The STOMP trial [NCT02343042] expands beyond the world that the BOSTON trial delineated. Basically, it’s a phase 1b/2 trial with selinexor plus a host of different partners, including lenalidomide, pomalidomide, bortezomib, carfilzomib [Kyprolis], and daratumumab.

With the different combinations, ORRs ranged somewhere between 70% and 90%. Different cohorts had different characteristics, but there’s substantial activity with different partners. This gives us some potential for flexibility in how to bring it into the clinic, especially given our scenario where so many patients are [exposed to] bortezomib in the first-line setting. Using bortezomib as a partner in the second or third line is a little less common.

_REFERENCES

_{1. FDA grants accelerated approval to selinexor for multiple myeloma. FDA. Updated July 3, 2019. Accessed October 3, 2022. https://bit.ly/2V0WgV0}

_{2. FDA approves selinexor for refractory or relapsed multiple myeloma. FDA. Updated December 18, 2020. Accessed October 3, 2022. https://bit.ly/2UX4AFq}

_{3. 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. doi:10.1016/S0140-6736(20)32292-3}

_{4. Richard S, Chari A, Delimpasi S, et al. Selinexor, bortezomib, and dexamethasone versus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by cytogenetic risk. Am J Hematol. 2021;96(9):1120-1130. doi:10.1002/ajh.26261}

_{5. Delimpasi S, Mateos MV, Auner HW, et al. Efficacy and tolerability of once-weekly selinexor, bortezomib, and dexamethasone in comparison with standard twice-weekly bortezomib and dexamethasone in previously treated multiple myeloma with renal impairment: subgroup analysis from the BOSTON study. Am J Hematol. 2022;97(3):E83-E86. doi:10.1002/ajh.26434}

_{6. Xpovio. Prescribing information. Karyopharm Therapeutics Inc; 2020. Accessed October 3, 2022. https://bit.ly/3eG0OqV}

_{7. Jagannath S, Facon T, Badros A, et al. Clinical outcomes in patients (pts) with dose reduction of selinexor in combination with bortezomib, and dexamethasone (XVd) in previously treated multiple myeloma from the BOSTON study. Blood. 2021;138(1):3793. doi: 10.1182/blood-2021-146003}