Clinical Commentary: Dose Reduction of Selinexor in Relapsed Patients With Multiple Myeloma

Case-Based Roundtable Meetings Spotlight, Case-Based Roundtable Meetings Spotlight: November 2, 2022,
Pages: 77

Event Summary

At a live virtual event, Sumit Madan, MD, broke down the use of quadruplet therapies in the frontline setting for patients with multiple myeloma and how to care for patients when they relapse on treatment. Using the example of a 70-year-old patient with multiple myeloma who relapsed after 2 lines of therapy, Madan discussed the use of selinexor (Xpovio) in this patient population and how treatment remains effective when you dose reduce for patients experiencing adverse events (AEs).

Quadruplet Therapy in Multiple Myeloma

I was not [initially] convinced about the [data regarding] quadruplet regimens, but the CASSIOPEIA trial [NCT02541383] with daratumumab [Darzalex] plus bortezomib [Velcade], thalidomide [Thalomid], and dexamethasone was a positive study.1 Moreover, the randomized phase 2 GRIFFIN study [NCT02874742] that looked at daratumumab plus bortezomib, lenalidomide [Revlimid], and dexamethasone [VRd] is also a positive trial.2 The response rates are significantly high in terms of the stringent complete responses that we have seen in the quadruplet regimens.

Recently, data also showed progression-free survival [PFS] was significantly in favor of patients that received the quadruplet regimen from GRIFFIN.3 Moreover, for transplant-eligible patients, we have not seen any issues with stem cell collection, so we have seen much deeper responses, stringent CRs [complete responses], and minimal residual disease– negativity rates...in our patients with induction transplant consolidation followed by maintenance.

Therefore, at this point, I'm using a lot of quadruplet regimens for treatment. I am using daratumumab plus VRd—if the insurance allows me to—and I’m also using daratumumab in combination with carfilzomib [Kyprolis], lenalidomide, and dexamethasone in patients with high-risk disease based on the results of the MASTER trial [NCT03224507].4

Handling Patients With Relapsed Disease

We need to make sure that we take care of the calcium levels in patients, and if the patient has elevated uric acid, then we need to correct the uric acid as well. Lenalidomide probably is not my choice in patients with renal failure, but once the renal function gets better, I do switch to lenalidomide. However, some of the other drugs work better in patients with renal failure.

[Now, in the case of a patient who had their] first relapse in 2 years our typical patients, our standard-risk patients, would relapse in 4 to 5 years. This patient is relapsing quite quickly, within 2 years, and is on lenalidomide maintenance [and] found to have disease relapse. [In this case then,] pomalidomide [Pomalyst] works well in patients who are lenalidomide resistant and so does daratumumab, which is probably one of the most used drugs at the time of first relapse.

[In this case,] daratumumab, pomalidomide, and dexamethasone give this patient 1 year before a second relapse, with the creatinine levels now down to 2.3. The creatinine clearance is down to 2.0, and PET [positron emission tomography]/CT scan on this patient shows new lytic lesion. But again, this is a second relapse. So if you look at the NCCN [National Comprehensive Cancer Network] guidelines, it’s kind of an embarrassment of riches here [for which treatments to use].5 For example, you can combine daratumumab with lenalidomide and bortezomib or combine carfilzomib [Kyprolis] and [isatuximab-irfc (Sarclisa)].

You can also do pomalidomide with bortezomib, but there are some newer options that are approved if you are looking for a newer mechanism, which is selinexor in combination with bortezomib and dexamethasone.6 So there are plenty of treatment options that we have in the category of these early relapses, which would be within 1 to 3 prior lines of therapy. For this patient case, at the time of second relapse, there are several treatment options, including the XPO1 inhibitor selinexor, which can be combined with bortezomib.

Other treatment options that are approved in later lines of therapy, especially anti-BCMA [B-cell maturation antigen] drugs or CAR [chimeric antigen receptor] T cells, and some of the other drugs on the horizon [that] are going to get approved, hopefully quickly, are bispecific. All the options are looking at other combinations, and anti-CD38 is probably another good option in some people who are already progressing on daratumumab. Isatuximab is not going to be a great option in patients that are progressing on daratumumab. The proteasome inhibitor carfilzomib probably is something that can be used, [but] I’m not sure if you’re going to get great mileage, but that’s certainly reasonable.

Managing Adverse Events on Selinexor With Dose Reductions

With the once-weekly selinexor, nausea is not a problem, because we just try to be more proactive in terms of controlling their nausea, and we also don’t see vomiting.7 One of the things that we do see—and we don’t know which patients will get it or not—is fatigue, and some patients will take the drug without any issues; some patients will have fatigue. Of course, there’s been thrombocytopenia, but we haven’t had any significant bleeding.

With nausea, we want the patient to take prophylaxis, and hydration becomes important, especially when I start the patient on this drug. I try to see them once a week and make sure we check their weight, that they’re eating well, check their electrolytes, especially sodium levels, and make sure if they’re not [staying hydrated] that we do adequate IV [intravenous] fluid hydration. [Nausea is] easily managed by dose reductions, and I think dose reductions become important when we are using this drug. It’s approved at the 100-mg dose, but you will find yourself reducing the dose to 80 mg, 60 mg, or even 40 mg, as we have seen in the STORM trial [NCT02336815] that dose reductions really help.8 Moreover, this drug still appears to be quite effective even at the lower dosages. [We have also seen] how we were able to at least mitigate or decrease the AEs by giving this drug once weekly.

The initial treatment approved from STORM was the 80-mg dose that was given biweekly. The BOSTON trial [NCT03110562] has the 100-mg once-weekly dose that was used much earlier, so we’re seeing significantly fewer grade 3 and 4 thrombocytopenias [and] neutropenias, and fatigue has been cut [in] half, from 25% to 13%. The recommended dosages are then 100 mg, 80 mg, 60 mg, 40 mg, and then permanently discontinue.

Most of the patients I find do well on the 80-mg dose, when I combine it with a proteasome. If one already dose reduces and keeps the patients on the drug, they’re going to have much better outcomes than if they stop the drug. PFS for patients with dose reduction was 16.6 months, and the PFS for those without selinexor dose reduction was only 9 months [Figure7]. Similarly, the response rates were also higher in patients who had dose reductions but were still able to continue the drug compared [with] those who did not have their dose reduced.

References

1. Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38. doi:10.1016/S0140-6736(19)31240-1

2. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood.2020005288

3. Laubach JP, Kaufman JL, Sborov DW, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (Pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 24 months of maintenance. Blood. 2021;138(suppl 1):79. doi:10.1182/blood-2021-149024

4. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma. J Clin Oncol. 202;40(25):2901-2912. doi:10.1200/JCO.21.01935

5. Callander NS, Baljevic M, Adekola K, et al. NCCN Guidelines insights: Multiple Myeloma, version 3.2022. J Natl Compr Canc Netw. 2022;20(1):8-19. doi:10.6004/jnccn.2022.0002

6. FDA approves selinexor for refractory or relapsed multiple myeloma. FDA. Updated December 18, 2020. Accessed October 28, 2022. https://bit.ly/3zvr5CU

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. Presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA.

8. Tremblay G, Daniele P, Breeze J, et al. Quality of life analyses in patients with multiple myeloma: results from the Selinexor (KPT-330) Treatment of Refractory Myeloma (STORM) phase 2b study. BMC Cancer. 2021;21(1):993. doi:10.1186/s12885-021-08453-9