Callander Discusses Data From Transplant-Ineligible Multiple Myeloma Trials

Natalie S. Callander, MD

During a Targeted Oncology Case-Based Roundtable event, Natalie S. Callander, MD, professor, Department of Medicine, director, University of Wisconsin Carbone Cancer Center Myeloma Clinical Program, vice chair, of the National Comprehensive Cancer Network Myeloma Committee, and interim director, Bone Marrow Transplant at the University of Wisconsin School of Medicine and Public Health, discussed the case of a 78-year-old patients with multiple myeloma.

Targeted Oncology^TM: What treatment options exist for this patient with transplant-ineligible multiple myeloma?

CALLANDER: [When considering] some of the choices preferred by the NCCN [National Comprehensive Care Network] for relapsed/refractory multiple myeloma.¹ I think it is important to remember that for some of those trials [ASPIRE (NCT01080391),² POLLUX (NCT02076009),³ and TOURMALINE-MM1 (NCT01564537)⁴], the patients were not lenalidomide refractory, so I’m not sure that they are completely applicable to this situation. But the pomalidomide [Pomalyst], bortezomib [Velcade], and dexamethasone [combination showed] a very good response rate in patients, many of whom were lenalidomide exposed [OPTIMISMM (NCT01734928)].⁵ The NCCN offers a huge, perhaps unhelpful, list [of preferred and recommended therapies]1; there’s going to be a move soon to try to make this list more relevant, to split [the list into] early-relapse and late-relapse [categories]. But there are many different choices. A more practical [list of options for lenalidomide-refractory patients after treatment with daratumumab, lenalidomide, and dexamethasone is presented by the European Hematology Association and the European Society for Medical Oncology]. This list includes the pomalidomide, bortezomib, dexamethasone combination; carfilzomib [Kyprolis] plus dexamethasone; selinexor [Xpovio], bortezomib, and dexamethasone; and venetoclax [Venclexta], bortezomib, and dexamethasone.⁶

A phase 2 trial [NCT01478048] of bortezomib plus dexamethasone, with and without elotuzumab [Empliciti], showed a median progression-free survival [PFS] of 9.7 months vs 6.9 months, respectively [HR, 0.72; 70% CI, 0.59-0.88; stratified log-rank P = .09]. The respective overall response rates [ORR] were 66% [95% CI, 55%-77%] and 63% [95% CI, 51%-74%]. A very good partial response [VGPR] or better occurred in 36% vs 27% of patients, respectively.⁷ This was perhaps not 1 of the better results. A trial of bortezomib plus dexamethasone with and without panobinostat [Farydak], PANORAMA-1 [NCT01023308], showed a PFS of 11.99 months vs 8.08 months, respectively [HR, 0.63; 95% CI, 0.52-0.76; P < .0001].

ORRs did not differ significantly between groups, but the rate of complete or near-complete response [CR] was superior at 27.6% [95% CI, 23.2%-32.4%] vs 15.7% [95% CI, 12.2%-19.8%; P = .00006].⁸

I don’t think panobinostat is used very much at this point. The OPTIMISMM trial [of pomalidomide, bortezomib, and dexamethasone (NCT01734928) showed good results]. Median PFS with vs without pomalidomide was 11.20 months [95% CI, 9.66-13.73] vs 7.10 months [95% CI, 5.88- 8.48], respectively [HR, 0.61; 95% CI, 0.49-0.77; P < .0001].⁵ [This combination is a] popular and reasonable choice.

What data support the use of selinexor in a patient like the one described?

Selinexor with dexamethasone was approved last year,9 but recently it was approved in combination with bortezomib and dexamethasone10 based on the results of the phase 3 BOSTON study [NCT03110562].

The BOSTON study was a randomized study conducted both in the United States and Europe. Patients had had 1 to 3 lines of therapy, and they could have received bortezomib, though they couldn’t be refractory to it. Prior lenalidomide treatment and prior transplant were allowed. Median age was 66 in the experimental arm and 67 in the comparator arm. The patients could not have significant peripheral neuropathy, and they were stratified based on whether or not they had had prior proteasome inhibitor therapy, the number of regimens [they had received], and their stage at diagnosis. The [comparator] regimen was a standard regimen of subcutaneous bortezomib administered twice weekly on days 1, 4, 8, and 11, with dexamethasone administered on both the day of and the day after bortezomib on days 1, 2, 4, 5, 8, 9, 11, and 12. Bortezomib and dexamethasone doses were lowered (administered on a weekly cycle instead of twice weekly) in the comparator arm after 8 cycles. The experimental arm consisted of 100 mg of selinexor given weekly along with bortezomib and dexamethasone; a second dose of dexamethasone was given on the second day of each week.¹¹

The primary end point was PFS. [Secondary] end points were ORR, VGPR, and the development of grade 2 peripheral neuropathy. Median PFS was 13.93 months [95% CI, 11.73- not evaluable] in the triplet arm and 9.46 months [95% CI, 8.11-10.78] in the doublet arm [HR, 0.70; 95% CI, 0.53-0.93; P = .0075]. I think some people were surprised that the ORR absolutely favored the [selinexor] triplet. The ORR was 76.4% [95% CI, 69.8%-82.2%] in the triplet arm and 62.3% [95% CI, 55.3%-68.9%] in the doublet arm [odds ratio [OR], 1.96; 95% CI, 1.3-3.1; P = .0012]. Among patients in the triplet arm, 44.6% [95% CI, 37.5%-51.9%] had a VGPR; among patients in the doublet arm, 32.4% [95% CI, 26.0%-39.2%] had a VGPR [OR, 1.66; 95% CI, 1.1-2.5; P = .0082]. Peripheral neuropathy of grade 2 or greater was observed in 21% of patients in the triplet arm and in 34% of patients in the doublet arm [OR, 0.50; 95% CI, 0.32-0.79; P = .0013].¹¹

What did subgroup analysis reveal about selinexor therapy?

I think the investigators were surprised to find that the patients with del(17p) did well [HR, 0.38; 95% CI, 0.16-0.86]. This group only represented 37 patients out of a 400-plus patient trial, a small number, but it did seem that there was a bit of a signal. Additionally, there were favorable responses in patients who had underlying renal insufficiency [HR, 0.49; 95% CI, 0.27- 0.89], those who had had previous treatment with proteasome inhibitors [HR, 0.78; 95% CI, 0.58-1.06], those who had had a stem cell transplant [HR, 0.55; 95% CI, 0.34-0.90], and those with higher-stage disease [for stage II, HR, 0.67; 95% CI, 0.47-0.95]. Interestingly, there was a more favorable signal in women [HR, 0.54; 95% CI, 0.34-0.85] than in men [HR, 0.74; 05% CI, 0.52-1.06]. Another point that’s relevant to the case here is that individuals 65 years and older seem to do better with the selinexor-containing regimen [HR, 0.55; 95% CI, 0.37-0.83].¹¹

What was the discontinuation rate in this trial, and what adverse events (AEs) were observed?

The rates of discontinuation attributable to treatment-emergent AEs were similar between groups—21% in the triplet group and 16% in the doublet group. In the doublet arm, [discontinuation because of an AE] was most [commonly] due to peripheral neuropathy, in 7% of patients. In the triplet arm, [AE-related discontinuation was primarily due to] peripheral neuropathy [in 5% of patients], fatigue [in 4%], nausea [in 3%], vomiting [in 2%], and decreased appetite [in 2%]. Thrombocytopenia of any grade occurred in 60% of the triplet group and led to discontinuation in 2% of patients; the incidence of thrombocytopenia in the doublet group was 27%. The most common treatment-emergent AEs of grade 3 or higher [observed in at least 10% of patients in either group] were thrombocytopenia, anemia, pneumonia, and fatigue, and the incidence of each was greater in the triplet group.¹¹

Does this study confirm your own experience as it pertains to selinexor dosing?

In this trial, the starting dosage was 100 mg per week. There were dose modifications in both arms, more in the triplet arm [89%] than in the doublet arm [76%].¹¹ I typically give patients 60 mg per week or, in some cases, even 40 mg per week. [The patients tolerate it much better, and that allows us to] keep patients on medication. [In my experience,] there’s really an issue with dosing of selinexor. I think there is a learning curve, like there is with every drug, about how to use this.

The STOMP study [NCT02343042] is examining selinexor in combination with many other drugs, including pomalidomide, carfilzomib, daratumumab, and lenalidomide. I’ve had some very good responses, including people going into CR. I really do think the key is trying to keep patients on the selinexor by using smaller doses.

When you say you use the 40 mg to 60 mg dose, do you maintain that dose, or do you increase the dose?

I [maintain the original dose]. I think a lot of our drugs are like this. [For example], if you start somebody on lenalidomide at 25 mg on days 1 through 21, [very] few people [could] stay at that dose, particularly if they’re [receiving a drug] combination. I think [a lower dose] helps them to be able to get the drug. [It is worth noting that] in the original lenalidomide studies, every dose level worked.

There are some dose modifications included with [selinexor] packaging, including modifications for patients with hematologic issues.¹² I have used selinexor in people who are platelet-transfusion dependent, and I don’t worry that much about it. [When patients report,] “I don’t feel great and I’m not very hungry,” [they usually] improve with dose reduction. You really do have the ability to [reduce the dose in response to] AEs.

What supportive care do you do for patients treated with selinexor?

Standard monitoring includes looking at nutritional status and volume status.¹² Many people use ondansetron [Zofran] if [dehydration] is a risk. Some people routinely administer olanzapine when patients are on selinexor. Some people have used eltrombopag [Promacta] in patients like this for platelet support. I think [the goal is] to make sure that you can [continue to administer the] drug, and the key is being judicious in your dosing. You [also] have to listen to your patient, and this really is a case of “less is more.”

_References:

1. _{NCCN Clinical Practice Guidelines in Oncology. Multiple myeloma, version 7.2021. Accessed July 13, 2021. https://bit.ly/36TOWx6}
2. _{Stewart AK, Rajkumar SV, Dimopoulos MA, et al; ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142-152. doi:10.1056/ NEJMoa1411321}
3. _{Dimopoulos MA, Oriol A, Nahi H, et al; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331. doi:10.1056/NEJMoa1607751}
4. _{Moreau P, Masszi T, Grzasko N, et al; TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374(17):1621-1634. doi:10.1056/NEJMoa1516282}
5. _{Richardson PG, Oriol A, Beksac M, et al; OPTIMISMM trial investigators. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(6):781-794. doi:10.1016/S1470-2045(19)30152-4}
6. _{Dimopoulos MA, Moreau P, Terpos E, et al; EHA Guidelines Committee, ESMO Guidelines Committee. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(3):309-322. doi:10.1016/j. annonc.2020.11.014}
7. _{Jakubowiak A, Offidani M, Pégourie B, et al. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016;127(23):2833-2840. doi:10.1182/blood-2016-01-694604}
8. _{San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195-1206. doi:10.1016/S1470-2045(14)70440-1}
9. _{FDA grants accelerated approval to selinexor for multiple myeloma. FDA. Updated July 3, 2019. Accessed July 14, 2021. https://bit.ly/2V0WgV0}
10. _{FDA approves selinexor for refractory or relapsed multiple myeloma. FDA. Updated December 18, 2020. Accessed July 14, 2021. https://bit. ly/2UX4AFq}
11. _{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}
12. _{Xpovio. Prescribing information. Karyopharm Therapeutics Inc; 2020. Accessed July 14, 2021. https://bit.ly/3eG0OqV}