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Selinexor triplets for relapsed/refractory multiple myeloma—an alternative to IMiD-based therapy?

Jul 17, 2020

The nuclear export protein, exportin 1 (XPO1), is overexpressed in multiple myeloma (MM), resulting in a decreased abundance of tumor suppressor proteins in the nucleus. Selinexor is a first-in-class, orally available, selective inhibitor of nuclear export (SINE), which binds to and inactivates XPO1, reinstating physiological tumor suppressor levels. 1

Data from part two of the STORM study provided grounds for the U.S. Food and Drug Administration (FDA) approval of selinexor in combination with low dose dexamethasone (dex) for the treatment of patients with relapsed/refractory MM (RRMM). Here, we provide a summary of the latest advances of selinexor in triplet regimens for the treatment of RRMM, as presented at thisyear’s virtual American Society of Clinical Oncology (ASCO) Annual Meeting.

STOMP 1,2

The STOMP study ( NCT02343042) is a phase Ib/ II dose escalation and expansion trial evaluating selinexor in combination with eight established MM backbone therapies across nine arms for the treatment of patients with RRMM. During this year’s ASCO Meeting, Cristina Gasparetto discussed the data from two arms of the STOMP study—watch the interview here. The Multiple Myeloma Hub is pleased to present a summary.

  • STOMP primary endpoints: Maximum tolerated dose and recommended phase II dose (RP2D) of respective treatment regimen
  • STOMP secondary endpoints: Overall response rate (ORR), progression-free survival (PFS), and duration of response

Selinexor, daratumumab, and dexamethasone (SDd; #8510 ) 1

Selinexor and daratumumab (dara) have both demonstrated single-agent clinical activity in MM. One arm of the STOMP study sought to determine the efficacy and safety profiles of SDd in patients with RRMM.

Study design

  • The study enrolled adult patients with MM who
    • had received ≥ 3 lines of prior therapy, including an immunomodulatory drug (IMiD®) and a proteasome inhibitor (PI), or
    • were refractory to an IMiD and a PI
  • Patients in the dose-expansion cohort were anti-CD38 monoclonal antibody naïve
  • The dose escalation phase followed a 3 × 3 design and enrolled patients in two cohorts to receive
    • 60 mg selinexor biweekly (BIW) + 16 mg/kg dara weekly (QW; n = 3) or
    • 100 mg selinexor QW + 16 mg/kg dara QW (n = 6)

Results

  • Dose-limiting toxicities were observed in two of the patients receiving BIW selinexor, but none were reported in the QW cohort
  • RP2D: QW selinexor 100 mg + dara 16 mg/kg + dex 40 mg
  • As of January 2, 2020, 34 patients had been enrolled onto the SDd arm of the STOMP study ( Table 1)

Table 1.Baseline characteristics of patients enrolled on the STOMP SDd arm 1

Auto-SCT, autologous stem cell transplantation; BIW, biweekly; dara, daratumumab; IMiD, immunomodulatory drug; PI, proteasome inhibitor; QW, weekly; SDd, selinexor + daratumumab + dexamethasone

* RP2D.

Patients pre-treated with bortezomib, carfilzomib, lenalidomide, and pomalidomide.

Characteristic

N = 34

Regimen, n

 

BIW selinexor

3

QW selinexor*

31

Median age, years (range)

68 (44–83)

Male, %

56

Median time from diagnosis to SDd, years (range)

5.6 (<1–14)

Median prior regimens, n (range)

3 (2–10)

Prior treatment, %

 

PI (exposed:refractory)

100:85

IMiD (exposed:refractory)

100:76

Quad exposed

23.5

Auto-SCT

73.5

Dara treated

6

Efficacy

  • Median PFS: 12.5 months across all groups
  • Patient outcomes are presented in Figure 1

Figure 1.Patient outcomes to SDd treatment regimen 1

AORRs and Bsurvival outcomes to SDd in all enrolled patients, patients who are dara naïve, and patients who received the RP2D.

CBR, clinical benefit rate; dara, daratumumab; ORR, overall response rates; PD, progressive disease; PR, partial response; RP2D, recommended phase II dose; SD, stable disease; SDd, selinexor + daratumumab + dexamethasone; VGPR, very good partial response

CBR = ORR + minimal response

Safety

  • No deaths due to treatment-related adverse events (TRAEs) or serious AEs (SAEs) were reported
  • Common Grade 3–4 TRAEs are outlined in Table 2

Table 2.Common Grade 3–4 TRAEs observed in > 5% of patients receiving SDd at the RP2D 1

RP2D, recommended phase II dose; TRAE, treatment-related adverse event

Grade 3–4 TRAEs

% of patients (N = 34)

Thrombocytopenia

47.0

Anemia

32.4

Neutropenia

26.5

Fatigue

17.6

Hyponatremia

11.8

Nausea

8.8

Study conclusions

The study identified an SDd treatment regimen that was well tolerated in patients with PI- and IMiD-refractory MM and suggests that clinical improvement is achievable with the RP2D.

Selinexor + carfilzomib + dexamethasone (SKd; #8530 ) 2

This study set out to determine the efficacy and safety profiles of SKd in patients with RRMM.

Study design

  • Adult patients with MM progressing or refractory to a previous regimen, excluding carfilzomib, were enrolled
  • The dose escalation phase followed a 3 × 3 design; the SKd dosing schedules are shown in Table 3

Table 3.Dosing schedules of SKd 2

IV, intravenous; PO, per os

* C1D1 dose of carfilzomib was 20 mg/m 2for all patients

Dose level

Selinexor, mg PO

Days 1, 8, 15, 22

Dex, mg IV or PO

Days 1, 8, 15, 22

Carfilzomib, mg/m 2IV*

Days 1, 8, 15

1

100

40

56

–1

80

40

56

–1a

80

40

70

  Results

  • Dose-limiting toxicities were observed in two patients in both the 1 and –1a dosing cohorts, but none were reported in the –1 cohort
  • RP2D: QW selinexor 80 mg + carfilzomib 56 mg/m 2+ dex 40 mg
  • As of May 1, 2020, 24 patients had been enrolled onto the SKd arm of the STOMP study ( Table 4)

Table 4.Baseline characteristics of patients enrolled on the STOMP SKd arm 2

SCT, stem cell transplantation; SKd, selinexor + carfilzomib + dexamethasone

*n = 23

Characteristic

N = 24

Median age, years (range)

70.5 (50–76)

Male, %

62.5

Median time from diagnosis to SKd, years (range)*

5.01 (2.7–11.3)

Median prior regimens, n (range)*

3 (1–8)

Prior treatment, %

 

Bortezomib

100

Carfilzomib

4.2

Lenalidomide

95.8

Pomalidomide

62.5

Daratumumab

58.3

SCT

79.2

Efficacy

  • Median PFS: Not reached
  • Patient outcomes are presented in Figure 2

Figure 2. Patient outcomes to SKd treatment regimen 2

CBR, clinical benefit rate; CR, complete response; PR, partial response; SD, stable disease; VGPR, very good partial response

CBR = ORR + minimal response.

Safety

  • No deaths due to TRAEs or serious AEs were reported
  • Common Grade 3–4 TRAEs are outlined in Table 5

Table 5. Common Grade 3–4 TRAEs observed in > 5% of patients receiving SKd at the RP2D 2

RP2D, recommended phase II dose; TRAE, treatment-related adverse event

*Data cutoff: May 1, 2020

Grade ≥ 3 TRAEs

% of patients (N = 24)*

Thrombocytopenia

54

Anemia

20.8

Leukopenia

12.5

Neutropenia

8.3

Fatigue

8.3

Study conclusions

QW SKd demonstrated deep responses and appears to be well tolerated in patients with RRMM following a median of four prior lines of therapy. These data support further investigation of the regimen.

BOSTON study( #8501) 3

The proteasome inhibitor, bortezomib, has demonstrated clinical efficacy in combination regimens for MM. However, prolonged treatment with bortezomib is associated with high rates of peripheral neuropathy (PN). The phase III BOSTON trial ( NCT03110562) aimed to compare the efficacy of selinexor + bortezomib + dex (SVd) with bortezomib + dex (Vd),and to determine if SVd reduces the rate of PN compared with Vd alone. At this year’s virtual ASCO Annual Meeting, Meletios A. Dimopoulos outlined the initial results, summarized below.

Study design

  • Primary endpoint: PFS
  • Secondary endpoints: ORR, ≥ very good partial response (VGPR), Grade ≥ 2 PN
  • Adult patients with progressive measurable MM (N = 402) with 1–3 lines of prior therapy underwent 1:1 randomization to receive
    • SVd (n = 195) or
    • Vd (n = 207)
  • Treatment regimens are presented in Table 6

Table 6.Dosing schedules of SVD vsVd 3

SVd, selinexor + bortezomib + dexamethasone; Vd, bortezomib + dexamethasone

*35-day cycles

Vd biweekly 21-day cycles (Cycles 1–8); Vd weekly 35-day cycles (Cycles ≥ 9)

 

Regimen

SVd*

Vd

Selinexor, 100 mg orally

 

Days 1, 8, 15, 22, 29

Dexamethasone, 20 mg orally

Days 1, 2, 8, 9, 15, 16, 22, 23, 29, 30

Cycles 1–8: Days 1, 2, 4, 5, 8, 9, 11, 12

Cycles ≥ 9: Days 1, 2, 8, 9, 15, 16, 22, 23, 29, 30

Bortezomib, 1.3 mg/m 2SC

 

Days 1, 8, 15, 22

Cycles 1–8: Days 1, 4, 8, 11

Cycles ≥ 9: Days 1, 8, 15, 22

Results

  • Patient characteristics are presented in Table 7

Table 7. Baseline characteristics of patients enrolled on the BOSTON study 3

PR, partial response; SVd, selinexor + bortezomib + dexamethasone; Vd, bortezomib + dexamethasone

* del (17p), t(14;16), t(14;14) or amp 1q21

Patients previously exposed to proteasome inhibitors should have achieved at least a PR

Characteristic

SVd (n = 195)

Vd (n = 207)

Median age, years (range)

66 (40–87)

67 (38–90)

Male, %

59

56

Median time from diagnosis, years (range)

3.8 (0.4–23)

3.6 (0.4–22)

High-risk cytogenetics*, %

50

46

Creatinine clearance 30–60 mL/min, %

27

29

Number of prior lines of therapy, %

1

2

3

 

51

33

16

 

48

31

21

Prior treatment, %

 

 

Bortezomib

68.7

70.0

Carfilzomib

10.3

10.1

Lenalidomide

39.5

37.2

Daratumumab

5.6

2.9

Efficacy

  • When compared to Vd, SVd was associated with significantly improved
    • response rates in overall population and by patient subgroup and PFS ( Table 8)
    • depth of response ( Figure 3; ≥ VGPR, p = 0.0082)
  • When patients in the control arm (Vd) presented a confirmed progressive disease, they were offered to cross over to a selinexor-based treatment
  • Although SVd was associated with lower overall PN rates vsVd (p = 0.001), PN remained the most common AE resulting in treatment discontinuation:
    • SVd: 4.6%
    • Vd: 7.4%

Table 8.Patient outcomes to SVd vsVd 3

HR, hazard ratio; PFS, progression-free survival; SVd, selinexor + bortezomib + dexamethasone; Vd, bortezomib + dexamethasone

* Data cutoff: February 18, 2020.

Patient outcome*

SVd (n = 195)

Vd (n = 207)

p value

Median follow-up, months

13.2

16.5

PFS, months

13.93

9.46

HR 0.70, 0.0066

ORR, %

76.4

62.3

0.0012

Aged ≥ 65 years

76.1

64.4

0.0243

High-risk cytogenetics

77.3

55.8

0.0008

Creatinine clearance 30 – 60 mL/min

79.2

56.7

0.0055

1 prior line of therapy

80.8

65.7

0.0082

Prior bortezomib treatment

77.6

59.3

0.0005

Prior lenalidomide treatment

67.5

53.2

0.0354

Median duration of response, months

20.3

12.9

  Figure 3.ORRs to SVd vsVd in the overall population 3

CR, complete response; ORR, overall response rate; PR, partial response; sCR, stringent complete response; SVd, selinexor + bortezomib + dexamethasone; Vd, bortezomib + dexamethasone; VGPR, very good partial response

Safety

  • TRAEs were manageable and reversible
  • To date, 17% and 11% of patients discontinued SVd and Vd, respectively, due to AEs or toxicities
  • Common Grade 3–4 TRAEs are outlined in Table 9

Table 9.Common Grade 3 – 4 TRAEs observed in > 5% of patients receiving SVd vsVd 3

TRAE, treatment-related adverse event; SVd, selinexor + bortezomib + dexamethasone; Vd, bortezomib + dexamethasone

Grade 3–4 TRAEs

SVd (n = 195)

Vd (n = 207)

Thrombocytopenia

39.5

17.2

Anemia

15.9

9.8

Fatigue

13.3

1.0

Neutropenia

8.7

3.4

Cataract

8.7

1.5

Asthenia

8.2

4.4

Nausea

7.7

0

Diarrhea

6.2

0.5

Study conclusions

QW SVd demonstrated significantly superior efficacy over BIW Vd, reducing the risk of progression or death by 30%, and standing as a novel, IMiD-free triplet therapy for patients with RRMM. QW administration of SVd has the potential to reduce hospital visits by up to 40% while also reducing levels of bortezomib-associated PN.

Conclusion

Data from the aforementioned studies support the incorporation of selinexor into triplet regimens for the treatment of MM. Selinexor appears to enhance the clinical efficacy of currently established regimens and could provide an alternative to IMiD-based therapeutics in the relapsed setting.

Additional resources

For more information on the current status of selinexor for the treatment of R/R diffuse large B-cell lymphoma, click here.

Expert Opinion

  1. Gasparetto C, Lentzsch S, Schiller GJ. Selinexor, daratumumab, and dexamethasone in patients with relapsed/refractory multiple myeloma (MM). Poster #8150. ASCO; May 29, 2020; Virtual. 
  2. Gasparetto C, Lipe B, Tuchman S, et al. Once weekly selinexor, carfilzomib, and dexamethasone (SKd) in patients with relapsed/refractory multiple myeloma (MM). Poster #8530. ASCO; May 29, 2020; Virtual.
  3. Dimopoulos MA, Delimpasi S, Simonova M, et al. Weekly selinexor, bortezomib, and dexamethasone (SVd) versus twice weekly bortezomib and dexamethasone (Vd) in patients with multiple myeloma (MM) after one to three prior therapies: Initial results of the phase III BOSTON study. Oral abstract #8501. ASCO; May 29, 2020; Virtual.