General MM

EHA 2019 | Selinexor plus daratumumab for RRMM: A phase Ib/II trial

On Sunday 16 June at the 24th Congress of the European Hematology Association (EHA), Darrell White, Dalhousie University, Nova Scotia, CN, on behalf of Christina Gasparetto, Duke University Cancer Center, North Carolina, US, presented a phase Ib/II trial on selinexor (S), daratumumab (D), and dexamethasone (d; SDd) in patients with relapsed or refractory multiple myeloma (RRMM).1

Selinexor is a first-in-class selective inhibitor of exportin-1 (XPO1), which is involved in nuclear protein exportation and is found in myeloma cells. Pre-clinical evidence indicates that selinexor blocks the translation of oncoproteins and that it works synergistically with dexamethasone to induce cytotoxicity in vitro2 and in heavily-pretreated MM patients.3

The primary objectives of this multicenter, open-label study were the determination of the maximum tolerated dose and recommended SDd phase II dose, as well as safety and preliminary SDd efficacy in patients with RRMM.

Study design & baseline characteristics

  • N=30 patients, who had received ≥3 prior lines of therapy (including an immunomodulatory drug [IMiD] and a proteasome inhibitor [PI]) or with MM refractory to IMiDs and PIs
  • Dosing:
    • Dosing escalation phase: 3+3 design in two cohorts:
      • SDd dose level 0 (n=3):
        • S: orally 60mg on Day 1, 3 twice weekly
        • D: intravenously 16mg/kg once weekly
        • d: orally 20mg twice weekly
      • SDd dose level -1 (n=6):
        • S: orally 100mg once weekly
        • D: intravenously 16mg/kg once weekly
        • d: orally 40mg once weekly
      • Expansion phase (n=31):
        • Patients received the recommended phase II dose

 Table 1. Key baseline characteristics:

Baseline characteristic

Patient cohort (N=34)

Median age (range)

68 (44–83)

Male patients

56%

Median time from diagnosis to SDd treatment (range)

5.6 (<1–14)

Median number of prior lines (range):

Treated: Refractory to PIs

Treated: Refractory to IMiDs

Autologous stem cell transplant (ASCT)

Daratumumab treated

3 (2–10)

100%:85%

100%:76%

71%

6%

 Key findings

  • The results of the dose escalation phase of this trial concluded that the recommended phase II dose, followed SDd dose level -1 (S: 100mg; D:16mg/kg; d:20mg)

Table 2. Preliminary efficacy outcomes:

 

Daratumumab-naïve patients (n=30)

Total cohort (n=32)

Overall response rate (ORR)

73%

69%

Very good partial response (VGPR)

37%

34%

Partial response (PR)

37%

34%

Minimal response (MR)

13%

13%

Clinical benefit rate (ORR+MR)

86%

81%

Stable disease (SD)

13%

16%

Progressive disease (PD)

-

3%

  • Patients with M-protein reductions >50%: 69%
  • Patients with M-protein reductions ≥90%: 34%
  • Median progression-free survival was not reached (95% CI, 7.6–not reached)
  • Median time-to-response: 1 month

Safety

Dosing escalation phase

  • Two dose-limiting toxicities (DLTs) were reported in the SDd dose level 0 cohort:
    • Grade 2 fatigue
    • Grade 3 thrombocytopenia
  • No DLTs were reported in the SDd dose level -1 cohort

Treatment with phase II approved dose (expansion phase):

  • Most common Grade 3 non-hematological treatment-related adverse events (TEAEs):
    • Fatigue: 16.1%
    • Hyponatremia: 12.9%
    • Nausea: 6.5%
    • Diarrhea: 3.2%
    • Hyperglycemia: 3.2%
    • Infusion-related reaction: 3.2%
  • Most common Grade 3–4 hematological TEAEs:
    • Thrombocytopenia: 41.9%
    • Leukopenia: 25.8% (only Grade 3)
    • Neutropenia: 22.6% (only Grade 3)
    • Anemia: 29.0% (only Grade 3)
    • Lymphopenia: 12.9%
  • No deaths were reported during the study

Conclusions

The recommended phase II SDd dose for the treatment of RRMM patients was 100mg of selinexor, 16mg/kg daratumumab plus 40mg dexamethasone, administered once a week. No DLTs occurred at this dose level and the safety profile was tolerable and manageable. Preliminary efficacy outcomes indicate that SDd treatment leads to deep and durable responses in RRMM patients with an ORR of 73% in daratumumab-naïve patients and 69% in the total cohort.

References
  1. Gasparetto C. Safety and efficacy of combination of selinexor, daratumumab, and dexamethasone (SDD) in patients with multiple myeloma (mm) previously exposed to proteasome inhibitors and immunomodulatory drugs. Abstract S1606. 24th Congress of EHA, Amsterdam, NL
  2. Argueta C. et al. 2018. Selinexor synergizes with dexamethasone to repress mTORC1 signaling and induce multiple myeloma cell death. Oncotarget 9, 25529–25544. DOI: 10.18632/oncotarget.25368
  3. Chari A. Results of the Pivotal STORM Study (Part 2): Deep and Durable Responses with Oral Selinexor plus Low Dose Dexamethasone in Patients with Penta-Exposed and Triple Class Refractory MM. Abstract #598. 2018 ASH Annual Meeting, 2018; San Diego, CA
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