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

On Sunday 16 June at the 24^th 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:

ASCT, autologous stem cell transplant; IMiDs, immunomodulatory drugs; PIs, proteasome inhibitors; SDd, Selinexor, daratumumab and dexamethasone
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 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:

MR, minimal response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial resonse
	Daratumumab-naïve patients (n=30)	Total cohort (n=32)
ORR	73%	69%
VGPR	37%	34%
PR	37%	34%
MR	13%	13%
Clinical benefit rate (ORR+MR)	86%	81%
SD	13%	16%
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.