Ixazomib, pomalidomide, and dexamethasone in lenalidomide-refractory RRMM patients

The appearance of novel agents has led to an improvement in the lives of many Multiple Myeloma (MM) patients. However, once patients become refractory to key agents such as bortezomib and lenalidomide, their prognosis is unfavorable. Due to an improved diagnosis, MM patients are living longer, making it necessary to identify drugs with high efficacy and favorable toxicity that can be used in advanced disease. Ixazomib (Ninlaro), is an oral peptide proteasome inhibitor, that has recently been approved by the National Institute for Health and Care Excellence (NICE) for the treatment of MM patients who have received two or three prior lines of therapies, in combination with lenalidomide and dexamethasone – read more here.

Amrita Krishnan, from the Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, USA, and colleagues, conducted a phase I/II study to assess the safety and efficacy of a new combination: ixazomib, pomalidomide, and dexamethasone (Ixa/Pom/Dex) for Relapsed and Refractory (RR) MM patients who are also refractory to lenalidomide. Phase I of the study identified the recommended phase II dose (RP2D) of ixazomib (Ixa), and phase II assessed the overall response rate and efficacy. The results of this study were published in Leukemia in December 2017.

Study design:

• N = 32 pts enrolled between July 2014 and March 2016
• All pts had RRMM and were refractory to lenalidomide
• Dosing:
  • Two doses of ixazomib: Dose Level 1 (DL1) = 3 mg; DL2 = 4 mg
  • Pom = 4 mg and Dex = 40 mg (for pts >75 years of age Dex = 20 mg)
  • Pts were given Ixa on days 1, 8, and 15 of a 28-day cycle; Pom daily on days 1–21; Dex on days 1, 8, 15, and 22

Key Data (given as DL1 vs DL2)

• Phase I followed a standard 3 + 3 dose-escalation
• DL1 = 7 pts (1 was later excluded); DL2 = 25 pts; 31 pts were evaluable
• RP2D: phase I = 6 pts; phase II = 19 pts
• Cytogenetic abnormalities = 12 pts
  • 1q amplification = 5 pts; 17p del = 5pts; both t(4,14) and 1q amplification= 2 pts
  • Normal cytogenetics = 6 pts; (not assessed for cytogenetics = 13 pts)  
• Median age (years) = 62 (range 38–84) vs 63 (range 38–84)
• Time from diagnosis (years) = 3.6 (range 1.0–8.9) vs 3.5 (range 1.0–8.9)
• No of prior lines of therapy = 2 (range 1–5) in both groups
• All pts had prior bortezomib (Bor) and lenalidomide (Len) exposure
• Pts refractory to Bor (%) = 59 vs 56; all pts refractory to Len
• Prior carfilzomib (Cfz) exposure (%) = 19 vs 20
• Pts refractory to Cfz (%) = 50 vs 40
• Double refractory (Bor/Len; %) = 59 vs 56
• Triple refractory (Bor/Len/Cfz; %) = 9 vs 8
• Prior Autologous Stem Cell Transplant (ASCT) (%) = 75 vs 72

Key Findings

Phase I:

• No of pts with Dose-Limiting Toxicities: DL1 = 1 pt; DL2 = 1 pt
• Adverse Events (AEs) on DL1 = fatigue and lung infection at grade 3; neutropenia and thrombocytopenia at grade 4
• Three more pts enrolled at DL1 and no further DLT observed
• Three pts enrolled on DL2; with 1 pt experiencing grade 4 AEs (febrile neutropenia, neutropenia and thrombocytopenia)
• Three further pts enrolled again on DL2 and no further DLT observed
• RP2D selected as DL2 (Ixa = 4 mg, Pom = 4 mg, Dex = 40 mg)

Phase II:

• N = 31 pts
• Additional pts treated at RPD2 = 19
• Median follow-up (months) = 12.0 (range 1.9–32.1)
• No of pts discontinued from the study = 2
• Partial Response (PR) or over = 48% (95% CI, 27.8–68.7)
• Very Good Partial Response (VGPR) = 20% (95% CI, 6.8–40.7)
• Stable Disease (SD) or better = 76% (95% CI, 54.9–90.6)
• Median Progression-Free Survival (PFS; months) = 8.6 (95% CI, 1.8–not reached)
• Overall Survival (OS):
  • 1-year OS (%) = 82 (95% CI, 59–93)
  • Median OS = not reached
• Duration of response (≥PR among pts treated at the RP2D; months) = 9.2 (range 0.9–13.9)
• Pts who were refractory to Bor:
  • PR or better (%) = 29
  • Clinical Benefit Rate (CBR; %) = 71 (95% CI, 41.9–91.6)
• Pts with cytogenetic abnormalities:
  • VGPR (%) = 17 (95% CI, 2.1–48.4)
  • Overall Response Rate (ORR; %) = 50 (95% CI, 21.1–78.9)
  • CBR (%) = 92 (95% CI, 61.5–99.8)

Safety

• No treatment-related deaths
• Grade 3/4 AEs = 74%; 100% of pts at DL1 and 68% of pts at DL2
• Most common AEs were grade 2 anemia, thrombocytopenia, neutropenia and infections
• Study discontinuation = 2 pts due to lung infection (grade 3) and febrile neutropenia (grade 4)
• Treatment delayed = 1 pt due to treatment-related heart failure (grade 3)
• Most common grade 3 AEs:
  • DL1 (pts) = lymphopenia (5); leukopenia (2); infections (3)
  • DL2 (pts) = neutropenia (10); leukopenia (7); lymphopenia (7) and thrombocytopenia (6)
• Infrequent peripheral neuropathy
• Grade 3 tumor lysis = 1 pt, settled within 48 h via supportive care
• Deaths = 10 pts; disease progression = 9 and hypertensive disease = 1

Conclusion:

This study is a promising precursor to further larger trials of a new orally administered combo, which substitutes pomalidomide for lenalidomide and ixazomib for bortezomib, in patients that are refractory to the lenalidomide, or double refractory to Len/Bor. Although only small numbers were assessed, the beneficial use of the triplet oral regimen (Ixa/Pom/Dex) was confirmed, with 48% of patients displaying a partial response. It was encouraging to observe a CBR of 92% in patients with high-risk cytogenetic abnormalities, and a manageable safety profile even for prolonged use, as many patients remained on treatment for over 2 years. At this late stage in the treatment journey it is paramount to find non-toxic regimens that can be self-administered, which is an important aspect of maintaining patient quality of life.