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Abstract

Abstract: P339

Type: Poster Presentation

Presentation during EHA22: On Friday, June 23, 2017 from 17:15 - 18:45

Location: Poster area (Hall 7)

Background
Bortezomib-MP is a standard-of-care regimen for elderly NDMM pts. Whereas bortezomib is administered IV or SC, ixazomib is an oral proteasome inhibitor with a safety profile amenable to extended dosing that is approved in the US and EU, in combination with lenalidomide-dexamethasone, for the treatment of MM pts who have received at least 1 prior therapy. Based on the demonstrated feasibility and efficacy of a proteasome inhibitor-MP combination, the all-oral ixazomib-MP (IMP) regimen was evaluated in elderly, transplant-ineligible NDMM pts.

Aims
Primary phase 1 objectives were to determine the safety, MTD, and recommended phase 2 dose (RP2D) of ixazomib in combination with MP. The primary phase 2 objective was to determine the rate of CR+VGPR; secondary objectives included PFS and OS.

Methods
In phase 1, pts were enrolled to 4 arms – Arm A: ixazomib 3.0–3.7 mg (days 1, 4, 8, 11, 22, 25, 29, 32) plus M 9 mg/m2 and P 60 mg/m2 (days 1–4) in 42-day cycles (max 9 cycles); Arm B: ixazomib 3.0–4.0 mg (days 1, 8, 15) plus M 6 mg/m2 and P 60 mg/m2 (days 1–4) in 28-day cycles (max 13 cycles); Arm C/D: ixazomib 3.0–4.0 mg (days 1, 8, 15, 22, 29)/ixazomib 4.0 mg (days 1, 8, 22, 29) plus M 9 mg/m2 and P 60 mg/m2 (days 1–4) in 42-day cycles (max 9 cycles). In phase 2, an expansion cohort was enrolled at the RP2D. On all arms, after IMP induction, pts could receive maintenance with single-agent ixazomib (days 1, 8, 15; 28-day cycles).

Results
61 pts were enrolled, 11, 34, 11, and 5 to Arms A, B, C, and D (median age 74 yrs; 31% ISS stage III, 56% creatinine clearance ≤60 mL/min). Among 38 DLT-evaluable pts in phase 1, 10 had DLTs of Gr 3 rash (n=2, Arm A), Gr 3-4 thrombocytopenia (n=4, 1 pt in each arm), Gr 3-4 neutropenia (n=1, Arm A; n=4, Arm C, n=1, Arm D), Gr 4 hemorrhagic oesophageal ulcer (n=1, Arm B), Gr 3 ileus/neurogenic bladder (n=1, Arm B), Gr 3 vomiting/diarrhea (n=1, Arm B), and Gr 3 respiratory infection (n=1, Arm C). The RP2D was ixazomib 4.0 mg in Arm B, based on observed rates of toxicity; this cohort was expanded to 26 pts. Among all 61 pts, the median number of treatment cycles was 16; 36 pts (13 at RP2D) completed IMP induction and entered maintenance. Median number of maintenance cycles was 12. The maximum treatment duration was 1841 days (>5 yrs) at RP2D. Five pts remain on treatment (2 at RP2D); primary reasons for discontinuation were disease progression (48%) and adverse events (AEs, 21%).

 
CR+VGPR rate was 43% (43% at RP2D), including 28% (22%) ≥CR and 19% (17%) sCR; median time to first response was 1.7 mos, and responses continued to mature over a long period (Table 1). Depth of response improved during ixazomib maintenance in 9/36 (25%) pts (VGPR to sCR in 5 pts; VGPR to CR in 2 pts; CR to sCR in 2 pts). Median TTP/PFS are shown in Table 1; median OS was not reached after median follow-up of 42.6/46.9 mos overall/at RP2D.

Conclusion
The RP2D was weekly ixazomib 4.0 mg plus M 6 mg/m2 and P 60 mg/m2 (days 1–4) in 28-day cycles, consistent with the ixazomib dose and schedule in TOURMALINE-MM1. AEs were mainly hematologic, infections, PN, and diarrhea. The all-oral IMP regimen is active in NDMM, with a 28% CR rate (19% sCR), a 43% ≥VGPR rate, and a median PFS of 23.5 mos; responses continued to improve over a prolonged period.

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): Proteasome inhibitor, Myeloma, Elderly

Abstract: P339

Type: Poster Presentation

Presentation during EHA22: On Friday, June 23, 2017 from 17:15 - 18:45

Location: Poster area (Hall 7)

Background
Bortezomib-MP is a standard-of-care regimen for elderly NDMM pts. Whereas bortezomib is administered IV or SC, ixazomib is an oral proteasome inhibitor with a safety profile amenable to extended dosing that is approved in the US and EU, in combination with lenalidomide-dexamethasone, for the treatment of MM pts who have received at least 1 prior therapy. Based on the demonstrated feasibility and efficacy of a proteasome inhibitor-MP combination, the all-oral ixazomib-MP (IMP) regimen was evaluated in elderly, transplant-ineligible NDMM pts.

Aims
Primary phase 1 objectives were to determine the safety, MTD, and recommended phase 2 dose (RP2D) of ixazomib in combination with MP. The primary phase 2 objective was to determine the rate of CR+VGPR; secondary objectives included PFS and OS.

Methods
In phase 1, pts were enrolled to 4 arms – Arm A: ixazomib 3.0–3.7 mg (days 1, 4, 8, 11, 22, 25, 29, 32) plus M 9 mg/m2 and P 60 mg/m2 (days 1–4) in 42-day cycles (max 9 cycles); Arm B: ixazomib 3.0–4.0 mg (days 1, 8, 15) plus M 6 mg/m2 and P 60 mg/m2 (days 1–4) in 28-day cycles (max 13 cycles); Arm C/D: ixazomib 3.0–4.0 mg (days 1, 8, 15, 22, 29)/ixazomib 4.0 mg (days 1, 8, 22, 29) plus M 9 mg/m2 and P 60 mg/m2 (days 1–4) in 42-day cycles (max 9 cycles). In phase 2, an expansion cohort was enrolled at the RP2D. On all arms, after IMP induction, pts could receive maintenance with single-agent ixazomib (days 1, 8, 15; 28-day cycles).

Results
61 pts were enrolled, 11, 34, 11, and 5 to Arms A, B, C, and D (median age 74 yrs; 31% ISS stage III, 56% creatinine clearance ≤60 mL/min). Among 38 DLT-evaluable pts in phase 1, 10 had DLTs of Gr 3 rash (n=2, Arm A), Gr 3-4 thrombocytopenia (n=4, 1 pt in each arm), Gr 3-4 neutropenia (n=1, Arm A; n=4, Arm C, n=1, Arm D), Gr 4 hemorrhagic oesophageal ulcer (n=1, Arm B), Gr 3 ileus/neurogenic bladder (n=1, Arm B), Gr 3 vomiting/diarrhea (n=1, Arm B), and Gr 3 respiratory infection (n=1, Arm C). The RP2D was ixazomib 4.0 mg in Arm B, based on observed rates of toxicity; this cohort was expanded to 26 pts. Among all 61 pts, the median number of treatment cycles was 16; 36 pts (13 at RP2D) completed IMP induction and entered maintenance. Median number of maintenance cycles was 12. The maximum treatment duration was 1841 days (>5 yrs) at RP2D. Five pts remain on treatment (2 at RP2D); primary reasons for discontinuation were disease progression (48%) and adverse events (AEs, 21%).

 
CR+VGPR rate was 43% (43% at RP2D), including 28% (22%) ≥CR and 19% (17%) sCR; median time to first response was 1.7 mos, and responses continued to mature over a long period (Table 1). Depth of response improved during ixazomib maintenance in 9/36 (25%) pts (VGPR to sCR in 5 pts; VGPR to CR in 2 pts; CR to sCR in 2 pts). Median TTP/PFS are shown in Table 1; median OS was not reached after median follow-up of 42.6/46.9 mos overall/at RP2D.

Conclusion
The RP2D was weekly ixazomib 4.0 mg plus M 6 mg/m2 and P 60 mg/m2 (days 1–4) in 28-day cycles, consistent with the ixazomib dose and schedule in TOURMALINE-MM1. AEs were mainly hematologic, infections, PN, and diarrhea. The all-oral IMP regimen is active in NDMM, with a 28% CR rate (19% sCR), a 43% ≥VGPR rate, and a median PFS of 23.5 mos; responses continued to improve over a prolonged period.

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): Proteasome inhibitor, Myeloma, Elderly

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