Dr. Giampaolo Merlini (University of Pavia, Italy) discusses the long-term outcome of a phase I clinical study of the investigational oral proteasome inhibitor ixazomib at the recommended phase 3 dose (RP3D) in patients with relapsed or refractory systemic light-chain (AL) amyloidosis (RRAL). These phase I study results were presented at the 56th American Society of Hematology (ASH) Annual Meeting. ASH 2014 abstract 3450.

Program: Oral and Poster Abstracts
Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II
Giampaolo Merlini, MD1, Vaishali Sanchorawala, MD2, Zonder A Jeffrey, MD3*, Vishal Kukreti, MD, FRCPC4, Stefan O Schoenland, MD5*, Arnaud Jaccard, MD6*, Angela Dispenzieri, MD7, Adam D. Cohen, MD8, Deborah Berg, RN, MSN9, Zheng Yuan, PhD10*, Ai-Min Hui, MD, PhD11, Palladini Giovanni, MD, PhD12* and Raymond L. Comenzo, MD13

1Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Department of Molecular Medicine, Pavia, Italy
2Hematology/Oncology, Boston University School of Medicine, Boston, MA
3Karmanos Cancer Institute, Wayne State University, Detroit, MI
4Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada
5University of Heidelberg, Heidelberg, Germany
6Clinical haematology, CHU Limoges, Limoges, France
7Division of Hematology, Mayo Clinic, Rochester, MN
8Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
9Millennium: The Takeda Oncology Company, Cambridge, MA
10Takeda Pharmaceuticals International, Co., Cambridge, MA
11Takeda Pharmaceuticals International Co., Cambridge, MA
12University of Pavia, Amyloidosis Research and Treatment Center, Department of Molecular Medicine, Pavia, Italy
13Division of Hematology-Oncology, Tufts Medical Center, Boston, MA


Systemic AL amyloidosis is a life-threatening disease with limited treatment options. Response criteria have been recently updated and retrospectively validated (Palladini et al, J Clin Oncol 2012). Hematologic response (suppression of FLCs) has been shown to predict for both organ response and survival (ibid). Preliminary results from the present phase 1 study (NCT01318902) regarding the safety, tolerability, and maximum tolerated dose (MTD) of ixazomib (the first oral PI to be investigated in the clinic) in RRAL were reported previously (Merlini et al, ASH 2012). At that time, 11 pts had received the MTD/RP3D of ixazomib - 4.0 mg. Here we update the safety data (primary objective) and report hematologic and organ responses, progression-free survival (PFS), and overall survival (OS) (secondary objectives) for the extended population of 22 pts receiving the RP3D.


Pts with RRAL after ≥1 prior therapy and with measureable heart/kidney involvement and cardiac biomarker stage I/II disease were eligible. Two expansion cohorts (PI-naïve and PI-exposed) were enrolled at the RP3D. Pts received oral ixazomib on days 1, 8, and 15 for up to 12 x 28-day cycles; continuation until disease progression was allowed. Pts with less than partial response (PR) after 3 cycles received added dexamethasone (Dex) 40 mg, days 1–4 from cycle 4 onwards. Adverse events (AEs) were graded by NCI-CTCAE v4.03. Responses were assessed per standard criteria (Palladini et al, J Clin Oncol 2012).


At data cut-off (Dec 6, 2013), 27 pts had been enrolled, 22 at the RP3D of ixazomib 4.0 mg; the other 5 pts were enrolled at 5.5 mg and are not included in these analyses. In pts who received ixazomib 4.0 mg, median age was 64.5 yrs (range 54–78); 13 were male. Mayo cardiac biomarker risk stage was I/II/III in 11/10/1 pts, respectively. Median baseline FLC differential (dFLC) and NT-proBNP were 146 mg/L (range 40–734) and 849 pg/mL (range 51–5691). Major organ involvement included heart, kidney, or both in 9, 8, and 5 pts, with a median of 2 (range 1–6) organ systems involved. Pts had received a median of 3 prior therapies, including transplantation in 16 pts; 16 pts had received prior bortezomib (PI exposed) and 6 were PI naïve. Other prior therapies included melphalan (n=21), Dex (n=16), IMiDs (n=11), and cyclophosphamide (n=10). Best hematologic response to prior therapy was complete response (CR) in 3 pts, very good PR (VGPR) in 4, PR in 14, and stable disease (SD) in 1 pt; organ response was achieved by 5 pts, with 12 pts having no response. Exposure and outcome data by prior PI exposure are shown in the table. Pts discontinued due to disease progression (n=6), pt withdrawal, symptomatic deterioration (each n=3), or unsatisfactory response (n=2); 5 pts completed 12 cycles; 3 pts are ongoing. Overall hematologic response rate (ORR) was 52%. After a median follow-up of 16.9 mos, the 9 pts who achieved ≥VGPR, had a median PFS of 17.0 mos compared with 10.7 mos in pts who achieved a lesser response (p=0.03). Cardiac/renal response was observed in 50%/18% of pts (all ≥VGPR). The most common drug-related AEs included diarrhea, nausea (each n=7), fatigue, thrombocytopenia (each n=6), peripheral neuropathy, and pyrexia (each n=4). Drug-related grade 3 AEs (>1 pt) were thrombocytopenia (n=3), diarrhea, and maculo-papular rash (each n=2).


This is one of the first studies prospectively assessing hematologic and organ response according to the updated consensus criteria. These data suggest weekly oral ixazomib 4.0 mg is feasible and generally well tolerated in RRAL pts with vital organ dysfunction. High quality hematologic responses (≥VGPR) were observed in 43% of pts; these responses were sustained at 1 yr in 60% of this heavily-pretreated population. Achieving ≥VGPR was associated with cardiac response and extended PFS. These results warrant a phase 3 study of ixazomib plus Dex vs physician's choice of treatment, which is ongoing (NCT01659658).

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Dr. Giampaolo Merlini received his medical degree and specialized in hematology and in-laboratory medicine at the University of Pavia. He is the Director of the Center for Research and Treatment of Systemic Amyloidosis, University Hospital Policlinico San Matteo, and the Director of Research of the University Hospital. He is a Professor of Clinical Biochemistry, Department of Molecular Medicine, University of Pavia, Italy. He was President of the International Society of Amyloidosis from 2005 to 2010. He received several awards, including the Jan G. Waldenström Award and the 2017 Ham-Wasserman Lecture of the American Society of Hematology. Visit Dr. Giampaolo Merlini's full biography.

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