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ASCO 2013: Dr. Kumar- Weekly MLN9708, an investigational oral proteasome inhibitor (PI), in relapsed/refractory multiple myeloma (MM): Results from a phase I study after full enrollment.

Shaji Kumar, MD
Mayo Clinic
Rochester, Minnesota, USA

06.03.13

Abstract Number: 
8514

Citation: 
J Clin Oncol 31, 2013 (suppl; abstr 8514)

Author(s): 
Shaji Kumar, William Bensinger, Todd M. Zimmerman, Craig B. Reeder, James R. Berenson, Deborah Berg, Ai-Min Hui, Neeraj Gupta, Alessandra Di Bacco, Jiang Yu, Yaping Shou, Ruben Niesvizky; Mayo Clinic, Rochester, MN; Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Medicine, University of Chicago, Chicago, IL; Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ; Institute for Myeloma and Bone Cancer Research, West Hollywood, CA; Millennium Pharmaceuticals, Inc., Cambridge, MA; Center of Excellence for Lymphoma and Myeloma, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY

ABSTRACT: 

Background: MLN9708 is an investigational, orally bioavailable, potent, reversible, specific inhibitor of the 20S proteasome that has demonstrated antitumor activity in in vivo models of MM. We report safety, activity and pharmacokinetics (PK) of weekly oral MLN9708 in a phase 1 trial in patients (pts) with relapsed and/or refractory MM after full enrollment (NCT00963820). 

Methods: Pts received MLN9708 (days 1, 8, 15; 28-day cycles) at 0.24–3.95 mg/m2 (dose-escalation phase) and at the MTD, 2.97 mg/m2, in relapsed and refractory (RR), bortezomib (btz)-relapsed, PI-naïve, and prior carfilzomib (CZ) expansion cohorts. Adverse events (AEs) were graded by NCI-CTCAE v3.0. Response was assessed by IMWG uniform criteria. 

Results: 60 pts (33 male, median age 64 yrs [40–79]) were enrolled, 32 in the dose-escalation phase and 31 to the expansion cohorts (11 RR, 10 btz-relapsed, 6 PI-naïve, 4 CZ; 2 RR and 1 btz-relapsed pts included from MTD dose-escalation cohort). Median time from MM diagnosis was 4.9 yrs (1.5–18.8). Median number of prior regimens was 6 (2–18), including btz, lenalidomide, thalidomide, and CZ in 83%, 95%, 52%, and 13%, respectively; 76% were refractory to last therapy (17% btz-refractory). At data cut-off (Nov 29, 2012) pts had received a median of 2 cycles (1–11); 5 pts remained on treatment. All-grade/grade ≥3 drug-related AEs were seen in 83%/52% of pts; common drug-related grade ≥3 AEs were thrombocytopenia (33%), diarrhea, neutropenia (17%), decreased appetite, fatigue, and lymphopenia (8%). 6 pts (10%) had drug-related PN (no grade ≥3). 5 pts discontinued due to drug-related AEs; 1 pt died on study due to an unrelated AE. By investigator assessment in 41 evaluable pts, responses included1 VGPR, 5 PR, 1 MR, and 15 with SD. MLN9708 was rapidly absorbed, with a terminal half-life of 4–12 days (supporting weekly dosing) and a proportional increase in plasma AUC with dose (0.8–3.95 mg/m2). PK data were similar across expansion cohorts. 

Conclusions: Current data suggest weekly oral MLN9708 is generally well tolerated with infrequent PN, and shows activity in this heavily pretreated population with prior exposure to immunomodulatory drugs and btz. 

Clinical trial information: NCT00963820


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You might also be interested in:

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Immunomodulatory Agents
ASCO 2013: Dr. Usmani - Total therapy 5 (TT5) for newly diagnosed high-risk multiple myeloma (HRMM): Comparison with predecessor trials total therapy 3a and 3b (TT3 a/b).

Saad Usmani, MD, FACP
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Katja Weisel, MD
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Tuebingen, Germany


ASCO 2013: Dr. Jakubowiak - Treatment outcome with the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) for newly diagnosed multiple myeloma (NDMM) after extended follow-up.

Andrzej Jakubowiak, MD
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, USA


ASCO 2013: Dr. Palumbo - Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) plus lenalidomide maintenance or no maintenance in newly diagnosed multiple myeloma (MM) patients.

Antonio Palumbio, MD
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ASCO 2013: Dr. Palumbo - Second primary malignancies (SPM) in newly diagnosed myeloma (MM) patients treated with lenalidomide (Len): Meta-analysis of 6,383 individual patient data (IPD).

Antonio Palumbio, MD
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ASCO 2013: Dr. Jagannath - Pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in patients (Pts) with relapsed and refractory multiple myeloma (RRMM): MM-002 phase II age subgroup analysis.

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Proteasome Inhibitors
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Saad Usmani, MD, FACP
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ASCO 2013: Dr. Usmani - Total therapy 5 (TT5) for newly diagnosed high-risk multiple myeloma (HRMM): Comparison with predecessor trials total therapy 3a and 3b (TT3 a/b).

Saad Usmani, MD, FACP
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences
Little Rock, Arkansa, USA


ASCO 2013: Dr. Nooka- Early versus delayed autologous stem cell transplant (ASCT) in patients receiving induction therapy with lenalidomide, bortezomib, and dexamethasone (RVD) for newly diagnosed multiple myeloma (MM).

Ajay Nooka, MD, MPH, FACP
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Atlanta, Georgia, USA


ASCO 2013: Dr. Richardson - MM-005: A phase I trial of pomalidomide, bortezomib, and low-dose dexamethasone (PVD) in relapsed and/or refractory multiple myeloma (RRMM).

Paul Richardson, MD
Dana-Farber Cancer Institute
Boston, Massachusetts, USA


ASCO 2013: Dr. Jakubowiak - Treatment outcome with the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) for newly diagnosed multiple myeloma (NDMM) after extended follow-up.

Andrzej Jakubowiak, MD
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, USA


ASCO 2013: Dr. Kumar- Weekly MLN9708, an investigational oral proteasome inhibitor (PI), in relapsed/refractory multiple myeloma (MM): Results from a phase I study after full enrollment.

Shaji Kumar, MD
Mayo Clinic
Rochester, Minnesota, USA


ASCO 2013: Dr. Richardson - Clinical response by baseline characteristics in patients (pts) with relapsed and bortezomib (BTZ)-refractory multiple myeloma treated with panobinostat (PAN), BTZ, and dexamethasone (DEX; PANORAMA 2).

Paul Richardson, MD
Dana-Farber Cancer Institute
Boston, Massachusetts, USA


Other Novel Agents
ASCO 2013: Dr. Ghobrial - Phase I study of TH-302, an investigational hypoxia-targeted drug, and dex in patients with RRMM

Irene M. Ghobrial, MD
Dana-Farber Cancer Institute
Boston, MA


ASCO 2013: Dr. Lokhorst - Phase I/II dose-escalation study of daratumumab in patients with relapsed or refractory multiple myeloma.

Henk M. Lokhorst, MD
University Medical Center Utrecht
Utrecht, Netherlands
Member, IMF Board of Scientific Advisors


ASCO 2013: Dr. Lonial - Phase (Ph) I/II study of elotuzumab (Elo) plus lenalidomide/dexamethasone (Len/dex) in relapsed/refractory multiple myeloma (RR MM): Updated Ph II results and Ph I/II long-term safety.

Sagar Lonial, MD
Emory University School of Medicine
Atlanta, Georgia, USA


ASCO 2013: Dr. Richardson - Clinical response by baseline characteristics in patients (pts) with relapsed and bortezomib (BTZ)-refractory multiple myeloma treated with panobinostat (PAN), BTZ, and dexamethasone (DEX; PANORAMA 2).

Paul Richardson, MD
Dana-Farber Cancer Institute
Boston, Massachusetts, USA


Transplant
ASCO 2013: Dr. Usmani - Total therapy 5 (TT5) for newly diagnosed high-risk multiple myeloma (HRMM): Comparison with predecessor trials total therapy 3a and 3b (TT3 a/b).

Saad Usmani, MD, FACP
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences
Little Rock, Arkansa, USA


ASCO 2013: Dr. Nooka- Early versus delayed autologous stem cell transplant (ASCT) in patients receiving induction therapy with lenalidomide, bortezomib, and dexamethasone (RVD) for newly diagnosed multiple myeloma (MM).

Ajay Nooka, MD, MPH, FACP
Winship Cancer Institute of Emory University
Atlanta, Georgia, USA


ASCO 2013: Dr. Palumbo - Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) plus lenalidomide maintenance or no maintenance in newly diagnosed multiple myeloma (MM) patients.

Antonio Palumbio, MD
University Of Turin
Turin, Italy


Others
ASCO 2013: Dr. Raje - Evaluating results from the multiple myeloma subset of patients treated with denosumab or zoledronic acid (ZA) in a randomized phase III study.

Noopur Raje, MD
Massachusetts General Hospital
Boston, Massachusetts, USA


ASCO 2013: Dr. Pandey - Beneficial effect of complete response and type of therapy in multiple myeloma.

Shivlal Pandey, MD
Mayo Clinic
Rochester, Minnesota, USA