PMID- 36450626
OWN - NLM
STAT- MEDLINE
DCOM- 20221220
LR  - 20230214
IS  - 2152-2669 (Electronic)
IS  - 2152-2669 (Linking)
VI  - 23
IP  - 1
DP  - 2023 Jan
TI  - Cobimetinib Alone and Plus Venetoclax With/Without Atezolizumab in Patients With 
      Relapsed/Refractory Multiple Myeloma.
PG  - e59-e70
LID - S2152-2650(22)01712-8 [pii]
LID - 10.1016/j.clml.2022.10.006 [doi]
AB  - INTRODUCTION: Mitogen-activated protein kinase pathway mutations are present in 
      >50% of patients with relapsed/refractory (R/R) multiple myeloma (MM). MEK 
      inhibitors show limited single-agent activity in R/R MM; combination with B-cell 
      lymphoma-2 (BCL-2) and programmed death-ligand 1 inhibition may improve efficacy. 
      This phase Ib/II trial (NCT03312530) evaluated safety and efficacy of cobimetinib 
      (cobi) alone and in combination with venetoclax (ven) with/without atezolizumab 
      (atezo) in patients with R/R MM. PATIENTS AND METHODS: Forty-nine patients were 
      randomized 1:2:2 to cobi 60 mg/day on days 1-21 (n = 6), cobi 40 mg/day on days 
      1-21 + ven 800 mg/day on days 1-28 with/without atezo 840 mg on days 1 and 15 of 
      28-day cycles (cobi-ven, n = 22; cobi-ven-atezo, n = 21). Safety run-in cohorts 
      evaluated cobi-ven and cobi-ven-atezo dose levels. RESULTS: Any-grade common 
      adverse events (AEs) with cobi, cobi-ven, and cobi-ven-atezo, respectively, 
      included diarrhea (33.3%, 81.8%, 90.5%) and nausea (16.7%, 50.0%, 66.7%); common 
      grade >/=3 AEs included anemia (0%, 22.7%, 23.8%), neutropenia (0%, 13.6%, 38.1%), 
      and thrombocytopenia (0%, 18.2%, 23.8%). The overall response rate for all-comers 
      was 0% (cobi), 27.3% (cobi-ven), and 28.6% (cobi-ven-atezo), and 0%, 50.0%, and 
      100%, respectively, in patients with t(11;14)+. Biomarker analysis demonstrated 
      non-t(11;14) patient selection with NRAS/KRAS/BRAF mutation or high 
      BCL-2/BCL-2-L1 ratio (>52% of the study population) could enrich for responders 
      to the cobi-ven combination. CONCLUSIONS: Cobi-ven and cobi-ven-atezo 
      demonstrated manageable safety with moderate activity in all-comers, and higher 
      activity in patients with t(11;14)+ MM, supporting a biomarker-driven approach 
      for ven in MM.
CI  - Copyright (c) 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Schjesvold, Fredrik
AU  - Schjesvold F
AD  - Oslo Myeloma Center, Department of Haematology, Oslo University Hospital, Oslo, 
      Norway; KG Jebsen Centre for B cell malignancies, University of Oslo, Oslo, 
      Norway. Electronic address: fredrikschjesvold@gmail.com.
FAU - Paiva, Bruno
AU  - Paiva B
AD  - Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), 
      Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC, Pamplona, 
      Spain.
FAU - Ribrag, Vincent
AU  - Ribrag V
AD  - Institut Gustave Roussy, Villejuif, France.
FAU - Rodriguez-Otero, Paula
AU  - Rodriguez-Otero P
AD  - Clinica Universidad de Navarra, CCUN, University of Navarra, Pamplona, Spain.
FAU - San-Miguel, Jesus F
AU  - San-Miguel JF
AD  - Clinica Universidad de Navarra, CCUN, University of Navarra, Pamplona, Spain.
FAU - Robak, Pawel
AU  - Robak P
AD  - Medical University of Lodz, Lodz, Poland.
FAU - Hansson, Markus
AU  - Hansson M
AD  - Skane University Hospital, Lund, Sweden and Sahlgrenska Academy, Gothenburg, 
      Sweden.
FAU - Onishi, Maika
AU  - Onishi M
AD  - Genentech, Inc, South San Francisco, CA.
FAU - Hamidi, Habib
AU  - Hamidi H
AD  - Genentech, Inc, South San Francisco, CA.
FAU - Malhi, Vikram
AU  - Malhi V
AD  - Genentech, Inc, South San Francisco, CA.
FAU - Dail, Monique
AU  - Dail M
AD  - Genentech, Inc, South San Francisco, CA.
FAU - Javery, Apurva
AU  - Javery A
AD  - Syneos Health, Raleigh, Raleigh, NC.
FAU - Ku, Grace
AU  - Ku G
AD  - Genentech, Inc, South San Francisco, CA.
FAU - Raab, Marc S
AU  - Raab MS
AD  - Heidelberg University Hospital, Department of Medicine V, Heidelberg, Germany.
LA  - eng
SI  - ClinicalTrials.gov/NCT03312530
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20221022
PL  - United States
TA  - Clin Lymphoma Myeloma Leuk
JT  - Clinical lymphoma, myeloma & leukemia
JID - 101525386
RN  - N54AIC43PW (venetoclax)
RN  - ER29L26N1X (cobimetinib)
RN  - 52CMI0WC3Y (atezolizumab)
RN  - 0 (Bridged Bicyclo Compounds, Heterocyclic)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
SB  - IM
MH  - Humans
MH  - *Multiple Myeloma/drug therapy/etiology
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects
MH  - Bridged Bicyclo Compounds, Heterocyclic/adverse effects
MH  - Proto-Oncogene Proteins c-bcl-2
OTO - NOTNLM
OT  - B-cell lymphoma-2, Programmed death-ligand 1
OT  - Biomarker
OT  - Mitogen-activated protein kinase pathway, Immunotherapy
EDAT- 2022/12/01 06:00
MHDA- 2022/12/21 06:00
CRDT- 2022/11/30 22:03
PHST- 2022/07/18 00:00 [received]
PHST- 2022/10/11 00:00 [revised]
PHST- 2022/10/17 00:00 [accepted]
PHST- 2022/12/01 06:00 [pubmed]
PHST- 2022/12/21 06:00 [medline]
PHST- 2022/11/30 22:03 [entrez]
AID - S2152-2650(22)01712-8 [pii]
AID - 10.1016/j.clml.2022.10.006 [doi]
PST - ppublish
SO  - Clin Lymphoma Myeloma Leuk. 2023 Jan;23(1):e59-e70. doi: 
      10.1016/j.clml.2022.10.006. Epub 2022 Oct 22.