Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma

Kristine A. Frerichs; Monique C. Minnema; Mark David Levin; Annemiek Broijl; Gerard M.J. Bos; Marie Jose Kersten; Tuna Mutis; Christie P.M. Verkleij; Inger S. Nijhof; Patricia W.C. Maas-Bosman; Saskia K. Klein; Sonja Zweegman; Pieter Sonneveld; Niels W.C.J. Van de Donk

doi:10.1182/bloodadvances.2021005220

Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma

Kristine A. Frerichs, Monique C. Minnema, Mark David Levin, Annemiek Broijl, Gerard M.J. Bos, Marie Jose Kersten, Tuna Mutis, Christie P.M. Verkleij, Inger S. Nijhof, Patricia W.C. Maas-Bosman, Saskia K. Klein, Sonja Zweegman, Pieter Sonneveld, Niels W.C.J. Van de Donk^*

^*Corresponding author for this work

Hematology

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Abstract

The efficacy of daratumumab depends partially on CD38 expression on multiple myeloma (MM) cells. We have previously shown that all-trans retinoic acid (ATRA) upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy, and safety of daratumumab combined with ATRA in patients with daratumumab-refractory MM in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty patients with daratumumabrefractory MM were subsequently enrolled in part B and treated with daratumumab (reintensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR $15%) was not met. However, most patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median progression-free survival (PFS) for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS compared with patients who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 vs 1.3 months). The median overall survival was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and reintensification of daratumumab had limited activity in patients with daratumumab-refractory MM, which may be explained by the transient upregulation of CD38 expression. This trial was registered at www.clinicaltrials.gov as #NCT02751255.

Original language	English
Pages (from-to)	5128-5139
Number of pages	12
Journal	Blood advances
Volume	5
Issue number	23
DOIs	https://doi.org/10.1182/bloodadvances.2021005220
Publication status	Published - 14 Dec 2021

Bibliographical note

Funding Information:
Conflict-of-interest disclosure: M.C.M. holds a consultancy or advisory role for Gilead Sciences, BMS, Alnylam, Janssen Cilag, Takeda, and Servier (all paid to employer) and hospitality from Cel-gene; A.B. received honoraria from Celgene, Janssen, Amgen, and Takeda; M.J.K. received research support from Kite/Gilead and honoraria from Kite/Gilead, Novartis, BMS/Celgene, Takeda, Roche, and Miltenyi Biotec (all paid to institution); T.M. received research support from Janssen Pharmaceuticals; S.Z. received honoraria from Celgene, Sanofi, Takeda, and Janssen and research funding from Celgene, Takeda, and Janssen; P.S. received honoraria from Amgen, BMS, Celgene, Janssen, Karyopharm, and Takeda and receives research funding from Amgen, Celgene, Janssen, Karyo-pharm, SkylineDx, and Takeda; N.W.C.J.v.d.D. received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis, and BMS and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Adaptive, and Servier. The remaining authors declare no competing financial interestst.

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© 2021 American Society of Hematology. All rights reserved.

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Frerichs, K. A., Minnema, M. C., Levin, M. D., Broijl, A., Bos, G. M. J., Kersten, M. J., Mutis, T., Verkleij, C. P. M., Nijhof, I. S., Maas-Bosman, P. W. C., Klein, S. K., Zweegman, S., Sonneveld, P., & Van de Donk, N. W. C. J. (2021). Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma. Blood advances, 5(23), 5128-5139. https://doi.org/10.1182/bloodadvances.2021005220

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title = "Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma",

abstract = "The efficacy of daratumumab depends partially on CD38 expression on multiple myeloma (MM) cells. We have previously shown that all-trans retinoic acid (ATRA) upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy, and safety of daratumumab combined with ATRA in patients with daratumumab-refractory MM in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty patients with daratumumabrefractory MM were subsequently enrolled in part B and treated with daratumumab (reintensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR $15%) was not met. However, most patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median progression-free survival (PFS) for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS compared with patients who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 vs 1.3 months). The median overall survival was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and reintensification of daratumumab had limited activity in patients with daratumumab-refractory MM, which may be explained by the transient upregulation of CD38 expression. This trial was registered at www.clinicaltrials.gov as #NCT02751255.",

author = "Frerichs, {Kristine A.} and Minnema, {Monique C.} and Levin, {Mark David} and Annemiek Broijl and Bos, {Gerard M.J.} and Kersten, {Marie Jose} and Tuna Mutis and Verkleij, {Christie P.M.} and Nijhof, {Inger S.} and Maas-Bosman, {Patricia W.C.} and Klein, {Saskia K.} and Sonja Zweegman and Pieter Sonneveld and {Van de Donk}, {Niels W.C.J.}",

note = "Funding Information: Conflict-of-interest disclosure: M.C.M. holds a consultancy or advisory role for Gilead Sciences, BMS, Alnylam, Janssen Cilag, Takeda, and Servier (all paid to employer) and hospitality from Cel-gene; A.B. received honoraria from Celgene, Janssen, Amgen, and Takeda; M.J.K. received research support from Kite/Gilead and honoraria from Kite/Gilead, Novartis, BMS/Celgene, Takeda, Roche, and Miltenyi Biotec (all paid to institution); T.M. received research support from Janssen Pharmaceuticals; S.Z. received honoraria from Celgene, Sanofi, Takeda, and Janssen and research funding from Celgene, Takeda, and Janssen; P.S. received honoraria from Amgen, BMS, Celgene, Janssen, Karyopharm, and Takeda and receives research funding from Amgen, Celgene, Janssen, Karyo-pharm, SkylineDx, and Takeda; N.W.C.J.v.d.D. received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis, and BMS and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Adaptive, and Servier. The remaining authors declare no competing financial interestst. Publisher Copyright: {\textcopyright} 2021 American Society of Hematology. All rights reserved.",

year = "2021",

month = dec,

day = "14",

doi = "10.1182/bloodadvances.2021005220",

language = "English",

volume = "5",

pages = "5128--5139",

journal = "Blood advances",

issn = "2473-9529",

publisher = "American Society of Hematology",

number = "23",

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Frerichs, KA, Minnema, MC, Levin, MD, Broijl, A, Bos, GMJ, Kersten, MJ, Mutis, T, Verkleij, CPM, Nijhof, IS, Maas-Bosman, PWC, Klein, SK, Zweegman, S, Sonneveld, P & Van de Donk, NWCJ 2021, 'Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma', Blood advances, vol. 5, no. 23, pp. 5128-5139. https://doi.org/10.1182/bloodadvances.2021005220

TY - JOUR

T1 - Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma

AU - Frerichs, Kristine A.

AU - Minnema, Monique C.

AU - Levin, Mark David

AU - Broijl, Annemiek

AU - Bos, Gerard M.J.

AU - Kersten, Marie Jose

AU - Mutis, Tuna

AU - Verkleij, Christie P.M.

AU - Nijhof, Inger S.

AU - Maas-Bosman, Patricia W.C.

AU - Klein, Saskia K.

AU - Zweegman, Sonja

AU - Sonneveld, Pieter

AU - Van de Donk, Niels W.C.J.

N1 - Funding Information: Conflict-of-interest disclosure: M.C.M. holds a consultancy or advisory role for Gilead Sciences, BMS, Alnylam, Janssen Cilag, Takeda, and Servier (all paid to employer) and hospitality from Cel-gene; A.B. received honoraria from Celgene, Janssen, Amgen, and Takeda; M.J.K. received research support from Kite/Gilead and honoraria from Kite/Gilead, Novartis, BMS/Celgene, Takeda, Roche, and Miltenyi Biotec (all paid to institution); T.M. received research support from Janssen Pharmaceuticals; S.Z. received honoraria from Celgene, Sanofi, Takeda, and Janssen and research funding from Celgene, Takeda, and Janssen; P.S. received honoraria from Amgen, BMS, Celgene, Janssen, Karyopharm, and Takeda and receives research funding from Amgen, Celgene, Janssen, Karyo-pharm, SkylineDx, and Takeda; N.W.C.J.v.d.D. received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis, and BMS and serves on advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Takeda, Roche, Novartis, Bayer, Adaptive, and Servier. The remaining authors declare no competing financial interestst. Publisher Copyright: © 2021 American Society of Hematology. All rights reserved.

PY - 2021/12/14

Y1 - 2021/12/14

N2 - The efficacy of daratumumab depends partially on CD38 expression on multiple myeloma (MM) cells. We have previously shown that all-trans retinoic acid (ATRA) upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy, and safety of daratumumab combined with ATRA in patients with daratumumab-refractory MM in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty patients with daratumumabrefractory MM were subsequently enrolled in part B and treated with daratumumab (reintensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR $15%) was not met. However, most patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median progression-free survival (PFS) for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS compared with patients who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 vs 1.3 months). The median overall survival was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and reintensification of daratumumab had limited activity in patients with daratumumab-refractory MM, which may be explained by the transient upregulation of CD38 expression. This trial was registered at www.clinicaltrials.gov as #NCT02751255.

AB - The efficacy of daratumumab depends partially on CD38 expression on multiple myeloma (MM) cells. We have previously shown that all-trans retinoic acid (ATRA) upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy, and safety of daratumumab combined with ATRA in patients with daratumumab-refractory MM in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty patients with daratumumabrefractory MM were subsequently enrolled in part B and treated with daratumumab (reintensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR $15%) was not met. However, most patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median progression-free survival (PFS) for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS compared with patients who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 vs 1.3 months). The median overall survival was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and reintensification of daratumumab had limited activity in patients with daratumumab-refractory MM, which may be explained by the transient upregulation of CD38 expression. This trial was registered at www.clinicaltrials.gov as #NCT02751255.

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JO - Blood advances

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ER -

Efficacy and safety of daratumumab combined with all-trans retinoic acid in relapsed/refractory multiple myeloma

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