Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib

Nijhof, Inger S.; Groen, Richard W.J.; Noort, Willy A.; Kessel, Berris van; Jong-Korlaar, Regina A. de; Bakker, Joost M.; Bueren, Jeroen J. Lammerts-van; Parren, Paul W.H.I.; Lokhorst, Henk M.; Donk, Niels W.C.J. van de; Martens, Anton C.; Mutis, Tuna

doi:10.1158/1078-0432.ccr-14-1813

Cited by 136 publications

(129 citation statements)

References 30 publications

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“…3 Preclinical studies indicate that the addition of lenalidomide to daratumumab enhances the killing of lenalidomide-resistant or bortezomib-resistant myeloma cells in vitro and reduces tumor growth in an in vivo xenograft model. 17 An ongoing phase 1-2 study of daratumumab in combination with lenalidomide and dexamethasone in patients with relapsed myeloma or relapsed and refractory myeloma has shown high response rates and responses that improved over time. 18 SAR650984, a humanized IgG1 monoclonal antibody, also targets CD38, 19 and clinical responses have been reported in patients with relapsed myeloma or relapsed and refractory myeloma who received the drug as monotherapy 20 or in combination with lenalidomide and dexamethasone, findings that further validate this approach.…”

Section: Discussionmentioning

confidence: 99%

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

et al. 2015

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BACKGROUNDMultiple myeloma cells uniformly overexpress CD38. We studied daratumumab, a CD38-targeting, human IgG1κ monoclonal antibody, in a phase 1-2 trial involving patients with relapsed myeloma or relapsed myeloma that was refractory to two or more prior lines of therapy. METHODSIn part 1, the dose-escalation phase, we administered daratumumab at doses of 0.005 to 24 mg per kilogram of body weight. In part 2, the dose-expansion phase, 30 patients received 8 mg per kilogram of daratumumab and 42 received 16 mg per kilogram, administered once weekly (8 doses), twice monthly (8 doses), and monthly for up to 24 months. End points included safety, efficacy, and pharmacokinetics. RESULTSNo maximum tolerated dose was identified in part 1. In part 2, the median time since diagnosis was 5.7 years. Patients had received a median of four prior treatments; 79% of the patients had disease that was refractory to the last therapy received (64% had disease refractory to proteasome inhibitors and immunomodulatory drugs and 64% had disease refractory to bortezomib and lenalidomide), and 76% had received autologous stem-cell transplants. Infusion-related reactions in part 2 were mild (71% of patients had an event of any grade, and 1% had an event of grade 3), with no dose-dependent adverse events. The most common adverse events of grade 3 or 4 (in ≥5% of patients) were pneumonia and thrombocytopenia. The overall response rate was 36% in the cohort that received 16 mg per kilogram (15 patients had a partial response or better, including 2 with a complete response and 2 with a very good partial response) and 10% in the cohort that received 8 mg per kilogram (3 had a partial response). In the cohort that received 16 mg per kilogram, the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 8.1), and 65% (95% CI, 28 to 86) of the patients who had a response did not have progression at 12 months.

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Section: Discussionmentioning

confidence: 99%

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

et al. 2015

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“…[1][2][3][4] Most recently, elotuzumab and daratumumab targeting cell surface antigens SLAMF7 and CD38, respectively, have been US Food and Drug Administration approved to treat relapsed and refractory MM. 1,2,5 Ongoing efforts are focusing on developing more effective immunotherapies targeting selective tumor antigens while simultaneously enhancing immune function in patients.…”

Section: Introductionmentioning

confidence: 99%

APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

Tai

Acharya

et al. 2016

Blood

277

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Here we show that overexpression or activation of B-cell maturation antigen (BCMA) by its ligand, a proliferation-inducing ligand (APRIL), promotes human multiple myeloma (MM) progression in vivo. BCMA downregulation strongly decreases viability and MM colony formation; conversely, BCMA overexpression augments MM cell growth and survival via induction of protein kinase B (AKT), MAPK, and nuclear factor (NF)-κB signaling cascades. Importantly, BCMA promotes in vivo growth of xenografted MM cells harboring p53 mutation in mice. BCMA-overexpressing tumors exhibit significantly increased CD31/microvessel density and vascular endothelial growth factor compared with paired control tumors. These tumors also express increased transcripts crucial for osteoclast activation, adhesion, and angiogenesis/metastasis, as well as genes mediating immune inhibition including programmed death ligand 1, transforming growth factor β, and interleukin 10. These target genes are consistently induced by paracrine APRIL binding to BCMA on MM cells, which is blocked by an antagonistic anti-APRIL monoclonal antibody hAPRIL01A (01A). 01A is cytotoxic against MM cells even in the presence of protective bone marrow (BM) myeloid cells including osteoclasts, macrophages, and plasmacytoid dendritic cells. 01A further decreases APRIL-induced adhesion and migration of MM cells via blockade of canonical and noncanonical NF-κB pathways. Moreover, 01A prevents in vivo MM cell growth within implanted human bone chips in SCID mice. Finally, the effect of 01A on MM cell viability is enhanced by lenalidomide and bortezomib. Taken together, these data delineate new molecular mechanisms of in vivo MM growth and immunosuppression critically dependent on BCMA and APRIL in the BM microenvironment, further supporting targeting this prominent pathway in MM

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“…9 IMiDs also stimulate antitumor response of the immune system through promotion of T-cell costimulation and increase in natural killer cell numbers and activation status. [10][11][12] Similarly, administration of cyclophosphamide, at a dose substantially lower than the maximum tolerated dose (MTD) (metronomic dosing), 13 has next to its direct antitumor activity several effects on the bone marrow microenvironment, including immune stimulatory activity. [14][15][16][17][18][19][20][21][22] We hypothesized that the addition of low-dose metronomic oral cyclophosphamide to lenalidomide may be an attractive strategy for lenalidomide-refractory MM patients.…”

Section: Introductionmentioning

confidence: 99%

Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma

Nijhof

Franssen

Levin

et al. 2016

Blood

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Key Points• REP is an active combination in MM patients refractory to lenalidomide.• REP is an all-oral and generally well-tolerated regimen.The prognosis of multiple myeloma (MM) patients who become refractory to lenalidomide and bortezomib is very poor, indicating the need for new therapeutic strategies for these patients. Next to the development of new drugs, the strategy of combining agents with synergistic activity may also result in clinical benefit for patients with advanced myeloma. We have previously shown in a retrospective analysis that lenalidomide combined with continuous low-dose cyclophosphamide and prednisone (REP) had remarkable activity in heavily pretreated, lenalidomide-refractory MM patients. To evaluate this combination prospectively, we initiated a phase 1/2 study to determine the optimal dose and to assess its efficacy and safety in lenalidomide-refractory MM patients. The maximum tolerated dose (MTD) was defined as 25 mg lenalidomide (days 1-21/28 days), combined with continuous cyclophosphamide (50 mg/d) and prednisone (20 mg/d). At the MTD (n 5 67 patients), the overall response rate was 67%, and at least minimal response was achieved in 83% of the patients. Median progression-free survival and overall survival were 12.1 and 29.0 months, respectively. Similar results were achieved in the subset of patients with lenalidomide-and bortezomib-refractory disease as well as in patients with high-risk cytogenetic abnormalities, defined as t(4;14), t(14;16), del(17p), and/or ampl(1q) as assessed by fluorescence in situ hybridization. Neutropenia (22%) and thrombocytopenia (22%) were the most common grade 3-4 hematologic adverse events. Infections (21%) were the most common grade 3-5 nonhematologic adverse events. In conclusion, the addition of continuous low-dose oral cyclophosphamide to lenalidomide and prednisone offers a new therapeutic perspective for multidrug refractory MM patients. This trial was registered at www.clinicaltrials.gov as

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Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib

Cited by 136 publications

References 30 publications

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma

APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma

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