Inclusion Criteria:
* Subjects must have high radiological likelihood of GBM with plan for resection/biopsy for histologically confirmed GBM
* ECOG Performance status ≤ 2
* Subjects must have normal organ and marrow function as defined below:
* Leukocytes ≥ 3,000/mcL
* Absolute neutrophil count ≥ 1,500/mcL
* Platelet count ≥ 100,000/mcL
* Total bilirubin within normal institutional limits
* AST (SGOT) ≤ 3 X institutional upper limit of normal
* ALT (SGPT) ≤ 3 X institutional upper limit of normal
* Serum Creatinine within normal institutional limits OR glomerular filtration rate (GFR) 60 mL/min/1.73 m2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m2
* The effects of Daratumumab on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.
* Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
* Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of Daratumumab and TMZ administration.
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
* Ability to understand and the willingness to sign a written informed consent document.
Exclusion Criteria:
* Patients who received prior treatment for GBM.
* Patients who are receiving any other investigational agents.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to Daratumumab and TMZ.
* BCG (Intravesical), Deferiprone, and Dipyrone are risk X category and should be avoided when Daratumumab is used. Chloramphenicol (Ophthalmic), promazine and Clozapine are in the risk category C and myelosuppression signs should be monitored when used in combination with Daratumumab.
* Avoid category Risk X drugs such as BCG (Intravesical), Deferiprone, Dipyrone, Natalizumab, Tacrolimus (Topical), Vaccines (Live) and Pimecrolimus concurrently with TMZ. Consider therapy modifications of category D drugs such as Baricitinib, Echinacea, Fingolimod, Leflunomide, Lenograstim, Lipegfilgrastim, Nivolumab, Palifermin, Roflumilast, Tofacitinib, Vaccines (Inactivated when used with TMZ. Monitor therapy for category risk C drugs such as Chloramphenicol (Ophthalmic), CloZAPine, Coccidioides immitis Skin Test, Denosumab, Ocrelizumab, Pidotimod, Promazine, Sipuleucel-T, Trastuzumab, and Valproate Products.
* Patients with uncontrolled intercurrent illness.
* Patients with psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant women are excluded from this study because there are no animal and human data to assess the risk of Daratumumab during pregnancy. On the other hand, TMZ is a category D drug where adverse events are observed in animal reproduction studies. May cause fetal harm when administered to pregnant females. Male and female patients should use effective contraception to avoid pregnancy while receiving temozolomide. May impair male fertility based on animal data).
* Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) \<50% of predicted normal.
o Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is \<50% of predicted normal.
* Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification.
o Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.
* Clinically significant cardiac disease, including:
* Myocardial infarction within 6 months before randomization, or unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV).
* Uncontrolled cardiac arrhythmia
