This research is being done to investigate the safety and effectiveness of Darzalex Faspro (daratumumab and hyaluronidase-fihj) (a monoclonal antibody that targets plasma cells that make antibodies) and whether it can lower donor specific antibodies (DSA) levels to low enough levels to permit patients to proceed with allogeneic peripheral blood transplant (alloBMT). Those being asked to participate have high DSA levels that puts those being asked to participate at high risk of rejecting the available donor's blood stem cells and making those being asked to participate ineligible to receive a stem cell transplant.

Allogeneic blood or bone marrow transplant (alloBMT) remains the definitive curative treatment for many with relapsed or refractory hematologic malignancies. In recent years, increased use of alternative (non-fully human leukocyte antigen (HLA)-matched) donors has led to increased rates of donor specific antibodies (DSA). DSA are pre-formed HLA-antibodies in the recipient directed against the donor's class I and/or class II HLA antigens. DSA can be formed by exposure to foreign HLA antigens most commonly by pregnancy, blood transfusions, and previous organ or blood transplantation.

High levels of circulating anti-HLA antibodies directed towards mismatched donor HLA antigens at the time of alloBMT can dramatically increase the risk of primary graft failure (PGF). The strength of these donor specific antibodies (DSA) can be assessed with several methodologies including cross-matched cellular based assays (cytotoxic or flow cytometric assessment) or the more sensitive solid phase immunoassay (SPI) that estimates antibody level. Methods to "desensitize" patients with elevated DSAs using therapeutic plasma exchange (TPE), intravenous immunoglobulin (IVIG), and immunosuppression (i.e., mycophenolate mofetil and tacrolimus) are successful in patients with moderate levels of DSAs. However, in many patients, the DSA levels are considered too high for desensitization, or, desensitization has failed to lower levels of the DSA, and suitable alternative donors cannot be readily identified.

In this single-institution study at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (SKCCC), we will identify patients in whom alloBMT is indicated, but where DSA levels are above a pre-defined threshold using a proprietary algorithm that combines information from flow cytometric crossmatch (FCXM) and SPI (the Johns Hopkins (JH)-DSA Semi-Quant Screen Score). Patients who meet eligibility criteria will undergo 4 weekly doses of treatment with Darzalex Faspro, an anti- 38 (cluster of differentiation 38) antibody that kills plasma cells and lowers immunoglobulin levels, followed by standard desensitization with TPE, IVIG, and immunosuppression. Eight subjects will be treated in this pilot study. The primary endpoint will be based on safety of Darzalex Faspro and the number of patients who have DSA levels lowered enough to proceed to conditioning based on a pre-defined algorithm called JH-DSA Semi-Quant Response Score.

Inclusion Criteria:

1. Participates must meet all other institutional criteria for the planned reduced intensity conditioning allogeneic peripheral blood stem cell transplant (RIC alloHSCT) as defined in Johns Hopkins BMT Policy; all potential non-cord blood donor sources are included: matched related, haploidentical, matched unrelated, mismatched unrelated.

2. Participants must be ≥18 years of age.

3. Participants must have adequate organ function for undergoing RIC allogeneic peripheral blood stem cell transplant, and for undergoing a clinical trial.

   a. Hematologic. i. White blood cell (WBC). ANC ≥ 500/mm3 (growth factor support allowed). ii. Hemoglobin. No specific cut-off. (PRBC transfusion allowed). iii. Platelets. Platelets ≥ 10,000/mm3 (platelet transfusion allowed). b. Liver. Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) < 5x Upper limit of normal (ULN) c. Renal. Serum creatinine ≤ 2.0 mg/dL. d. Cardiac. Left ventricular ejection fraction ≥ 35%. e. Pulmonary. FEV1 ≥ 50%.

4. Subjects are eligible if there are high levels of Donor Specific Antibody levels based on protocol specific scoring system regardless of prior attempts at standard desensitization.

5. Participants must have a no other readily available suitable alternative donor.

6. All potential Participants must be pre-approved by BMT faculty consensus.

7. Participants must have adequate willingness to participate in a clinical trial.

Exclusion Criteria:

1. Previous exposure to Daratumumab-SC or other anti-CD38 therapy

   1. Exposure to Daratumumab-SC or other anti-CD38 therapies (unless a re-treatment study)
   2. Exposure to an investigational drug (including investigational vaccine) or invasive investigational medical device for any indication within 4 weeks or 5 pharmacokinetic half-lives, whichever is longer.
   3. Focal radiation therapy within 14 days prior to beginning of planned RIC allogeneic peripheral blood stem cell transplant regimen with the exception of palliative radiotherapy for symptomatic management but not on measurable extramedullary plasmacytoma

2. Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is < 50% of predicted normal.

3. Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate.

4. Known hypersensitivity or intolerance to boron or mannitol, sorbitol, corticosteroids, monoclonal antibodies or human proteins, or the excipients

5. Diagnosis of multiple myeloma or Amyloid light-chain (AL) amyloidosis

6. A planned myeloablative alloBMT or the planned use of bone marrow or cord blood as a stem cell source

7. History of HIV infection at any time in past.

8. Seropositive for hepatitis B (HBV) (defined by a positive test for hepatitis B surface antigen [HBsAg] positive, or antibodies to hepatitis B surface and/or core antigens [antiHBs or antiHBc, respectively] with hepatitis B virus [HBV]- DNA quantitation positive). Patients who are positive for antiHBs and/or antiHBc must have a negative polymerase chain reaction (PCR) for HBV-DNA quantitation result during screening. Patients with serologic findings suggestive of HBV vaccination (antiHBs positivity as the only serologic marker) AND a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR. Those who are PCR positive will be excluded.

9. Seropositive for hepatitis C (except in the setting of a sustained virologic response (SVR), defined as aviremia at least 12 weeks after completion of antiviral therapy)

10. Clinically significant cardiac disease, including:

    1. Myocardial infarction within 6 months before RIC alloHSCT or unstable or uncontrolled disease/condition related to or affection cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV)
    2. Uncontrolled cardiac arrhythmia