• Documented informed consent of the participant and/or legally authorized representative

‣ Assent, when appropriate, will be obtained per institutional guidelines

• Age \>= 18 years

• Karnofsky performance status (KPS) \> 60%

• Multiple myeloma according to International Myeloma Working Group (IMWG) criteria with measurable disease defined as one of the following:

‣ Serum monoclonal protein \>= 1.0 g/dL (or 0.5 g/dL in patients with immunoglobulin A \[IgA\] multiple myeloma \[MM\])

⁃ 24 hour urine monoclonal protein \>= 200 mg/24 hour

⁃ Serum free light chain (FLC) of \> 10 mg/dL and an abnormal kappa:lambda ratio

• Minimum of two prior lines of therapy

• Previously received treatment with all of the following: a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Refractory (defined per IMWG Consensus Criteria) to daratumumab

• CD38 expression on multiple myeloma (MM) cells from bone marrow aspirate or biopsy as demonstrated by flow cytometry or immunohistochemistry

• Refractory (defined per IMWG Consensus Criteria) or intolerant to most recent therapy

• Fully recovered from the acute toxic effects (except alopecia) to =\< grade 1 to prior anti-cancer therapy

• Prior antitumor therapy must have been completed prior to enrollment as follows:

‣ \>= 21 days for investigational agents, cytotoxic chemotherapy

⁃ \>= 21 days for radiation therapy. Note: Patients must have measurable disease that has been untreated/unaffected by local radiation therapy

⁃ \>= 3 months for prior anti-CD38-targeted therapy, adoptive cell therapy

⁃ \>=14 days for proteasome inhibitor therapy

⁃ \>= 7 days for immunomodulatory agents

• Absolute neutrophil count (ANC) \>= 1,000/mm\^3 (within 14 days prior to day 1 of protocol therapy)

‣ NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement

• Platelets \>= 75,000/mm\^3 (\>= 50,000/mm\^3 if \>= 50% marrow involvement) (within 14 days prior to day 1 of protocol therapy)

‣ NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement

• Total bilirubin =\< 1.5 x upper limit of normal (ULN) (unless has Gilbert's disease) (within 14 days prior to day 1 of protocol therapy)

• Aspartate aminotransferase (AST) =\< 3 x ULN (within 14 days prior to day 1 of protocol therapy)

• Alanine aminotransferase (ALT) =\< 3 x ULN (within 14 days prior to day 1 of protocol therapy)

• Creatinine =\< 1.5 mg/dl AND/OR creatinine clearance of \>= 40 mL/min per 24 hour urine test or the Cockcroft-Gault formula (within 14 days prior to day 1 of protocol therapy)

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

‣ If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (within 14 days prior to day 1 of protocol therapy)

• Woman of childbearing potential must be practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies: e.g., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system; barrier methods; condom with spermicidal foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; male partner sterilization; true abstinence (when this is in line with the preferred and usual lifestyle of the subject) during and after the study (6 months after the last dose of 225Ac-DOTA-Daratumumab for women).

∙ A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control, e.g., either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study and for 6 months after receiving the last dose of study drug

• Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)