Measurable Residual Disease-Guided Post-Transplant Elranatamab Maintenance

Criteria for Pre-Screening Blood Draw

* Newly diagnosed multiple myeloma (either untreated or receiving first line therapy).
* Potentially eligible for autologous hematopoietic cell transplant (with or without tandem transplant) for frontline therapy.

Inclusion Criteria:

* At least 18 years of age
* Ability to understand and willingness to sign an IRB approved written informed consent document. (Legally authorized representatives may sign and give informed consent on behalf of study participants.)
* Received autologous hematopoietic cell transplantation (with or without tandem transplant) as part of frontline therapy for newly diagnosed IgG or IgA multiple myeloma. Frontline therapy in this setting is defined as treatment received prior to first relapse and may include multiple lines of therapy per the Rajkumar et al definition if treatment changes were made for either toxicity or inadequate response to initial induction.
* Received frontline treatment with at least a triplet regimen including a PI and an IMID (+/- an anti-CD38 antibody)
* Disease response of ≥ partial response (PR) by IMWG criteria at time of study screening (post-transplant).
* MRD-positive on Day 100 landmark assessment (80 to 160 days after AHCT), defined as \>1 x 10-5 myeloma cells/cell by clonoSEQ assay (Adaptive Biotechnologies, Seattle, WA) performed on bone marrow aspirate.
* ECOG performance status ≤ 2
* All toxicities from prior treatment should have resolved to Grade ≤ 1 prior to enrollment.
* Adequate bone marrow and organ function within 28 days prior to start of treatment as defined below:

  * Platelets ≥ 75 k/cumm
  * Absolute neutrophil count ≥ 1.0 k/cumm
  * Hemoglobin ≥ 8 g/dL without the use of growth factors or transfusion for at least 2 weeks.
  * Total bilirubin ≤ 2 × upper limit of normal (ULN; ≤ 3 x ULN if documented Gilbert's syndrome)
  * Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 × ULN
  * Creatinine clearance ≥ 30 ml/min.
* The effects of elranatamab on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 5 months after end of treatment. Should a woman become pregnant or suspect she is pregnant while participating in this study, or should a man suspect he has fathered a child, s/he must inform her treating physician immediately.

Exclusion Criteria:

* Inability to identify a trackable clonoSEQ ID.
* A history of other malignancy with the exception of non-melanoma skin cancers, low or very low risk prostate cancer by NCCN criteria status post definitive therapy or currently on active surveillance, and malignancies for which all treatment was completed at least 2 years before registration and the patient has no evidence of disease. Adjuvant endocrine therapy for hormone receptor-positive breast cancer is not exclusionary.
* Currently receiving any other investigational agents.
* Prior BCMA-based treatment.
* CNS involvement of disease.
* A history of allergic reactions attributed to compounds of similar chemical or biologic composition to elranatamab or other agents used in the study.
* Uncontrolled intercurrent illness including, but not limited to, plasma cell leukemia, POEMS syndrome, systemic amyloidosis, ongoing or active infection (bacterial, fungal, or viral).
* Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 28 days prior to first dose of elranatamab.
* HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.