Inclusion Criteria:
1. Able and willing to sign the informed consent form and comply with the protocol and the restrictions and assessments therein.
2. ≥ 18 years of age.
3. Active relapsed or refractory multiple myeloma with at least 3 prior lines of therapy, OR ineligible for or did not tolerate standard approved treatment and have no available therapies open to them.
1. For Dose Escalation Phase: No prior T-cell engager therapies. No prior BCMA targeting antibody-drug conjugate (ADC) therapy. CAR-T therapy received ≥2 years prior to study enrollment is permitted.
2. For Expansion Phase: T cell engagers therapies and anti-BCMA ADC \> 6 months prior, and CAR-T therapy received \> 9 months prior to study enrollment is permitted.
4. Measurable disease as defined by RECIST.
5. ECOG Performance Status (PS) 0 or 1.
6. Life expectancy ≥12 weeks.
7. For those who received prior autologous stem cell transplant, they must be at least 100 days post-transplant, prior to registration and have recovered from side-effects of stem cell transplant.
8. For those who received prior allogeneic stem cell transplant or donor lymphocyte infusion, they must be at least 100 days post-transplant prior to registration with no signs of acute or chronic graft-versus-host disease.
Exclusion Criteria:
1. Has monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or AL amyloidosis. Has Waldenstrom macroglobulinemia, primary amyloid light chains (AL) amyloidosis, primary plasma cell leukemia, or polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin abnormalities (POEMS) syndrome. Patients with secondary plasma cell leukemia or extramedullary myeloma disease are permitted.
2. Failed to recover from acute, reversible effects of prior therapy regardless of interval since last treatment.
EXCEPTION: Grade 1 peripheral (sensory) neuropathy that has been stable for at least 1 month since completion of prior treatment.
3. Any of the following because this study involves an integrating lentiviral vector.
* Pregnant
* Nursing
* Women of childbearing potential (and persons able to father a child) who are unwilling to employ adequate contraception
4. Known hypersensitivity to VV169 or any of its excipients.
5. Has active (untreated or relapsed) CNS involvement of multiple myeloma.
6. Major surgery ≤ 28 days prior to registration.
7. Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
8. Acute DVT or pulmonary embolism diagnosed within 3 months of registration.
9. Immunocompromised patients and patients known to be HIV positive (current and previous, as HIV antiretroviral therapy is expected to interfere with the lentiviral delivery mechanism of VV169).
10. Has significant and symptomatic cardiovascular disease (such as congestive heart failure New York Heart Association class III or higher, myocardial infarction, cerebrovascular disease, unstable angina, unstable arrhythmia) within the 3 months prior to study drug.
11. Has another malignant disease requiring treatment, with the exception of curatively treated in-situ or Stage I malignancies or malignancies with very low potential for recurrence or progression.
12. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
13. Known active infection with hepatitis B or hepatitis C, defined by a detectable viral load. Note: Testing is not required for eligibility.
