Inclusion Criteria:
1. Male or female ≥ 18 years of age.
2. Has a prior history of (h/o) MM (based on International Myeloma Working Group (IMWG)
criteria) and now has evidence of relapsed or refractory MM. RRMM of progressive
disease as defined by the IMWG 2006 and 2016 criteria (Kumar at al).
3. Specific criteria for dose escalation and dose expansion:
1. Phase 1 dose escalation: patients will be required to have TCE RRMM (including a
proteasome inhibitor (PI) (≥ 2 cycles or 2 months of treatment), an
immunomodulatory drug (IMiD)) (≥ 2 cycles or 2 months of treatment) and a CD38
antibody (≥ 2 cycles or 2 months of treatment) after receiving ≥ 3 prior lines of
therapy. Prior BCMA exposure is allowed. (Subjects with discontinued
PI/IMiD/Cluster of differentiation 38 (CD38) therapy due to severe adverse event
after < 2 months are allowed)
2. Dose expansion cohort: RRMM patients will be lenalidomide refractory, TCE
(exposed to IMiD, PI and CD38 antibody therapy (≥ 2 cycles or 2 months of
treatment for each) and have received ≥ 2 prior lines of therapy. Prior BCMA
targeted therapy is allowed, not required. (Subjects with discontinued
PI/IMiD/CD38 therapy due to severe adverse event after < 2 months are allowed.
Lenalidomide refractory is defined as having evidence of progressive disease on
lenalidomide (≥ 10 mg or greater, ≥ 21 days/28) or within 60 days of stopping
lenalidomide therapy.)
4. Has measurable disease defined as at least 1 of the following:
1. Serum M-protein ≥ 0.5 g/dL (dose escalation) and 1.0 g/dL (dose expansion
cohorts)
2. Urine M-protein ≥ 200 mg/24 hours. 3. Serum free light chain (FLC) assay: involved FLC assay ≥ 10 mg/dL (≥ 100 mg/L)
AND an abnormal serum FLC ratio (< 0.26 or > 1.65). (Can be used to fulfill the
inclusion criteria of measurable disease in patients who do not have measurable
disease by M-protein).
5. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Has adequate baseline organ function, as demonstrated by the following:
1. Calculated creatinine clearance > 30 mL/min as assessed by the Cockcroft-Gault
equation, Modification of Diet in Renal Disease (MDRD) equation (National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 2015) or as
assessed by 24-hour urine collection.
2. Serum bilirubin ≤ 1.5 mg/dL, excluding Gilbert's.
3. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × institutional
upper limit normal (ULN).
4. Total serum calcium (corrected for serum albumin) or ionized calcium within
normal limits (WNL) (treatment of hypercalcemia is allowed and patients may
enroll if hypercalcemia returns to WNL with standard treatment).
7. Has adequate baseline hematologic function, as demonstrated by the following:
1. Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L (myeloid growth factors must not
have been administered within 7 days (14 days for extended 1/2-life products).
2. Hemoglobin ≥ 8 g/dL (red blood cell transfusions permitted provided the anemia is
disease-related).
3. Platelet count ≥ 100 x 10^9/L and no platelet transfusions during the 7 days
before first dose (without transfusions). (Dose expansion cohorts will be allowed
to have platelets counts ≥ 75 x 10^9/L with no platelet transfusions during the
prior 7 days).
8. Must have at least 2 negative serum beta-human chorionic gonadotropin (β-hCG)
pregnancy test result obtained prior to initiating therapy. The first test should be
performed within 10-14 days and the second within 24 hours prior to initiating therapy
if the patient is a female of childbearing potential (FCBP; defined as a sexually
mature woman who has not undergone a hysterectomy or bilateral oophorectomy or has not
been naturally postmenopausal for at least 24 consecutive months).
9. Men and women of childbearing potential must agree to not donate sperm and eggs (ova
and oocytes) throughout study therapy and for 3 months after the last treatment.
10. Men and women agree to use acceptable contraceptive methods for the duration of time
on the study, and continue to use acceptable contraceptive methods for 3 months after
the last treatment with study treatment.
1. Women of childbearing potential must agree to 2 methods of reliable birth control
simultaneously while receiving study treatment and until 100 days after last dose
of study treatment: one highly effective form of contraception (tubal ligation,
intrauterine device, hormonal [oral, injectable, transdermal patches, vaginal
rings or implants] or partner's vasectomy, and 1 additional effective
contraceptive method (male latex or synthetic condom, diaphragm or cervical cap).
2. Males must agree to always use a latex or synthetic condom during any sexual
contact with females of reproductive potential.
11. All patients should be encouraged to be fully vaccinated prior to initiation of
therapy including being up-to-date on vaccines against pneumococcus, yearly influenza,
Coronavirus disease (COVID) booster(s), and any age appropriate vaccine. Live
attenuated vaccines are not allowed while on study treatment or within 4 weeks of
starting treatment.
12. Has provided signed informed consent before initiation of any study-specific
procedures or treatment.
13. Must agree to, and be capable of, adhering to the study visit schedule and other
protocol requirements, including follow-up for overall survival.
Exclusion Criteria:
1. Has persistent clinically significant toxicities (grade ≥ 2; per National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0)
from previous anticancer therapy (excluding alopecia which is permitted and excluding
grades 2 and 3 laboratory abnormalities (including hematologic abnormalities) if
participants are not associated with symptoms, are not considered clinically
significant by the investigator, and can be managed with available medical therapies.
2. Has NCI CTCAE grade ≥ 3 peripheral neuropathy from any etiology or grade ≥ 2
peripheral neuropathy with pain.
3. Has received treatment with cytotoxic (alkylators) within 3 weeks, biologic
(IMiDs/PIs) within 2 weeks, targeted therapies (monoclonal antibodies) within 4 weeks,
chimeric antigen receptor (CAR) T-cell (CAR-T)or autologous stem cell transplant
therapy within 3 months or any novel therapy within 5- 1/2 lives of therapy.
4. Has had radiation therapy within 14 days of first dose of study therapy, unless less
than 5% marrow exposure, then no limit.
5. Has had any prior GPRC5D targeted bispecific antibody therapy or GPRC5D CAR-T therapy
or has had previous treatment with Iber.
6. Has any active or uncontrolled infection including any viral, bacterial or fungal
infection; and/or HIV, active hepatitis (Hep) C and active Hep B (hepatitis B (HB)
surface antigen (HBsAg) (+), HB core antigen (HBcAb) (+) or (+) Hep B deoxyribonucleic
acid (DNA) by polymerase chain reaction (pcr), Hep C ribonucleic acid (RNA) (+) by
pcr. Patients who have received Intravenous immunoglobulin therapy (IVIG) replacement
therapy may have (+) HBcAb results from the IVIG therapy. These patients can enroll if
Hep B DNA by pcr test is negative. These patients need to be on antiviral therapy and
be monitored for hepatitis B virus (HBV) DNA throughout study therapy per local
guidelines and as clinically indicated.
7. Has an additional active malignancy that may confound the assessment of the study
endpoints. If the patient has a past cancer history (active malignancy within 2 years
before study entry) with substantial potential for recurrence, this must be discussed
with the sponsor/investigator before study entry. Patients with the following
concomitant neoplastic diagnoses are eligible: nonmelanoma skin cancer and carcinoma
in situ (including transitional cell carcinoma, cervical cancer, anal carcinoma,
ductal carcinoma in situ (DCIS) and melanoma in situ), any cancer resected with
curative intent, low-grade cancer not requiring therapy.
8. Is pregnant or breast feeding.
9. Has clinically significant cardiovascular disease including, albeit not limited to:
1. Uncontrolled or any New York Heart Association Class 3 or 4 congestive heart
failure. 2. Uncontrolled angina, history of myocardial infarction, unstable angina or stroke
within 6 months before study entry. 3. Uncontrolled hypertension or clinically significant arrhythmias not controlled by
medication.
10. Has active POEMS (polyneuropathy, organomegaly, endocrinopathy/edema,
monoclonal-protein, skin syndrome), amyloid light (AL) amyloidosis, primary plasma
cell leukemia or active central nervous system (CNS) or parenchymal/leptomeningeal
myeloma.
11. Has uncontrolled, clinically significant organ dysfunction that in the opinion of the
investigator would put the patient at significant risk for toxicity from study
therapy.
12. Has recent major surgery within 4 weeks or significant gastrointestinal (GI) disease
that would interfere with GI absorption of oral medications.
13. Has a condition, including autoimmune disease, requiring systemic treatment with
either corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days before study therapy administration.
Inhaled or topical steroids and adrenal replacement doses <10 mg daily prednisone
equivalents are permitted in the absence of active autoimmune disease.
14. Has received treatment with allogeneic stem cell transplant within 6 months before the
first dose of study treatment and if > 6 months from allogeneic stem cell
transplantation (alloSCT) must be off all immunosuppression and without evidence of
active graft-versus-host disease (GVHD).
15. Uncontrolled epilepsy or new/recent seizure activity within 6 months of study entry.
16. Live vaccine administered within 4 weeks prior to study therapy.