Daratumumab, Bortezomib, and Dexamethasone With or Without Venetoclax in Treating Patients With Relapsed or Refractory Multiple Myeloma

PRIMARY OBJECTIVES:

I. To determine the dose limiting toxicities and the recommended phase II dose of venetoclax
in combination with daratumumab, bortezomib, and dexamethasone for patients with
relapsed/refractory multiple myeloma. (Phase I) II. To evaluate the safety of venetoclax
(VEN) in combination with bortezomib and dexamethasone (DVd). (Phase I) III. To compare
efficacy of DVd-VEN versus DVd as measured by minimal residual disease negative rate after 8
cycles of therapy. (Phase II) IV. To inform the role of t(11;14) as a biomarker in a
subsequent evaluation of the regimen. (Phase II)

SECONDARY OBJECTIVES:

I. To compare rates of very good partial response between arms. II. To assess improvement in
progression-free and overall survival with the addition of VEN.

III. To evaluate the safety of VEN in combination with DVd and compare overall toxicity rates
between arms.

IV. To assess association of cycle 8 minimal residual disease (MRD) status with overall and
progression-free survival.

V. To estimate the impact of t(11;14) status on very good partial response, overall and
progression-free survival.

EXPLORATORY OBJECTIVES:

I. To measure treatment exposure and adherence. II. To estimate time to progression with the
addition of VEN. III. To measure MRD levels longitudinally and assess the kinetics of
relapse. IV. To assess association of MRD status after 8 cycles with survival outcomes. V. To
evaluate agreement and discordance between methods determining disease-free status.

OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II study.

PHASE I:

Patients receive daratumumab intravenously (IV) on days 1, 8, and 15 of cycles 1-3 and on day
1 of subsequent cycles, bortezomib subcutaneously (SC) on days 1, 8, and 15 of cycles 1-8,
dexamethasone orally (PO) on days 1, 8, and 15 of cycles 1-8, and venetoclax PO once daily
(QD) on days 1-21. Cycles repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 arms.

ARM D: Patients receive venetoclax PO QD on days 1-21, daratumumab IV on days 1, 8, and 15 of
cycles 1-3 and on day 1 of subsequent cycles, bortezomib SC on days 1, 8, and 15 of cycles
1-8, and dexamethasone PO on days 1, 8, and 15 of cycles 1-8. Cycles repeat every 21 days in
the absence of disease progression or unacceptable toxicity.

ARM E: Patients receive daratumumab IV on days 1, 8, and 15 of cycles 1-3 and on day 1 of
subsequent cycles, bortezomib SC on days 1, 8, and 15 of cycles 1-8, and dexamethasone PO on
days 1, 8, and 15 of cycles 1-8. Cycles repeat every 21 days in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for 10 years.

Inclusion Criteria:

- PHASE I (ARMS A, B, C) - STEP 1: Eastern Cooperative Oncology Group (ECOG) performance
status of 0-2.

- PHASE I (ARMS A, B, C) - STEP 1: Patients must have been diagnosed with symptomatic
relapsed/refractory multiple myeloma.

- NOTE: Relapsed/refractory myeloma is defined as a disease which becomes
non-responsive or progressive on therapy or within 60 days of the last treatment
in patients who had achieved a minimal response (MR) or better on prior therapy.

- PHASE I (ARMS A, B, C) - STEP 1: t(11;14) status must be determined.

- PHASE I (ARMS A, B, C) - STEP 1: Patients must not have bortezomib refractory disease.
Prior lenalidomide refractory patients are allowed.

- PHASE I (ARMS A, B, C) - STEP 1: Patients must have been treated with 1 or more lines
of therapy. 1 prior line of systemic therapy is defined as 1 or more planned cycles of
single agent or combination therapy, as well as a planned series of treatment regimens
administered in a sequential manner (e.g. lenalidomide, bortezomib and dexamethasone
induction therapy for 4 cycles followed by autologous stem cell transplantation and
then lenalidomide maintenance therapy would be considered 1 line of prior therapy).
Auto stem cell transplant is allowed provided the patient is 100 days out from stem
cell infusion. Patients must not have had prior venetoclax. Allogeneic stem cell
transplantation (SCT) patients are excluded.

- PHASE I (ARMS A, B, C) - STEP 1: Patients must have measurable disease as defined by
having one or more of the following, obtained within 14 days prior to randomization:

- >= 0.5 g/dL monoclonal protein (M-protein) on serum protein electrophoresis.

- >= 200 mg/24 hrs of monoclonal protein (M-protein) on a 24 hour urine protein
electrophoresis.

- Involved free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to
lambda free light chain ratio (< 0.26 or > 1.65).

- PHASE I (ARMS A, B, C) - STEP 1: Serum protein electrophoresis (SPEP), urine protein
electrophoresis (UPEP), and serum free light chain (FLC) assay are required to be
performed within 14 days prior to randomization.

- NOTE: UPEP (on a 24 hour collection) is required, no substitute method is
acceptable. Urine must be followed monthly if the baseline urine M-spike is >=
200 mg/24 hr and urine in addition to serum must be followed in order to confirm
a very good partial response (VGPR) or higher response.

- NOTE: The serum free light chain test is required to be done if the patient does
not have measurable disease in the serum or urine. Measurable disease in the
serum is defined as having a serum M-spike >= 1 g/dL. Measurable disease in the
urine is defined as having a urine M-spike >= 200mg/24 hr.

- PHASE I (ARMS A, B, C) - STEP 1: Platelet count >= 100,000 cells/mm^3 (within 14 days
prior to randomization).

- PHASE I (ARMS A, B, C) - STEP 1: Absolute neutrophil count >= 1000 cells/mm^3 (within
14 days prior to randomization).

- PHASE I (ARMS A, B, C) - STEP 1: Aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) =< 2.5 x the upper limit of normal (within 14 days prior to
randomization).

- PHASE I (ARMS A, B, C) - STEP 1: Total bilirubin =< 1.5 x the upper limit of normal
(within 14 days prior to randomization).

- PHASE I (ARMS A, B, C) - STEP 1: Calculated creatinine clearance >= 30 mL/min (within
14 days prior to randomization).

- PHASE I (ARMS A, B, C) - STEP 1: Hemoglobin >= 8.0 g/dL (within 14 days prior to
randomization).

- PHASE I (ARMS A, B, C) - STEP 1: Women must not be pregnant or breast-feeding due to
risk of fetal harm by the chemotherapeutic agents prescribed in this protocol. All
females of childbearing potential must have a blood test or urine study within 7 days
prior to registration to rule out pregnancy. A female of childbearing potential is any
woman, regardless of sexual orientation or whether they have undergone tubal ligation,
who meets the following criteria: 1) has achieved menarche at some point, 2) has not
undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing
potential) for at least 24 consecutive months (i.e., has had menses at any time in the
preceding 24 consecutive months).

- PHASE I (ARMS A, B, C) - STEP 1: Women of childbearing potential and sexually active
males must use an accepted and highly effective method(s) of contraception or abstain
from sexual intercourse for the duration of their participation in the study and for 3
months after the last dose of daratumumab or 30 days after the last dose of
venetoclax, whichever is longer. Male patients must also agree not to donate sperm for
the duration of their participation in the study for 3 months after the last dose of
daratumumab or 30 days after the last dose of venetoclax whichever is longer.

- PHASE I (ARMS A, B, C) - STEP 1: Patients must not have > grade 2 neuropathy and/or a
syndrome characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal
gammopathy, and skin change (POEMS).

- PHASE I (ARMS A, B, C) - STEP 1: Patients must not have New York Heart Association
(NYHA) class III or IV heart failure or myocardial infarction within 6 months prior to
registration.

- PHASE I (ARMS A, B, C) - STEP 1: Patients must avoid concomitant use of venetoclax
with moderate or strong CYP3A inhibitors, strong or moderate CYP3A inducers,
P-glycoprotein (P-gp) inhibitors, or narrow therapeutic index P-gp substrates.

- PHASE II (ARMS D, E) - STEP 1: ECOG performance status of 0-2.

- PHASE II (ARMS D, E) - STEP 1: Patients must have been diagnosed with symptomatic
relapsed/refractory multiple myeloma.

- NOTE: Relapsed/refractory myeloma is defined as a disease which becomes
non-responsive or progressive on therapy or within 60 days of the last treatment
in patients who had achieved a minimal response (MR) or better on prior therapy.

- PHASE II (ARMS D, E) - STEP 1: t(11;14) status must be determined.

- PHASE II (ARMS D, E) - STEP 1: Patients must not have bortezomib refractory disease.
Prior lenalidomide refractory patients are allowed.

- PHASE II (ARMS D, E) - STEP 1: Patients must have been treated with 1 or more lines of
therapy. 1 prior line of systemic therapy is defined as 1 or more planned cycles of
single agent or combination therapy, as well as a planned series of treatment regimens
administered in a sequential manner (e.g. lenalidomide, bortezomib and dexamethasone
induction therapy for 4 cycles followed by autologous stem cell transplantation and
then lenalidomide maintenance therapy would be considered 1 line of prior therapy).
Auto stem cell transplant is allowed provided the patient is 100 days out from stem
cell infusion. Patients must not have had prior venetoclax. Allogeneic SCT patients
are excluded.

- PHASE II (ARMS D, E) - STEP 1: Patients must have measurable disease as defined by
having one or more of the following, obtained within 14 days prior to randomization:

- >= 0.5 g/dL monoclonal protein (M-protein) on serum protein electrophoresis.

- >= 200 mg/24 hours (hrs) of monoclonal protein (M-protein) on a 24 hour urine
protein electrophoresis.

- Involved free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to
lambda free light chain ratio (< 0.26 or > 1.65).

- PHASE II (ARMS D, E) - STEP 1: SPEP, UPEP, and serum FLC assay are required to be
performed within 14 days prior to randomization.

- UPEP (on a 24 hour collection) is required, no substitute method is acceptable.
Urine must be followed monthly if the baseline urine M-spike is >= 200 mg/24 hr.
Please note that if both serum and urine m-components are present, both must be
followed in order to evaluate response.

- PHASE II (ARMS D, E) - STEP 1: Platelet count >= 100,000 cells/mm^3 (within 14 days
prior to randomization).

- PHASE II (ARMS D, E) - STEP 1: Absolute neutrophil count >= 1000 cells/mm^3 (within 14
days prior to randomization).

- PHASE II (ARMS D, E) - STEP 1: AST and ALT =< 2.5 x the upper limit of normal (within
14 days prior to randomization).

- PHASE II (ARMS D, E) - STEP 1: Total bilirubin =< 1.5 x the upper limit of normal
(within 14 days prior to randomization).

- PHASE II (ARMS D, E) - STEP 1: Calculated creatinine clearance >= 30 mL/min (within 14
days prior to randomization).

- PHASE II (ARMS D, E) - STEP 1: Hemoglobin >= 8.0 g/dL (within 14 days prior to
randomization).

- PHASE II (ARMS D, E) - STEP 1: Women must not be pregnant or breast-feeding due to
risk of fetal harm by the chemotherapeutic agents prescribed in this protocol. All
females of childbearing potential must have a blood test or urine study within 7 days
prior to registration to rule out pregnancy. A female of childbearing potential is any
woman, regardless of sexual orientation or whether they have undergone tubal ligation,
who meets the following criteria: 1) has achieved menarche at some point, 2) has not
undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally
postmenopausal (amenorrhea following cancer therapy does not rule out childbearing
potential) for at least 24 consecutive months (i.e., has had menses at any time in the
preceding 24 consecutive months).

- PHASE II (ARMS D, E) - STEP 1: Women of childbearing potential and sexually active
males must use an accepted and highly effective method(s) of contraception or abstain
from sexual intercourse for the duration of their participation in the study and for 3
months after the last dose of daratumumab or 30 days after the last dose of
venetoclax, whichever is longer. Male patients must also agree not to donate sperm for
the duration of their participation in the study for 3 months after the last dose of
daratumumab or 30 days after the last dose of venetoclax, whichever is longer.

- PHASE II (ARMS D, E) - STEP 1: Patients must not have > grade 2 neuropathy and/or
POEMS.

- PHASE II (ARMS D, E) - STEP 1: Patients must not have NYHA Class III or IV heart
failure or myocardial infarction within 6 months prior to registration.

- PHASE II (ARMS D, E) - STEP 1: Patients must avoid concomitant use of venetoclax with
moderate or strong CYP3A inhibitors, strong or moderate CYP3A inducers, P-gp
inhibitors, or narrow therapeutic index P-gp substrates.