Daratumumab and Dexamethasone With Pomalidomide or Carfilzomib in Treating Patients With Relapsed Multiple Myeloma

PRIMARY OBJECTIVES:

I. To determine the overall response rate (partial response [PR], very good partial response
[VGPR], complete response [CR], or stringent complete response [sCR]) of daratumumab
retreatment in combination with either pomalidomide and dexamethasone (DPd) (Arm A) or
carfilzomib and dexamethasone (DKd) (Arm B) in patients with relapsed refractory multiple
myeloma.

SECONDARY OBJECTIVES:

I. To assess progression free survival and overall survival associated with retreatment with
daratumumab in combination with either pomalidomide and dexamethasone (DPd) or carfilzomib
and dexamethasone (DKd) in patients with relapsed and refractory multiple myeloma.

II. To determine the toxicities associated with retreatment with daratumumab in combination
with either pomalidomide and dexamethasone (DPd) or carfilzomib and dexamethasone (DKd) in
patients with relapsed and refractory multiple myeloma.

III. To assess the overall response rate (PR, VGPR, CR, and sCR) of crossover treatment in
each arm.

CORRELATIVE OBJECTIVES:

I. To examine the proportion of minimal residual disease (MRD) negativity, and changes in
clonal population and CD38 expression on plasma cells following retreatment with daratumumab
in combination with either pomalidomide and dexamethasone (DPd) or carfilzomib and
dexamethasone (DKd) in patients with relapsed and refractory multiple myeloma.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive pomalidomide orally (PO) on days 1-21 and dexamethasone PO on days 1,
8, 15, and 22. Patients also receive daratumumab intravenously (IV) on days 1, 8, 15, and 22
of cycles 1 and 2, on days 1 and 15 of cycles 3-6, and on day 1 of subsequent cycles.
Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or
unacceptable toxicity. Patients whose disease progresses at any time or fails to achieve a
minimal response (MR) after 3 cycles may receive treatment as in Arm B.

ARM B: Patients receive carfilzomib IV over 30 minutes on days 1, 8, and 15 and dexamethasone
PO on days 1, 8, 15, and 22 of cycles 1-12. Patients also receive daratumumab IV on days 1,
8, 15, and 22 on cycles 1 and 2, on days 1 and 15 of cycles 3-6, and on day 1 of subsequent
cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable
toxicity. Patients also receive dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats
every 28 days for up to 12 cycles in the absence of disease progression or unacceptable
toxicity. Patients whose disease progresses at any time or fails to achieve a MR after 3
cycles may receive treatment as in Arm A.

After completion of study treatment, patients are followed up for every 3 months until
subsequent treatment or progressive disease, then every 6 months for up to 3 years.

Inclusion Criteria:

- Calculated creatinine clearance (using Cockcroft-Gault equation) >=30 mL/min (obtained
=< 14 days prior to registration)

- Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 14 days prior to
registration)

- Untransfused platelet count >= 75,000/mm^3 (obtained =< 14 days prior to registration)

- Hemoglobin >= 8.0 g/dL (obtained =< 14 days prior to registration)

- Total bilirubin =< 1.5 x upper limit of normal (ULN) (except for patients with
Gilbert?s syndrome) (obtained =< 14 days prior to registration)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
(obtained =< 14 days prior to registration)

- Measurable disease of multiple myeloma as defined by at least ONE of the following:

- Serum monoclonal protein >= 1.0 g/dL

- >= 200 mg of monoclonal protein in the urine on 24 hour electrophoresis

- Serum immunoglobulin free light chain >= 10 mg/dL AND abnormal serum
immunoglobulin kappa to lambda free light chain ratio

- Bone marrow >= 30% plasma cells

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

- Relapsed multiple myeloma (MM) requiring treatment who have previously received a
daratumumab alone or in a daratumumab containing combination and

- Had at least a partial response to therapy, and had disease progression on or
within 60 days of discontinuation

- At least 3 months should have elapsed since last exposure to daratumumab

- Patients must have been previously exposed to both a proteasome inhibitor and an
immunomodulatory imide drug (IMiD)

- Examples of proteasome inhibitors:

- Bortezomib, carfilzomib, ixazomib, marizomib, oprozomib

- Examples of IMiD?s:

- Thalidomide, lenalidomide, pomalidomide

- Negative pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only

- Willing to follow strict birth control measures

- Female patients: If they are of childbearing potential, agree to one of the
following:

- Practice 2 effective methods of contraception, at the same time, from the
time of signing the informed consent form through 90 days after the last
dose of study drug, AND must also adhere to the guidelines of any
treatment-specific pregnancy prevention program, if applicable, OR

- Agree to practice true abstinence when this is in line with the preferred
and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar,
ovulation, symptothermal, post-ovulation methods] and withdrawal are not
acceptable methods of contraception.)

- Male patients: even if surgically sterilized (i.e., status post-vasectomy), must
agree to one of the following:

- Agree to practice effective barrier contraception during the entire study
treatment period and through 90 days after the last dose of study drug, OR

- Must also adhere to the guidelines of any treatment-specific pregnancy
prevention program, if applicable, OR lifestyle of the subject. (Periodic
abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods]
and withdrawal are not acceptable methods of contraception.)

- Willing to follow the requirements of the Pomalyst Risk Evaluation and Mitigation
Strategy (REMS) program

- Willing to provide bone marrow and blood samples for planned research

- OPTIONAL CROSSOVER PHASE: ANC >= 1000/UL

- OPTIONAL CROSSOVER PHASE: Platelets >= 75,000/UL

- OPTIONAL CROSSOVER PHASE: Serum creatinine =< 2.0 mg/dL OR

- OPTIONAL CROSSOVER PHASE: Calculated (Calc.) creatinine clearance >= 40 mL/min by
Cockcroft-Gault

- OPTIONAL CROSSOVER PHASE: AST, ALT =< 2 x ULN

- OPTIONAL CROSSOVER PHASE: Total bilirubin =< 1.5 x ULN (except for patients with
Gilbert?s syndrome)

Exclusion Criteria:

- Refractory to both carfilzomib and pomalidomide

- Concurrent amyloid light chain (AL) amyloidosis with organ involvement

- Diagnosed or treated for another malignancy =< 2 years prior to registration or
previously diagnosed with another malignancy and have any evidence of residual
disease. NOTE: Patients with nonmelanoma skin cancer or carcinoma in situ of any type
are not excluded if they have undergone complete resection

- Any of the following because this study involves an investigational agent, whose
genotoxic, mutagenic and teratogenic effects, on the developing fetus and newborn are
unknown:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Other concurrent chemotherapy, or any ancillary therapy considered investigational.
NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and
are thus allowed while on protocol treatment

- Major surgery =< 14 days prior to registration

- Evidence of current uncontrolled cardiovascular conditions, including hypertension,
cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial
infarction =< 6 months. Note: Prior to entry, any electrocardiogram (ECG) abnormality
at screening must be documented by the investigator as not medically relevant

- Known human immunodeficiency virus (HIV) positive

- Known hepatitis B surface antigen-positive status, or known or suspected active
hepatitis C infection

- Any serious medical or psychiatric illness that could, in the investigator?s opinion,
potentially interfere with the completion of treatment according to this protocol

- Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal
antibodies or human proteins, or their excipients (refer to respective package inserts
or investigator's brochure) or known sensitivity to mammalian-derived products

- Known chronic obstructive pulmonary disease with a forced expiratory volume in 1
second (FEV1) < 50% of predicted normal

- Known moderate or severe persistent asthma within the past 2 years or currently has
uncontrolled asthma of any classification

- Total bilirubin =< 1.5 x ULN (except for patients with Gilbert?s syndrome)