A Phase 2 Study of Daratumumab Subcutaneous (Dara-SC) Administration in Combination with Carfilzomib and Dexamethasone (DKd) Compared with Carfilzomib and Dexamethasone (Kd) in Participants with Multiple Myeloma who have been Previously Treated with Daratumumab to Evaluate Daratumumab Retreatment

Each potential participant must satisfy all of the following criteria to be
enrolled in the study:
1. At least 18 years of age.
2. Documented multiple myeloma as defined by the criteria below: Measurable
disease at screening as defined by any of the following: Serum M-protein level
>=1.0 g/dL in participants with immunoglobulin G (IgG) type, or serum M-protein
level >=0.5 g/dL in participants with non- IgG type, or urine M-protein level
>=200 mg/24 hours; or Light chain multiple myeloma without measurable disease in
the serum or the urine: Serum immunoglobulin free light chain (FLC) >=10 mg/dL
and abnormal serum immunoglobulin kappa lambda FLC ratio.
3. Evidence of a response (partial response or better based on investigator*s
determination of response by IMWG criteria) to daratumumab-containing therapy
with response duration of at least 4 months.
4. Relapsed or refractory disease as defined below: Relapsed disease is defined
as an initial response to previous treatment, followed by confirmed PD by IMWG
criteria >60 days after cessation of treatment. Refractory disease is defined
as <25% reduction in M-protein or confirmed PD by IMWG criteria during previous
treatment or <=60 days after cessation of treatment.
5. Received 1 to 3 prior line(s) of treatment of which one contained
Daratumumab and completed Daratumumab at least 3 months prior to randomization.
A single line of therapy may consist of 1 or more agents, and may include
induction, hematopoietic stem cell transplantation, and maintenance therapy.
Radiotherapy, bisphosphonate, or a single short course of corticosteroids (no
more than the equivalent of dexamethasone 40 mg/day for 4 days) would not be
considered prior lines of therapy.
6. ECOG Performance Status score of 0, 1, or 2.
7. Pretreatment clinical laboratory values meeting the following criteria
during the Screening Phase:
a) hemoglobin >=8 g/dL (>=5mmol/L) (without prior RBC transfusion within 7 days
before the laboratory test; recombinant human erythropoietin use is permitted);
b) absolute neutrophil count (ANC) >=1.0 × 10^9/L (prior growth factor support
is permitted but must be without support within the 7 days prior to the
laboratory test);
c) platelet count >=75 ×10^9/L for participants in whom <50% of bone marrow
nucleated cells are plasma cells; otherwise platelet count of >=50×10^9/L.
Transfusions are not permitted within 7 days of testing to achieve this minimum
platelet count.
d) aspartate aminotransferase (AST) <=2.5 × upper limit of normal (ULN);
e) alanine aminotransferase (ALT) <=2.5 × ULN;
f) total bilirubin <=1.5 × ULN; except in participants with congenital
bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin <=1.5×
ULN is required);
g) estimated creatinine clearance (CrCl) >=20mL/min per 1.73m^2. CrCl to be
calculated using estimated glomerular filtration rate Modification of Diet in
Renal Disease (MDRD) formula.
h) albumin-corrected serum calcium <=14 mg/dL (<=3.5 mmol/L) or free ionized
calcium <=6.5 mg/dL (<=1.6mmol/L)
8. Women of childbearing potential must commit to either abstain continuously
from heterosexual sexual intercourse or to use 2 methods of reliable birth
control simultaneously. This includes one highly effective form of
contraception (tubal ligation, intrauterine device, hormonal [birth control
pills, injections, hormonal patches, vaginal rings or implants] or partner's
vasectomy) and one additional effective contraceptive method (male latex or
synthetic condom, diaphragm, or cervical cap). Contraception must begin 4 weeks
prior to dosing. Reliable contraception is indicated even where there has been
a history of infertility, unless due to hysterectomy.
9. Women of childbearing potential must have a negative urine or serum
pregnancy test at screening within 14 days prior to randomization.
10. Each participant must sign an informed consent form (ICF) (or their legally
acceptable representative must sign) indicating that he or she understands the
purpose of, and procedures required for, the study and is willing to
participate in the study. Participants must be willing and able to adhere to
the prohibitions and restrictions specified in this protocol, as referenced in
the ICF





*

Any potential participant who meets any of the following criteria will be
excluded from participating in the study:

2. Previous treatment with carfilzomib.
3. Previous treatment with daratumumab within the last 3 months prior to
randomization.
4. Discontinuation of Daratumumab due to a daratumumab-related AE.
5. History of malignancy (other than multiple myeloma) unless all treatment of
that malignancy was completed at least 2 years before consent and the patient
has no evidence of disease. Further exceptions are squamous and basal cell
carcinomas of the skin and carcinoma in situ of the cervix, or breast, or other
non-invasive lesion, that in the opinion of the investigator, with concurrence
with the sponsor's medical monitor, is considered cured with minimal risk of
recurrence within 3 years.
6. Allergies, hypersensitivity, or intolerance to daratumumab, hyaluronidase,
mAbs, human proteins, or their excipients (refer to the IB), or known
sensitivity to mammalian derived products. Known history of allergy to Captisol
(a cyclodextrin derivative used to solubilize carfilzomib).
7. Contraindications to the use of any components of the backbone treatment
regimens, per local prescribing information.
8. Received an investigational intervention (including investigational
vaccines) or used an invasive investigational medical device within 4 weeks
before randomization (except for investigational anti-myeloma treatments, which
cannot be taken within 2 weeks or 5PK half-lives of the treatment from the
first dose of daratumumab, whichever is longer, before the date of
randomization).
9. Pregnant, or breast-feeding, or planning to become pregnant while enrolled
in this study or within 3 months after the last dose of study intervention.
10. Plans to father a child while enrolled in this study or within 3 months
after the last dose of study intervention.
11. Any condition for which, in the opinion of the investigator, participation
would not be in the best interest of the participant (eg, compromise the
well-being) or that could prevent, limit, or confound the protocol-specified
assessments.
12. Received anti-myeloma treatment within 2 weeks or 5 PK half-lives of the
treatment from the first dose of daratumumab, whichever is longer, before the
date of randomization. The only exception is emergency use of a short course of
corticosteroids (equivalent of dexamethasone 40 mg/day for a maximum of 4 days)
up to 21 days before treatment. A list of anti-myeloma treatments with the
corresponding PK half-lives is provided in the Site Investigational Product
Procedures Manual.
13. Received autologous stem cell transplant within 12 weeks before the date of
randomization, or the participant has previously received allogeneic stem cell
transplant (regardless of timing).
14. Plans to undergo a stem cell transplant prior to progression of disease on
this study.
15. Focal radiation therapy within 14 days prior to randomization with the
exception of palliative radiotherapy for symptomatic management but not on
measurable extramedullary plasmacytoma. Radiotherapy within 14 days prior to
randomization on measurable extramedullary plasmacytoma is not permitted even
in the setting of palliation for symptomatic management.
16. Clinical signs of meningeal involvement of multiple myeloma.
17. Either of the following:
a) Known chronic obstructive pulmonary disease (COPD) with a forced expiratory
volume in 1 second (FEV1) is <50% of predicted normal. Note that FEV1
testing also is required for participants suspected of having COPD and
participants must be excluded if FEV1 is <50% of predicted normal.
b) Known moderate or severe persistent asthma, or a history of asthma within
the last 2 years, or currently has uncontrolled asthma of any classification.
(Participants who currently have controlled intermittent asthma or controlled
mild persistent asthma are allowed to participate in the study.)
18. Participant is:
a) known to be seropositive for human immunodeficiency virus (HIV), with 1 or
more of the following:
i. Not receiving highly active antiretroviral therapy (ART)
ii. Had a change in ART within 6 months of the start of screening
iii. Receiving ART that may interfere with study treatment (consult Sponsor for
review of medication prior to enrollment)
iv. CD4 count <350 at screening
v. Acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection
within 6 months of start of screening
vi. Not agreeing to start ART and be on ART >4 weeks plus having HIV viral load
<400 copies/mL at end of 4-week period (to ensure
ART is tolerated and HIV controlled)
b) seropositive for hepatitis B (defined by a positive test for hepatitis B
surface antigen [HBsAg]). Participants with resolved infection (ie,
participants who are HBsAg negative but positive for antibodies to hepatitis B
core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-
HBs]) must be screened using real-time polymerase chain reaction (PCR)
measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive
will be excluded. EXCEPTION: Participants with serologic findings suggestive of
HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known
history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR
(See Appendix 16).
c) known to be seropositive for hepatitis C (except in the setting of a
sustained virologic response [SVR], defined as aviremia at least 12 weeks after
completion of antiviral therapy).
19. Concurrent medical or psychiatric condition or disease (eg, active systemic
infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease,
pulmonary hypertension) that is likely to interfere with study procedures or
results, or that in the opinion of the investigator would constitute a hazard
for participating in this study.
20. Uncontrolled hypertension, defined as an average systolic blood pressure
>159mmHg or diastolic >99 mmHg despite optimal treatment (measured following
European Society of Hypertension/European Society of Cardiology 2013
guidelines).
21. Clinically significant cardiac disease, including:
Myocardial infarction within 6 months before date of randomization, or unstable
or uncontrolled disease/condition related to or affecting cardiac function (eg,
unstable angina, congestive heart failure, New York Heart Association Class
III-IV; Appendix 12).
Uncontrolled cardiac arrhythmia (Grade 2 or higher by National Cancer Institute
Common Terminology Criteria for Adverse Events [NCI-CTCAE] Version 4.03) or
clinically significant electrocardiogram (ECG) abnormalities.
Transthoracic echocardiogram or MUGA scan showing left ventricular ejection
fraction <40%.
22. Gastrointestinal disease that may significantly alter the absorption of
oral drugs.
23. Myelodysplastic syndrome, plasma cell leukemia (>2.0 × 109/L circulating
plasma cells by standard differential) or Waldenström's macroglobulinemia or
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, and
skin changes) or amyloidosis.
24. Not able to comply with the study protocol (eg, because of alcoholism, drug
dependency, or psychological disorder) or the participant has any condition for
which, in the opinion of the investigator, participation would not be in the
best interest of the participant (eg, compromise their well-being) or that
could prevent, limit, or confound the protocol-specified assessments.
25. Major surgery within 2 weeks before randomization, or has not fully
recovered from an earlier surgery, or has major surgery planned during the time
the participant is expected to participate in the study or within 2 weeks after
the last dose of study intervention administration. Kyphoplasty or
vertebroplasty are not considered major surgery. Note: participants with
planned surgical procedures to be conducted under local anesthesia may
participate. If there i