Relapsed or Refractory Multiple Myeloma

The primary objective is to compare the efficacy of daratumumab when combined with VELCADE® and dexamethasone (DVd) to that of VELCADE and dexamethasone (Vd), in terms of progression-free survival (PFS) in Chinese subjects with relapsed or refractory MM.

Daratumumab

Daratumumab

intravenous infusion
subcutaneous

100
1800

Primary Endpoints
The primary endpoint is PFS, which is defined as the duration from the date of randomization to
either progressive disease, according to the IMWG criteria15,46 or death, whichever occurs first.
Secondary Endpoints
The secondary efficacy endpoints include:
 Time to disease progression, defined as the time from the date of randomization to the date of
first documented evidence of PD, as defined in the IMWG criteria.
 Overall response rate, defined as the proportion of subjects who achieve PR or better rate
according to the IMWG criteria, during or after the study treatment.
 VGPR or better rate, defined as the proportion of subjects achieving VGPR or CR rate (including
sCR) according to the IMWG criteria during or after the study treatment at the time of data
cut-off. Subjects who meet all other criteria for CR or sCR, with demonstrated daratumumab
interference on serum immunofixation assay (IFE), will be considered complete responders.
 Time to response, defined as the time between the date of randomization and the first efficacy
evaluation that the subject has met all criteria for response (PR or better rate).
 Duration of response will be calculated from the date of initial documentation of a response (PR
or better rate) to the date of first documented evidence of progressive disease, as defined in the
IMWG criteria.
 Overall survival is measured from the date of randomization to the date of the subject’s death.
Other secondary endpoints include a change from baseline in the EQ-5D-5L utility score and the
EORTC-QLQ-C30 global health status/quality of life subscale at each time point over the duration of
the study.

Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1. Male or female subjects of at least 18 years of age.
2. Documented MM as defined by the criteria below:
 Monoclonal plasma cells in the bone marrow 10% at some point in the subject’s disease
course or presence of a biopsy-proven plasmacytoma.
3. Measurable disease at Screening as defined by any of the following:
 Serum M-protein ≥1g/dL (≥10 g/L) or 0.5 g/dL (≥5 g/L) for subjects with IgA, IgD, IgE, or
IgM multiple myeloma; or
 Urine M-protein level ≥200 mg/24 hours; or
 Light chain MM 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
4. Received at least 1 prior line of therapy for MM (Note: for the definition of a “line of therapy”,
please refer to Attachment 1).
5. Documented evidence of PD based on investigator’s determination of response as defined by the
IMWG criteria on or after their last regimen.
6. Achieved a response (partial response [PR] or better based on investigator’s determination of
response by the IMWG criteria) to at least 1 prior regimen (refer to Attachment 1).
7. ECOG Performance Status score of 0, 1, or 2 (refer to Attachment 2).
8. For subjects experiencing toxicities resulting from previous therapy (including peripheral
neuropathy), the toxicities must be resolved or stabilized to ≤Grade 1.
9. Subject meets all of the following laboratory criteria during the Screening Phase:
 Absolute neutrophil count ≥1.0 × 109
/L (granulocyte colony stimulating factor [G-CSF] use
is permitted);
 Hemoglobin level ≥7.5 g/dL (≥5 mmol/L; prior red blood cell [RBC] transfusion or
recombinant human erythropoietin use is permitted ) (transfusion is not allowed within
14 days prior to screening laboratory testing);
 Platelet count ≥75 × 109
/L for subjects in whom <50% of bone marrow nucleated cells are
plasma cells; otherwise platelet count ≥50 × 109
/L (transfusion is not allowed within 14 days
prior to screening laboratory testing);
 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≤2.5 times the
upper limit of normal (ULN);
 Total bilirubin level ≤2.0 × ULN, (except in subjects with congenital bilirubinemia, such as
Gilbert syndrome (direct bilirubin ≤2.0 x ULN);
 Creatinine clearance ≥20 mL/min (may be calculated using the Cockcroft-Gault formula,
Modification of Diet in Renal Disease [MDRD] formula or Chronic Kidney Disease
Epidemiology Collaboration [CKD-EPI] formula, provided in Attachment 3);
 Corrected serum calcium ≤14 mg/dL (≤3.5 mmol/L), or free ionized calcium ≤6.5 mg/dL
(≤1.6 mmol/L). (Attachment 4)
10. A woman of childbearing potential must have a negative urine or serum pregnancy test at
screening within 14 days prior to randomization.
11. Each subject (or their legally acceptable representative) must sign an Informed Consent Form
(ICF) indicating that he or she understands the purpose of and procedures required for the study
and are willing to participate in the study.
12. Contraceptive use by men or women should be consistent with local regulations regarding the
use of contraceptive methods for subject participating in clinical studies. Before randomization, a
woman must be either:
a. Not of childbearing potential defined as:
o postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL
in the postmenopausal range may be used to confirm a postmenopausal state in women
not using hormonal contraception or hormonal replacement therapy, however in the
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
o permanently sterile
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral
tubal occlusion/ligation procedures, and bilateral oophorectomy.
b. Of childbearing potential and
o practicing a highly effective method of contraception (failure rate of <1%
per year when used consistently and correctly)
Examples of highly effective contraceptives include
- user-independent methods:
implantable progestogen-only hormone contraception associated with
inhibition of ovulation; intrauterine device (IUD); intrauterine
hormone-releasing system (IUS); vasectomized partner; sexual
abstinence (sexual abstinence is considered a highly effective method
only if defined as refraining from heterosexual intercourse during the
entire period of risk associated with the study drug. The reliability of
sexual abstinence needs to be evaluated in relation to the duration of
the study and the preferred and usual lifestyle of the subject.)
- user-dependent methods:
combined (estrogen- and progestogen-containing ) hormonal
contraception associated with inhibition of ovulation: oral,
intravaginal, and transdermal; progestogen-only hormone
contraception associated with inhibition of ovulation: oral and injectable.
Typical use failure rates may differ from those when used consistently and
correctly. Use should be consistent with local regulations regarding the
use of contraceptive methods for subjects participating in clinical studies.
Hormonal contraception may be susceptible to interaction with the study
drug, which may reduce the efficacy of the contraceptive method.
o agrees to remain on a highly effective method throughout the study and for
at least 3 months after the last dose of study drug.
A woman using oral contraceptives must use an additional birth control method (see list
of highly effective methods of contraception above).
Note: If the childbearing potential changes after start of the study (or the risk of
pregnancy changes (eg, a woman who is not heterosexually active becomes active,) a
woman must begin a highly effective method of contraception, as described throughout
the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
13. A woman must agree not to donate eggs (ova, oocytes) for the purposes of assisted
reproduction during the study and for a period of 3 months after receiving the last
dose of study drug.
14. During the study and for a minimum of 1 spermatogenesis cycle (defined as
approximately 3 months) after receiving the last dose of study drug, in addition to
the highly effective method of contraception, a man
 who is sexually active with a woman of childbearing potential must agree to
use a barrier method of contraception (eg, condom with spermicidal
foam/gel/film/cream/suppository)
 who is sexually active with a woman who is pregnant must use a condom
 must agree not to donate sperm.
15. Subjects must be willing and able to adhere to the prohibitions and restrictions
specified in this protocol.

Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating in
the study:
1. Received daratumumab or other anti-CD38 therapies.
2. Refractory to VELCADE, or another PI, like ixazomib and carfilzomib (ie, subject had
progression of disease while receiving VELCADE therapy or within 60 days of ending
VELCADE therapy, or another PI, like ixazomib and carfilzomib, etc).
3. Intolerant to VELCADE (ie, discontinued due to any adverse event while on VELCADE
treatment).
4. Received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic half-lives of the
treatment, 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) before treatment. A list of anti-myeloma treatments with the
corresponding pharmacokinetic half-lives is provided in the Site Investigational Product
Procedures Manual (SIPPM).
5. Received ASCT within 12 weeks before the date of randomization, or the subject has
previously received an allogenic stem cell transplant (regardless of timing).
6. Planning to undergo a stem cell transplant prior to progression of disease on this study, ie,
these subjects should not be enrolled in order to reduce disease burden prior to transplant.
7. History of malignancy (other than MM) within 3 years before the date of randomization
(exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the
cervix or breast, or malignancy 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).
8. Known meningeal involvement of MM.
9. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) most
recent version.
10. Subject has either of the following:
a. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory
volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is
required for subjects suspected of having COPD and subjects must be excluded if
FEV1 <50% of predicted normal.
b. Known moderate or severe persistent asthma, or a history of asthma within the last
2 years (see Attachment 8), or currently has uncontrolled asthma of any classification.
(Note that subjects who currently have controlled intermittent asthma or controlled
mild persistent asthma are allowed to participate in the study).
11. Active infection with hepatitis B or hepatitis C. Serologic testing for hepatitis is required at
screening, If Hepatitis B surface antigen is positive, the patient will be excluded. Hepatitis B
DNA needs to be performed if Hepatitis B core antibody is positive. DNA PCR needs to be
confirmed negative prior to randomization in subjects who are Hepatitis B core Ab positive. If
Hepatitis C antibody is positive, RNA polymerase chain reaction (PCR) needs to be
performed and confirmed negative prior to randomization.
12. Known to be seropositive for human immunodeficiency virus (HIV).
13. Concurrent medical condition or disease (eg, active systemic infection, uncontrolled diabetes,
acute diffuse infiltrative pulmonary disease) 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.
14. Vaccination with live attenuated vaccines within 4 weeks of first study agent administration.
15. Clinically significant cardiac disease, including:
 Myocardial infarction within 6 months before Cycle 1, Day 1, 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, Attachment 14 )
 Uncontrolled cardiac arrhythmia (Common Terminology Criteria for Adverse Events
[CTCAE] most recent version Grade 2 or higher) or clinically significant ECG
abnormalities.
 Screening 12-lead ECG showing a baseline QT interval as corrected by QTc >470 msec.
16. Known allergies, hypersensitivity, or intolerance to VELCADE, monoclonal antibodies or
human proteins, or their excipients (refer to most recent Package Insert for VELCADE and/or
IB Daratumumab,23 or known sensitivity to mammalian-derived products.
17. Plasma cell leukemia (>2.0X109
/L circulating plasma cells by standard differential) or
Waldenström’s macroglobulinemia or polyneuropathy, organomegaly, endocrinopathy,
monoclonal protein, and skin changes syndrome (POEMS) or amyloidosis.
18. Known or suspected of not being able to comply with the study protocol (eg, because of
alcoholism, drug dependency, or psychological disorder) or the subject has any condition for
which, in the opinion of the investigator, participation would not be in the best interest of the
subject (eg, compromise their well-being) or that could prevent, limit, or confound the
protocol-specified assessments.
19. Pregnant or breastfeeding or planning to become pregnant while enrolled in this study or
within 3 months after the last dose of study drug or, subject is a man who plans to father a
child while enrolled in this study or within 3 months after the last dose of study drug.
20. Received an investigational drug (including investigational vaccines) or used an invasive
investigational medical device within 4 weeks before Cycle 1 Day 1 (except for
investigational anti-myeloma agents, which cannot be taken within 2 weeks prior to
randomization, as described in exclusion criterion 4).
21. Any condition for which, in the opinion of the investigator, participation would not be in the
best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or
confound the protocol-specified assessments.
22. Plasmapheresis within 28 days before randomization
23. Major surgery within 2 weeks before randomization, or has not fully recovered from an earlier
surgery, or has surgery planned during the time the subject is expected to participate in the
study or within 2 weeks after the last dose of study drug administration.
Note: subjects with planned surgical procedures to be conducted under local anesthesia may
participate. Kyphoplasty or vertebroplasty are not considered major surgery.