This single arm, two-stage, open-label Phase II study is designed with the primary objective
of evaluating the efficacy of induction therapy comprised of 8 cycles of carfilzomib,
lenalidomide, dexamethasone and daratumumab (KRd+daratumumab) in terms of complete response
or better (CR) in subjects with NDMM, and comparing to relevant historical controls. Post
induction, all subjects will undergo disease evaluation, including assessment of minimal
residual disease (MRD). Post-induction disease evaluation will be followed by an MRD-based
treatment algorithm. This trial will allow us to gather preliminary data on use of MRD status
to direct post-induction therapy.
Inclusion Criteria:
Subject must meet all of the following applicable inclusion criteria to participate in this
study:
1. Written informed consent and HIPAA authorization for release of personal health
information signed by the subject or his/her legally authorized representative. NOTE:
HIPAA authorization may be included in the informed consent or obtained separately.
2. Age ≥ 18 years at the time of consent.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 (see Appendix A,
Section 18.1) within 28 days prior to day 1 of treatment.
4. Confirmation of newly diagnosed multiple myeloma (NDMM) as per the IMWG 2014 criteria
(see Appendix D, Section 18.4). Newly diagnosed MM patients who may have deferred
transplant are also allowed.
5. Measurable disease present at baseline assessments. Baseline disease assessments are
defined as disease assessments collected within 28 days of initiation of the first
pre-study induction cycle (subjects who received prior therapy) or within 28 days
prior to day 1 of study treatment (subjects with no prior therapy). Measurable disease
is defined as:
1. Serum M-protein ≥ 1 g/dL (> 0.5 g/dL for IgA or IgM) OR
2. Urine M-protein ≥ 200 mg/24 h OR
3. Involved free light chain (FLC) level ≥ 10 mg/dL provided serum FLC ratio is
abnormal
6. No more than one prior cycle of systemic therapy (completed within 6 weeks of consent)
for MM (to accommodate subjects who needed emergent therapy at diagnosis); any prior
radiotherapy must be completed at least 14 days prior to day 1 of treatment. Subject
must have recovered from treatment-induced toxicities to ≤ grade 1 or baseline.
7. Demonstrate adequate organ function within 1 week of day 1 of treatment as defined in
the table below:
Hematological:
- White Blood Cell (WBC) : ≥ 2,000/mm3
- Absolute Neutrophil Count (ANC) : ≥ 1,000/mm3 without growth factors within 1
week of day 1 of treatment
- Hemoglobin (Hgb) : ≥ 8 g/dL
- Platelet count : ≥ 70,000/mm3 if bone marrow plasmacytosis of <50%; otherwise ≥
50,000/mm3
Renal:
Serum creatinine with Creatinine clearance : ≤ 1.5 × upper limit of normal (ULN) with
creatinine clearance
≥ 30 mL/min as measured by a 24-hour urine collection or estimated by the Cockcroft -
Gault formula ( See formula in Appendix B, Section 18.2 )
Hepatic:
- Bilirubin : ≤ 2 × ULN; < 3.0 for subjects with Gilbert's Syndrome
- Aspartate aminotransferase (AST) : ≤ 2.5× ULN
- Alanine aminotransferase (ALT) : ≤ 2.5 × ULN
8. Adequate cardiac function as defined by ≥ 45% Left Ventricular Ejection Fraction
(LVEF) by ECHO or MUGA within 28 days prior to day 1 of treatment.
9. Females of childbearing potential (FCBP) must have a negative serum pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to day
1 of treatment, and be willing to undergo serial serum or urine pregnancy testing.
NOTE: Females are considered of child bearing potential unless they are surgically
sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral
oophorectomy) or are postmenopausal (at least 12 consecutive months with no menses
without an alternative medical cause).
10. FCBP must be willing to use a highly effective contraceptive method (i.e., achieves a
failure rate of <1% per year when used consistently and correctly) plus a second
contraceptive method (considered acceptable [failure rate of >1% per year] or highly
effective) from the time of informed consent until 3 months after the last protocol
prescribed therapy (which also includes FCBP on carfilzomib) has been discontinued.
NOTE: estrogens may further increase the risk of thrombosis (beyond that associated
with lenalidomide) and their use should be based on a benefit-risk decision. For the
highly effective contraceptive method, a method with low user dependency is preferable
but not required (see tables, adapted from:
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2
014_09_HMA_CTFG_Contraception.pdf)
Highly Effective Birth Control Methods:
- combined (estrogen and progestogen containing) hormonal contraception associated
with inhibition of ovulation
- oral
- intravaginal
- transdermal
- progestogen-only hormonal contraception associated with inhibition of ovulation
- oral
- injectable
- implantable (Contraception method considered to have low user dependency)
- intrauterine devide (IUD) (Contraception method considered to have low user
dependency)
- intrauterine hormone-releasing system (IUS) (Contraception method considered to
have low user dependency)
- vasectomised partner (Contraception method considered to have low user
dependency) Vasectomised partner is a highly effective birth control method
provided that partner is the sole sexual partner of the FCBP trial participant
- 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 treatments)
Acceptable Birth Control Methods:
- Progestogen-only oral hormonal contraception, where inhibition of ovulation is
not the primary mode of action
- Male or female condom with or without spermicide (A combination of male condom
with either cap, diaphragm or sponge with spermicide (double barrier methods) are
also considered acceptable, but not highly effective, birth control methods.
11. Male subjects (even those who have had a vasectomy) who are sexually active with a
FCBP must be willing to use latex or synthetic condoms from initiation of study
treatment until 3 months after the last protocol prescribed therapy has been
discontinued. They must also refrain from donating sperm for at least 90 days after
the last dose of carfilzomib and at least 90 days from the last dose of daratumumab.
The FCBP partner should also consider contraception recommendations (see inclusion
#10).
12. As determined by the enrolling physician, ability of the subject to understand and
comply with study procedures for the entire length of the study.
Exclusion Criteria:
Subjects meeting any of the criteria below may not participate in the study:
1. Any infection requiring systemic therapy (i.e. involving IV antibiotics) (NOTE: at
discretion of investigator, subjects with uncomplicated urinary tract infections may
be eligible).
2. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study, and any female subject must agree not to donate eggs
during the study and for 3 months after the last protocol prescribed therapy has been
discontinued).
3. Has a known additional malignancy that is active and/or progressive requiring
treatment; exceptions include basal cell or squamous cell skin cancer, in situ
cervical or bladder cancer, carcinoma of the prostate with a current PSA value of <0.5
ng/mL or other cancer for which the subject has completed treatment, been disease-free
for at least five years, and is considered by Sponsor-Investigator to be at <30% risk
of relapse, or on hormonal therapy for a history of either prostate cancer or breast
cancer, provided that there has been no evidence of disease progression during the
previous three years.
4. Non-secretory MM.
5. Active involvement of the central nervous system by MM.
6. Prior cardiovascular cerebrovascular accident with persistent neurological deficit.
7. Has chronic obstructive pulmonary disease with a forced expiratory volume in 1 second
(FEV1) < 50% of predicted normal. FEV1 is required for subjects suspected of having
chronic obstructive pulmonary disease and are not eligible if FEV1 is < 50% of
predicted normal.
8. Has had moderate or severe persistent asthma within the past 2 years from enrollment
and/or has currently uncontrolled asthma of any classification. Note that participants
who currently have controlled intermittent asthma or controlled mild persistent asthma
are allowed to participate.
9. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly,
endocrinopathy, monoclonal protein, and skin changes).
10. Had major surgery within 2 weeks prior to day 1 of treatment.
11. Exposure to any investigational drug (including investigational vaccine) or invasive
investigational medical device within 4 weeks or 5 pharmacokinetic half-lives prior to
day 1 of treatment, whichever is longer.
12. Uncontrolled clinically significant illness including, but not limited to,
uncontrolled hypertension (as per the most updated Joint National Committee for the
Management of Hypertension definitions), symptomatic congestive heart failure (as per
New York Heart Association [NYHA] class III or IV [see Appendix C, Section 18.3],
uncontrolled angina pectoris, myocardial infarction within the past 6 months from
consent, known or suspected amyloidosis, uncontrolled cardiac arrhythmia, psychiatric
illness/social situations that would limit compliance with study requirements as
determined by the investigator, or any other condition (including laboratory
abnormalities) that would, in the opinion of the investigator, place the subject at
unacceptable risk if he/she were to participate in the study.
13. Known allergies, hypersensitivity or intolerance to monoclonal antibodies or human
proteins, daratumumab +hyaluronidase or its excipients or known sensitivity to
mammalian-derived products, carfilzomib or its excipients, lenalidomide or its
excipients, or dexamethasone or its excipients.
14. Is seropositive for hepatitis B (defined by a positive test for hepatitis B surface
antigen [HBsAg]). Subjects with resolved infection (i.e. subjects 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: subjects with serologic
findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic
marker) AND a known history of HBV vaccination do not need to be tested for HBV DNA by
PCR.
15. Is 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). Subject is not required to have hepatitis C testing at screening.
16. Is known to be seropositive for human immunodeficiency virus.
17. Transplant ineligible subjects > 70 years old only: Defined frail, per IMWG criteria
of 'frailty'. Frailty assessment does not need to be performed unless the subject is
transplant ineligible and > 70 years old. "Frail" is defined as a frailty score of ≥
2.
18. Prior or current exposure to daratumumab or other anti-CD-38 therapies.
19. Focal radiation therapy within 14 days prior to C1D1 with the exception of palliative
radiotherapy for symptomatic management but not on measurable extramedullary
plasmacytoma.
