| Eligibility |
Inclusion Criteria:
1. Confirmed diagnosis of Multiple Myeloma(MM) (IMWG consensus guidelines)
2. Newly diagnosed or relapsed (patients should have received a maximum of one line of
prior therapy) patients presenting with extramedullary disease (EMD) of the skin,
liver, lungs, central nervous system, lymph nodes or other tissues, but not solely
paraskeletal plasmacytoma (expanding soft tissue masses)* detected by physical exam
and confirmed (when required) by Weight Bearing CT/MRI/PET-CT and/or biopsy**.
Documentation of plasma cell infiltration is highly recommended unless it requires
invasive surgical intervention such as intracerebral infiltration of plasmacytomas.
*Note: patients with only paraosseous extension of MM forming soft tissue
plasmacytomas are not eligible
**Note: An additional radiologic assessment at screening is not required to confirm
EMD. Documentation in terms of physician's/pathologist's report and/or radiologic
assessments performed within 42 days of C1D1 will suffice for the purposes of
eligibility. All patients however will undergo a baseline radiologic assessment at
C1D1 for response purposes.
3. Patients with one prior line of therapy must have:
- achieved a response (PR or better based on investigator's determination of
response by the IMWG criteria) to at least one prior regimen.
- documented evidence of PD based on Investigator's determination of response as
defined by the IMWG criteria on or after the last line of treatment.
4. Age = 18 years
5. Eastern Cooperative Oncology Group (ECOG) performance status = 2. Note: for patients
with central nervous system (CNS) involvement, an ECOG performance status >2 is also
acceptable
6. Each patient 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. Patients must be willing and able to adhere to the
prohibitions and restrictions specified in this protocol, as referenced in the ICF.
7. Patient must have measurable disease of MM as defined by the below criteria:
- IgG MM: Serum M protein level =1.0 g/dL or urine M protein level =200 mg/24
hours, or
- IgA, IgD, IgE, IgM MM: Serum M-protein level =0.5 g/dL or urine M-protein level
=200 mg/24 hours; or
- Light chain MM, for patients without measurable disease in the serum or urine:
Serum immunoglobulin free light chain (FLC) =10 mg/dL and abnormal serum
immunoglobulin kappa lambda FLC ratio.
8. Reproductive Status
- Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test at screening. Females are not of childbearing potential if they
have been in natural menopause for at least 24 consecutive months, or have had a
hysterectomy and/or bilateral oophorectomy
- Women must not be breastfeeding
- WOCBP must agree to follow instructions for reliable methods of birth control.
This includes one highly effective (< 1% failure rate per year) form of
contraception (tubal ligation, intrauterine device (IUD), combined or progestogen
only hormonal contraception associated with inhibition of ovulation [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 before the start of treatment and continue for the duration of study
treatment and for 3 months after cessation of daratumumab or 12 months after
cessation of cyclophosphamide, whichever is longer.
- Males who are sexually active must always use a latex or synthetic condom during
any sexual contact with females of reproductive potential, even if they have
undergone a successful vasectomy. They must also agree to follow instructions for
methods of contraception for 4 weeks before the start of study treatment, for the
duration of study treatment, and for 3 months after cessation of daratumumab or 6
months after cessation of cyclophosphamide, whichever is longer.
- Female patients must not donate eggs for up to 3 months after cessation of
daratumumab or 12 months after cessation of cyclophosphamide, whichever is
longer.
- Male patients must not donate sperm for up to 3 months after cessation of
daratumumab or 6 months after cessation of cyclophosphamide, whichever is longer.
- Azoospermic males and WOCBP who are not heterosexually active are exempt from
contraceptive requirements. However, WOCBP will still undergo pregnancy testing
as described above.
Exclusion Criteria:
1. Solitary plasmacytoma
2. Paraosseous extension of MM forming soft tissue plasmacytomas only (without EMD).
3. Previous therapy with any anti-CD38 or anti-CS1 monoclonal antibody
4. Patients refractory to bortezomib based regimens (PD on or within 60 days of
completion of bortezomib OR failure to achieve at least a minimal response [MR]) as
the prior line of therapy
5. Patients who have Bortezomib or Daratumumab hypersensitivity
6. Patients who have active or chronic infections
7. Patients who have received anti-myeloma treatment within 2 weeks or 5 pharmacokinetic
half-lives of the treatment, whichever is longer, before Cycle 1 Day 1 (C1D1). The
only exception is emergency use of a short course of corticosteroids (equivalent of
dexamethasone 40 mg/day for a maximum of 4 days) for palliative treatment before C1D1.
8. Previous autologous stem cell transplant (ASCT) within 12 weeks before C1D1.
9. Previous allogenic stem cell transplant (alloSCT) regardless of timing.
10. Patient has received radiotherapy within 14 days from C1D1. NOTE: Urgent localized
radiotherapy for Spinal Cord Compression or Central Nervous System Involvement is
allowed.
11. Patient has 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 patients suspected of having COPD and patients must be excluded if
FEV1 <50% of predicted normal
12. Patient has known moderate or severe persistent asthma within the past 2 years (see)
or currently has uncontrolled asthma of any classification. Note: Patients who
currently have controlled intermittent asthma or controlled mild persistent asthma are
allowed in the study).
13. Severe cardiovascular disease (arrhythmias [CTCAE Grade 3 or higher] requiring chronic
treatment, congestive heart failure [New York Heart Association (NYHA) Class III - IV]
or symptomatic ischemic heart disease);
14. Severe pulmonary dysfunction (CTCAE grade 3-4, see appendix D);
15. Severe neurological or psychiatric disease;
16. Significant hepatic dysfunction (serum bilirubin or transaminases = 3 times the upper
limit of normal (ULN)) unless related to hepatic involvement with MM.
Note: Patients with Gilbert Syndrome are not excluded provided that direct bilirubin
is =2 x ULN.
17. Significant renal dysfunction (creatinine clearance <30 ml/min after rehydration)
Note: refer to Appendix F for creatinine clearance calculation;
18. Significant bone marrow suppression as evidenced by any of the below laboratory tests
during screening:
- Absolute neutrophil count =1.0 × 109/L;
- Hemoglobin level =7.5 g/dL (=4.65 mmol/L); transfusions are not allowed to reach
this level
- Platelet count =75 × 109/L in patients in whom <50% of bone marrow nucleated
cells are plasma cells and platelet count =50 × 109/L in patients in whom =50% of
bone marrow nucleated cells are plasma cells; transfusions are NOT allowed to
reach this level
19. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes,
active systemic infection, uncontrolled hypertension, cancer, etc.) that is likely to
interfere with the study procedures/results or which, in the opinion of the
investigator, would constitute a hazard for participating in this study.
20. History of active malignancy during the past 5 years with the exception of basal
carcinoma of the skin or stage 0 cervical carcinoma;
21. Any of the following:
- Known active hepatitis A
- Patient is seropositive for hepatitis B (defined by a positive test for hepatitis
B surface antigen [HBsAg]). Patients with resolved infection (ie, patients who
are positive for antibodies to hepatitis B core antigen [antiHBc] and/or
antibodies to hepatitis B surface antigen [antiHBs]) 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: Patients with serologic findings suggestive of HBV vaccination (antiHBs
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.
o Known to be seropositive for hepatitis C (except in the setting of a sustained
virologic response, defined as aviremia at least 12 weeks after completion of
antiviral therapy).
22. Patient known to be HIV-positive;
23. Current participation in another clinical trial
24. Any psychological, familial, sociological and geographical condition potentially
hampering compliance with the study protocol and follow-up schedule
|
