This is a single center, open-label, phase 2 study in elderly (age ≥ 70) subjects with newly
diagnosed multiple myeloma who are transplant ineligible. Subjects will receive subcutaneous
daratumumab, dose-attenuated bortezomib, revlimid, and dexamethasone until confirmed disease
progression, discontinuation of study treatment due to unacceptable drug toxicity, or other
reasons. Throughout the study, subjects will be monitored closely for adverse events,
laboratory abnormalities, and clinical response.
This is a single center, open-label, phase 2 study in elderly (age ≥ 70) subjects with newly
diagnosed multiple myeloma who are transplant ineligible. The main study consists of the
following phases: a 28-day screening phase; followed by initial therapy with 12 cycles of
daratumumab in combination with dose-attenuated VRd; and a maintenance phase that starts
after Cycle 12 of therapy. Cycles are 28 days in length. Treatment can continue until disease
progression or unacceptable toxicity. After 12 cycles of initial therapy, maintenance therapy
will begin with 28 day cycles of daratumumab with either lenalidomide or ixazomib and the
choice of maintenance therapy will be based on cytogenetic risk status at diagnosis. All
subjects will continue maintenance treatment until disease progression, except maintenance
daratumumab will be discontinued after 2 years if subjects remain on maintenance treatment at
that time. All subjects will be followed in the longterm follow-up for at least 1 year after
last dose of study treatment and will continue until death, withdrawal of consent for study
participation, or the end of study definition is met. The end of study is defined as when all
subjects have completed at least 1 year of long-term follow up and until death, withdrawal of
consent for study participation, or 5 years after first patient begins daratumumab therapy,
whichever occurs first.
Inclusion Criteria:
- Newly diagnosed, untreated, symptomatic MM as defined by standard criteria. Clonal
bone marrow plasma cells >10% or biopsy-proven bony or extramedullary plasmacytoma*
and any one or more of the following myeloma-defining events:
- Evidence of end-organ damage that can be attributed to the underlying plasma cell
proliferative disorder, specifically:
- Hypercalcemia: serum calcium >0.25 mmol/L (> 1mg/dL) higher than the upper
limit of normal or > 2.75 mmol/L (>11 mg/dL) and/or,
- Renal insufficiency: creatinine clearance <40 mL per min or serum creatinine
>177 µmol/L (>2 mg/dL) and/or,
- Anemia: hemoglobin value of >20 g/L (>2g/100 mL)below the lower limit of
normal, or a hemoglobin value <100 g/L (10g/100 mL) and/or,
- Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or
PET-CT (if bone marrow has less than 10% clonal plasma cells, more than one
bone lesion is required to distinguish from solitary plasmacytoma with
minimal marrow involvement)
- Any one or more of the following biomarkers of malignancy:
- Clonal bone marrow plasma cell percentage** (clonality should be
established by showing kappa/lambda-light-chain restriction on flow
cytometry, immunohistochemistry, or immunofluorescence. Bone marrow
plasma cell percentage should preferably be estimated from a core
biopsy specimen; in case of a disparity between the aspirate and core
biopsy, the highest value should be used ≥60% or
- Serum free light chain (FLC) ratio greater than or equal to 100
provided involved FLC level is 100 mg/L or higher, or
- More than one focal lesion on MRI*** (Each focal lesion must be 5 mm or
more in size.
- Age ≥ 70 and ineligible for autologous hematopoietic stem cell transplantation
(defined as age, ≥ 80 or age < 80 with cardiac/pulmonary/ or other comorbidities
deemed by investigator likely to have a negative impact on tolerability of high dose
chemotherapy with stem cell transplantation).
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
- Patients must have measurable disease defined by at least 1 of the following 3
measurements:
- Serum M-protein > 1 g/dL (10 g/L) or > 0.5 g/dL if IgA
- Urine M-protein > 200 mg/24 hours.
- Serum free light chain assay: involved free light chain level >10 mg/dL (> 100
mg/L) provided the serum free light chain ratio is abnormal
- Due to the teratogenicity of lenalidomide and the lack of adequate reproductive
toxicity data for daratumumab, if a male subject is sexually active with a woman of
child bearing potential, in addition to the user independent highly effective method
of contraception, a male or female condom with or without spermicide, diaphragm, or
cervical cap is required. Male condom and female condom should not be used together
(due to risk of failure with friction).
- During the study (including during dose interruptions), and for 4 weeks following
discontinuation of lenalidomide, and if receiving daratumumab, for 3 months after the
last dose, in addition to the user independent highly effective method of
contraception (even if he has undergone a successful vasectomy), a man:
1. Who is sexually active with a woman of childbearing potential must agree to use a
barrier method of contraception (ie, latex or synthetic condom with spermicidal
foam/gel/film/cream/suppository)
2. Who is sexually active with a woman who is pregnant must use a latex or synthetic
condom.
3. Must agree not to donate sperm
- Willing and able to adhere to the prohibitions and restrictions specified in this
protocol and referenced in the informed consent form (ICF)
- Must sign an 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.
Exclusion Criteria:
- Peripheral neuropathy > Grade 2 or >Grade 1 with pain on clinical examination during
the Screening period.
- Kidney failure with CrCl ≤ 15 mL/min by Cockfraft Gault
- Significant cardiac disease as determined by the investigator including:
1. Known or suspected cardiac amyloidosis
2. Congestive heart failure of Class III or IV of the NYHA classification
3. Uncontrolled angina, hypertension or arrhythmia
4. Myocardial infarction in the past 6 months
5. Any uncontrolled or severe cardiovascular disease
6. QTc > 470 milliseconds (msec) on a 12-lead ECG obtained during the Screening
period. If a machine reading is above this value, the ECG should be reviewed by a
qualified reader and confirmed on a subsequent ECG or by manual calculation.
- Prior cerebrovascular event with persistent neurologic deficit.
- Subject is:
1. Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
antigen [HBsAg]). Subjects with resolved infection (ie, 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 realtime 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 prior HBV
vaccination, do not need to be tested for HBV DNA by PCR.
2. 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).
- Human immunodeficiency virus infection
- Any medical conditions that, in the investigator's opinion, would impose excessive
risk to the subject.
- Prior or concurrent malignancy, except for the following:
1. Adequately treated basal cell or squamous cell skin cancer
2. Cervical carcinoma in situ
3. Adequately treated Stage I or II cancer from which the subject is currently in
complete remission.
4. Or any other cancer from which the subject has been disease-free for ≥ 3 years
- Known GI disease or GI procedure that could interfere with the oral absorption or
tolerance of study drug, including difficulty swallowing.
- Males sexually active with females of childbearing potential who do not agree to
practice 2 effective methods of contraception, at the same time, from the time of
signing the informed consent form (ICF) through 90 days after the last dose of study
drug, or do not agree to practice true abstinence.
- Central nervous system involvement.
- Diagnosis of primary amyloidosis (with the exception of patients whose amyloidosis has
been documented as a complication of MM, who will be evaluated on a case-by-case basis
for trial participation).
- Infection requiring systemic antibiotic therapy or other serious infection within 14
days before study drug administration.
- Known chronic obstructive pulmonary disease with a forced expiratory volume in 1
second (FEV1) <50% of predicted normal (for subjects > 65 years old FEV1 <50% or DLCO
<50%). Note: FEV1 testing is required for subjects suspected of having chronic
obstructive pulmonary disease and subjects must be excluded if FEV1 <50% of predicted
normal.
- Known moderate or severe persistent asthma within the past 2 years or currently has
uncontrolled asthma of any classification. Note: Subjects who currently have
controlled intermittent asthma or controlled mild persistent asthma are allowed in the
study.
- Persistent corrected serum calcium ≥ 14 mg/dL within 2 weeks of enrollment (despite
appropriate measure such a short course of steroids, bisphosphonates, hydration,
calcitonin).
- Absolute neutrophil count < 1000 cells/mm3. No growth factors allowed within 1 week of
enrollment.
- Platelets < 75,000 cell/mm3 (75 x 109/L). Qualifying laboratory value must occur at
most recent measurement before enrollment and must be no more than 14 days before
enrollment. No transfusions are allowed within 72 hours prior to study drug
administration.
- Hemoglobin < 8 g/dL. Qualifying laboratory value must occur at most recent measurement
before enrollment and must be no more than 14 days before enrollment. No transfusions
are allowed within 72 hours before qualifying laboratory value.
- Total bilirubin > 1.5 x ULN, unless known have Gilbert's syndrome in which case 3 x
ULN).
- AST or ALT ≥ 3 x ULN.
- Major surgery or radiation therapy within 14 days before study drug administration.
- Kyphoplasty or vertebroplasty within 1 week of enrollment.
- Administration of Anti-myeloma chemotherapy, biological, immunotherapy, or
investigational agent (therapeutic or diagnostic) within 3 weeks before enrollment;
however, a cumulative dose of ≤ 160 mg dexamethasone or equivalent during screening is
permitted.
- NSAIDs, IV contrast, aminoglycosides, or other potentially nephrotoxic drugs within 2
weeks of enrollment, except aspirin.
- Known hypersensitivity to bortezomib, lenalidomide, dexamethasone, or daratumumab
