This is a single-arm, phase II, open-label trial to investigate the effects of selinexor (S)
in combination with daratumumab, lenalidomide, and dexamethasone (DRd) for first-line
treatment of multiple myeloma (MM).
FDA has approved selinexor plus dexamethasone in multiple myeloma after four prior therapies,
and DRd is also already approved by the FDA for multiple myeloma. This study will use all
four (S-DRd) together to treat MM as an initial treatment.
Multiple myeloma (MM) is an incurable disease with high death rates as a result of developing
resistance to treatments. Even with the advent of novel therapies, myeloma patients
ultimately progress from frontline therapy. Common treatments include glucocorticoids,
chemotherapy, proteasome inhibitors (PIs), Immunomodulatory imide drugs (IMiDs), stem cell
transplants, and radiation therapy. Optimal frontline therapy with deeper remissions
translates to improved overall survival and progression free survival. The purpose of this
study is to investigate and improve upon reported outcomes in the frontline setting.
Selinexor has shown potent anti-myeloma activity in preclinical models of MM and Phase 1,
Phase 2 clinical studies as well as in a randomized phase 3 clinical trial called BOSTON.
Selinexor was approved by the US FDA in July 2019 in combination with dexamethasone for the
treatment of adult patients relapsed/refractory (RR) MM who have received at least four prior
therapies and whose disease is refractory to at least two proteasome inhibitors, at least two
immunomodulatory agents, and an anti-CD38 (anti-cluster of differentiation 38) monoclonal
antibody. In June 2020, Selinexor was approved as a monotherapy by the FDA for adult patients
with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 lines of
systemic therapy.
Treatment with combination therapies including daratumumab, lenalidomide, and dexamethasone
has shown improvement in response rates, time to progression, and survival. Daratumumab is an
approved CD38-directed cytolytic antibody used as a monotherapy for patients with heavily
pre-treated MM, and in combination with lenalidomide and dexamethasone. The risk of death or
disease progression was 44% lower and increased overall response rate (ORR) of 92.9% was
observed in patients with newly diagnosed MM that received the triplet combination of
daratumumab, lenalidomide, and dexamethasone (DRd) compared to lenalidomide and dexamethasone
alone (Rd).
Tolerability of the DRd combination in patients was consistent between DRd and Rd treatments.
The safety profile of DRd was shown to be consistent with known safety profiles of
daratumumab and Rd. Higher rates of infections (upper respiratory tract infection and
pneumonia) and neutropenia in DRd treated patients than in Rd treated patients were observed.
However, grade 3 or 4 infections were similar between DRd and Rd treatment groups and were
managed by standard of care. After exposure to DRd for a median of 34 months, no new safety
concerns were observed in the extended follow-up of the POLLUX phase III study.
Preclinical data demonstrated that patient-derived MM cells were sensitized to the
combination of Selinexor and daratumumab compared to the single agents. Clinical data
demonstrate an ORR of 74% in patients with relapsed myeloma treated with Selinexor,
daratumumab, and dexamethasone.
The rationale for the combination of Selinexor, lenalidomide, daratumumab, and dexamethasone
(S-DRd) in the current study is based on the following: preclinical synergistic activities
observed with Selinexor and dexamethasone, the preclinical activity of Selinexor combined
with both lenalidomide and daratumumab; as well as the clinical experience of the combination
of Selinexor and lenalidomide/dexamethasone can be safely combined with 92% ORR in patients
with relapsed myeloma; and the combination of Selinexor and daratumumab/dexamethasone can
also be safely combined with an ORR of 74%. There is an urgent need to induce more efficient,
deeper and durable responses in patients with newly diagnosed MM.
Inclusion Criteria:
1. At least 18 years of age.
2. Have documented multiple myeloma as defined by the International Myeloma Working Group
(IMWG) 2015 criteria below:
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary
plasmacytoma. * In addition, the patient must meet one of the criteria in either 2a or
2b.
1. Evidence of end organ damage that can be attributed to the underlying plasma cell
proliferative disorder, specifically at least one of the following:
- i. Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the
upper limit of normal (ULN) or >2.75 mmol/L (>11 mg/dL)
- ii. Renal insufficiency: creatinine clearance 20-40 mL per min or serum
creatinine >177 μmol/L (>2 mg/dL)
- iii. Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or
a hemoglobin value <100 g/L*
- iv. * Using Calcium elevation, Renal dysfunction, Anemia, and Bone disease
(CRAB) criteria Bone lesions: one or more osteolytic lesions on skeletal
radiography, or CT (computed tomography) **.
2. Any one or more of the following:
- i. Clonal bone marrow plasma cell percentage* ≥60%
- ii. Involved: uninvolved serum free light chains (FLC) ratio*** >100
- iii. >1 focal lesions on MRI (magnetic resonance imaging) studies; Each
focal lesion must be 5 mm or more in size.
- Clonality should be established by showing κ/λ-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.
- 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.
- These values are based on the serum Freelite assay. The involved FLC must be
≥100 mg/L.
3. Have measurable disease as defined by any of the following:
1. Serum M-protein level ≥1.0 g/dL or urine M protein level ≥200 mg/24 hours; or
2. Immunoglobulins A, D, E or M multiple myeloma: serum M-protein level ≥0.5 g/dL or
urine M-protein level ≥200 mg/24 hours; or
3. Light chain multiple myeloma without measurable disease in the urine: serum Ig
FLC ≥10 mg/dL and abnormal serum Ig kappa/lambda FLC ratio
4. Have previously untreated myeloma. For previously untreated patients an emergency
course of steroids (defined as no greater than 40 mg of dexamethasone, or equivalent
per day for a maximum of 4 days) is permitted. In addition, radiation therapy is
permitted prior to study entry, during screening, and during Cycles 1-2 of study
treatment as needed for lytic bone disease.
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or
2.
6. Female patients of childbearing potential must have a negative serum pregnancy test at
screening and agree to use highly effective methods of contraception throughout the
study and for 90 days following the last dose of study treatment. Childbearing
potential excludes: Age >50 years and naturally amenorrhoeic for >1 year, or previous
bilateral salpingo-oophorectomy, or hysterectomy.
7. Male patients who are sexually active must use highly effective methods of
contraception throughout the study and for 4 weeks after receiving the last dose of
study drug. Male patients must agree not to donate sperm during the study treatment
period and for 3 months after receiving the last dose of study drug.
8. Patients must be willing and able to adhere to the prohibitions and restrictions
specified in this protocol and referenced in the informed consent form (ICF).
9. Each patient (or their legally acceptable representative) must sign an ICF indicating
that he or she understands the purpose of, and procedures required for the study and
are willing to participate in the study.
Exclusion Criteria:
1. Exhibiting clinical signs of or has a known history of meningeal or central nervous
system involvement by multiple myeloma.
2. Is known to be seropositive for human immunodeficiency virus, known to have hepatitis
B surface antigen positivity, or known to have a history of hepatitis C.
Patients who completed treatment for hepatitis C and have no detectable circulating
hepatitis C virus (HCV) by hepatitis C RNA polymerase chain reaction (PCR) for at
least 6 months prior to screening and have no detectable, may participate in the
study.
Such patients will be required to undergo regular assessment for HCV reactivation
during their participation in the study. Patients who test positive for HCV at any
time during these assessments will be withdrawn from the study.
3. Has any concurrent medical condition or disease (e.g., active systemic infection) 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.
4. Has clinically significant cardiac disease, including:
- Myocardial infarction (MI) within 6 months before first day of first cycle
(C1D1), or unstable or uncontrolled disease/condition related to or affecting
cardiac function (e.g., unstable angina, congestive heart failure, New York Heart
Association Class III-IV)
- Uncontrolled cardiac arrhythmia (NCI-CTCAE Version 5.0 Grade 2 or higher) or
clinically significant electrocardiogram (ECG) abnormalities
5. Screening 12-lead ECG shows a baseline QT interval (QTc) >470 msec
6. Has any of the following laboratory test results during the screening phase:
- Absolute neutrophil count ≤1.0 × 109 /L; (granulocyte colony stimulating factor
use is permitted)
- Hemoglobin level ≤7.5 g/dL (≤5 mmol/L); blood transfusions to maintain hemoglobin
>7.5 are acceptable
- Platelet count <75 × 109 /L for patients in whom <50% of bone marrow nucleated
cells are plasma cells; otherwise platelet count <50 × 109 /L; no platelet
transfusions in the past 7 days are allowed
- Alanine aminotransferase (ALT) level ≥2.5 × upper limit of normal (ULN)
- Aspartate aminotransferase (AST) level ≥2.5 × ULN
- Total bilirubin level ≥1.5 × ULN, (except for Gilbert Syndrome: direct bilirubin
2 × ULN)
- Creatinine clearance ≤20 mL/min estimated using Cockcroft-Gault;
7. Has known allergies, hypersensitivity, or intolerance to monoclonal antibodies or
human proteins, daratumumab or its excipients (refer to Investigator's Brochure), or
known sensitivity to mammalian-derived products
8. Has plasma cell leukemia (>2.0 × 109 /L circulating plasma cells by standard
differential), Waldenström's macroglobulinemia, POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy, monoclonal protein, and/or skin changes), or amyloid
light-chain amyloidosis
9. Is known or suspected of not being able to comply with the study protocol (e.g.,
because of alcoholism, drug dependency, or psychological disorder) or the patient has
any condition for which, in the opinion of the investigator, participation would not
be in the best interest of the patient (e.g., compromise their well-being) or that
could prevent, limit, or confound the protocol-specified assessments
10. Is considering becoming pregnant
11. Has any condition for which, in the opinion of the investigator, participation would
not be in the best interest of the patient (e.g., compromise the well-being) or that
could prevent, limit, or confound the protocol- specified assessments
12. Has had major surgery within 2 weeks before C1D1, or will not have fully recovered
from surgery, or has surgery planned during the time the patient is expected to
participate in the study or within 2 weeks after the last dose of study drug
administration. (Note: patients with planned surgical procedures to be conducted under
local anesthesia may participate. Kyphoplasty is not considered a major surgery.)
13. Is eligible for stem cell transplant.
NOTE: Investigators should ensure that all study enrollment criteria have been met at
screening. If a patient's status changes (including laboratory results or receipt of
additional medical records) after screening but before C1D1 such that he or she no longer
meets all eligibility criteria, then the patient should be excluded from participation in
the study.
