Multiple Myeloma Multipel Myeloom Progressive or Refractory Progressief of refractair safety and tolerability of selinexor
Conditions
Interventions
The following treatments will apply:
Patients who have not previously received an autologous transplant and who are eligible for ASCT will be treated with 4 cycles of selinexor, bortezomib and
dexame
Sponsors
Erasmus University Medical Center
Eligibility
Inclusion criteria
Inclusion criteria: - The subject must understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted. - Age ≥ 18 years at the time of signing the informed consent form. - Able to adhere to the study visit schedule and other protocol requirements. - Documented diagnosis of multiple myeloma and measurable disease (serum M-protein ≥ 5 g/L or urine M-protein ≥ 200 mg/24 hours or abnormal FLC ratio with involved free light chain (FLC) > 100 mg/L); - Documented progression as per the IMWG uniform response criteria (Durie, 2006) during or after the anti-myeloma regimen; or never achieved a response better than PD after at least 2 cycles of their previous anti-myeloma regimen. - At least one prior anti-myeloma regimen. Induction therapy followed by autologous stem cell transplant (ASCT) and consolidation/ maintenance will be considered as one regimen. - Normal renal function with a Creatinine Clearance > 30mL/min according to the Modification of Diet in Renal Disease (MDRD) equation for estimation of Glomerular Filtration Rate (GFR) - WHO performance status score of 0, 1 or 2 (see Appendix B). - Female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential. Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. For both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose. - All subjects must agree to refrain from donating blood while on study drug and for 28 days after discontinuation from this study treatment. - All subjects must agree not to share medication.
Exclusion criteria
Exclusion criteria: - Prior resistance/refractory disease to bortezomib - Systemic AL amyloidosis - Non secretory myeloma - Known CNS involvement - Absolute neutrophil count (ANC) 14 mg/dL (> 3.5 mmol/L). - Hemoglobin 3.0 x upper limit of normal (ULN) or serum total bilirubin > 2 x ULN unless due to inheritable syndrome such as Gilbert’s) - Prior history of malignancies, other than MM, unless the subject has been free of the disease for ≥ 5 years. Exceptions include the following: o Basal or squamous cell carcinoma of the skin. o Carcinoma in situ of the cervix or breast. o Incidental histological finding of prostate cancer (TNM stage of T1a or T1b). - Hypersensitivity to bortezomib or dexamethasone (this includes ≥ Grade 3 rash during prior bortezomib therapy). - Peripheral neuropathy ≥ Grade 2 at time of registration. - Subjects who received an allogeneic bone marrow or allogeneic peripheral blood stem cell transplant less than 12 months prior to initiation of study treatment - Congestive heart failure (NY Heart Association Class III or IV) (see appendix C). - Myocardial infarction within 12 months prior to starting study treatment - Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris. - Subjects who received any of the following within the last 14 days of initiation of study treatment: o Major surgery (kyphoplasty is not considered major surgery). o Use of any anti-myeloma drug therapy at the time of registration in the trial. - Use of any investigational agents within 28 days or five half-lives (whichever is longer) of treatment. - Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subjects from signing the informed consent form. - Any active uncontrolled infections - Pregnant or breastfeeding females. - Known human immunodeficiency virus (HIV) positivity, active infectious hepatitis A, B or C or chronic hepatitis B or C.  Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part I: Evaluate the safety and tolerability of selinexor at 3 different dose levels in combination with bortezomib/dexamethasone & determine the recommended dose level (RDL) of selinexor for Part II Part II: Evaluate the efficacy of the combination of selinexor, bortezomib and dexamethasone (SVd) for induction and consolidation in subjects with progressive or refractory multiple myeloma (MM). This objective will be investigated after 4 induction cycles and after 8 cycles. | — |
Secondary
| Measure | Time frame |
|---|---|
| Evaluate the response (sCR, CR, VGPR, PR) after 8 cycles of selinexor, bortezomib and dexamethasone. Evaluation of biomarkers, including baseline markers predictive of response to selinexor combined with bortezomib and dexamethasone.  Evaluate effect on quality of stem cell transplant.  Evaluate the gene expression profiles in particular of nuclear pore transporters in relation to the treatment outcomes.  Evaluate pharmacodynamic (PDn) changes in XPO1 and related markers in peripheral blood leukocytes and in plasma cytokine levels following selinexor dosing.  Evaluate limited pharmacokinetics (PK) of selinexor in combination with bortezomib and/or dexamethasone. | — |
Contacts
Public ContactE. Asselbergs
Outcome results
None listed