Multiple Myeloma
Conditions
Keywords
NEWLY DIAGNOSED, TRANSPLANT ELEGIBLE, BELANTAMAB MAFODOTIN
Brief summary
This is a multicenter, open label clinical trial evaluating the safety of the combination of belantamab mafodotin + the combination treatment VRd (bortezomib, lenalidomide, dexamethasone) in newly diagnosed (ND) transplant eligible multiple myeloma (MM) patients. Eligible patients will be included in the study and they will receive three induction cycles with belantamab mafodotin (8-week cycles) and six induction cycles with VRd (4-week cycles). Immediately after the fourth VRd cycle, and in the absence of progression or unacceptable toxicity, mobilization of hematopoietic stem cells with G-CSF and subsequent apheresis will take place. Then, patients will receive one additional induction cycle with belantamab mafodotin (8-week cycle) and two additional induction cycles with VRd (4-week cycles) followed by intensification with high-dose melphalan (200mg/m2) and the autologous stem cell transplant. Three months after transplantation, and as long as clinical and hematological conditions allow, patients will receive one cycle of consolidation with belantamab mafodotin (8-week cycle) and two additional cycles of consolidation with VRd (4-week cycles) at the same doses as during induction and, subsequently, patients will receive maintenance treatment with lenalidomide (continuously until disease progression, patient withdrawal, unacceptable toxicity, loss to follow up, end of study or death) and belantamab mafodotin (for 2 years).
Detailed description
This is a multicenter, open label clinical trial evaluating the safety of the combination of belantamab mafodotin + the combination treatment VRd (bortezomib, lenalidomide, dexamethasone) in newly diagnosed (ND) transplant eligible multiple myeloma (MM) patients. The study comprise the following phases: Induction: Cycles 1-6 Cycles will be of 8 weeks of duration for belantamab mafodotin and 28 days of duration for VRd: * Belantamab mafodotin will be administered at the dose of 2.5 mg/kg/every 8 weeks on day 1, intravenously. * Bortezomib will be given subcutaneously, at 1.3 mg/m2, on days: 1, 4, 8 and 11 of every 28-day cycle. * Lenalidomide will be given as an oral drug, in the dose of 25 mg/day on days 1-21. * Dexamethasone will be given as an oral drug, in the dose of 20 mg on days: 1, 2, 4, 5, 8, 9, 11 and 12. Peripheral stem cell harvest will be performed after the fourth cycle of treatment to prevent mobilization failure. Intensification with high-dose melphalan (200 mg/m2) and autologous stem cell transplant (ASCT) will be performed as per routine practice. Mobilization of hematopoietic stem cells (HSCs) will be carried out using high-dose G-CSF after the fourth induction cycle with VRd. The dose of G-CSF used will be at the discretion of each site according to the local rules. Apheresis will be initiated on day 4-5 of stimulation, once the number of CD34+ cells in peripheral blood have reached the minimum to proceed with the collection. The minimum number of CD34+ cells needed to carry out the transplant will be determined at the discretion of each site, although a minimum of 2 x106 CD34+/Kg is recommended, as well as cryopreservation, storage, defrosting and infusion of HSCs. If mobilization fails using G-CSF alone, the recommended action is to utilize plerixafor during the same procedure in order to save this time. Sites should administer plerixafor in accordance with their own established procedures. If this second attempt fails, the site can proceed to a third mobilization attempt using cyclophosphamide plus G-CSF. Consolidation: Cycles 6-8 At day +90, after autologous stem cell transplant patients will receive consolidation treatment with 1 additional cycle of belantamab mafodotin + 2 additional cycles of VRd following the same scheme as in the induction: * Belantamab mafodotin will be administered at the dose of 2.5 mg/kg/every 8 weeks on day 1, intravenously. * Bortezomib will be given subcutaneously, at 1.3 mg/m2, on days: 1, 4, 8 and 11 of every 28-day cycle. * Lenalidomide will be given as an oral drug, in the dose of 25 mg/day on days 1-21. * Dexamethasone will be given as an oral drug, at the dose of 20 mg on days: 1, 2, 4, 5, 8, 9, 11 and 12 of every 28-day cycle. Maintenance: After completion of the consolidation treatment, all the responding patients will receive maintenance treatment with Lenalidomide (10 mg/day) + belantamab mafodotin (2.5 mg/kg/every 8 weeks, intravenously). Lenalidomide will be administered continuously until disease progression, patient withdrawal, unacceptable toxicity loss to follow up, end of study or death. Belantamab mafodotin will be administered for 2 years until disease progression, patient withdrawal, loss to follow up, unacceptable toxicity, end of study or death. The trial has the following objectives: Objectives: Primary objective ● To evaluate the safety and tolerability of the combination of belantamab mafodotin + VRd in newly diagnosed transplant eligible multiple myeloma patients. Secondary objectives ● To assess the efficacy of belantamab mafodotin in combination with VRd in terms of response rate focusing on complete response and MRD. • Efficiency of hematopoietic stem cell collection after 2 induction cycles of treatment of belantamab mafodotin + 4 induction cycles of treatment of VRd.
Interventions
DRUGBelantamab mafodotin
Dose of 2.5 mg/kg/every 8 weeks on day 1, intravenously, Induction: three induction cycles with belantamab mafodotin in combination with VRd. Consolidation: one cycle after 90 days of transplantation with belantamab mafodotin in combination with VRd. Maintenance: belantamab mafodotin in combination with lenalidomide until disease progression, patients withdrawal, death or up to two years, whichever occurs first
DRUGBortezomib
Dose of 1.3 mg/m2, on days: 1, 4, 8 and 11 of every 28-day cycle. Subcutaneous administration Induction: 6 cycles Consolidation: 2 cycles
DRUGLenalidomide
Dose of 25 mg/day on days 1-21 of every 28-day cycle. Oral administration. Induction: 6 cycles Consolidation: 2 cycles Maintenance: 10 mg/day on days 1-21 continuously (may increase up to 15 mg/day) until disease progression, patients withdrawal, death, whichever occurs first
DRUGDexamethasone
Dose of 20 mg on days: 1, 2, 4, 5, 8, 9, 11 and 12 of every 28-day cycle. Oral administration Induction: 6 cycles Consolidation: 2 cycles
High-dose melphalan (200 mg/m2) and ASCT will be performed as per routine practice
Sponsors
PETHEMA Foundation
GlaxoSmithKline
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a multicenter, open label, non-randomized single arm clinical trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participant must have Newly diagnosed multiple myeloma. Newly diagnosed subjects must have symptomatic disease following the IMWG updated criteria (Rajkumar Lancet 2014, Appendix 6). 2. Participant must have a measurable secretory disease defined as either serum monoclonal protein of ≥ 0,5 g/dl or urine monoclonal (light chain) protein ≥ 200mg/24h.For patients whose disease is only measurable by serum FLC, the involved FLC should be ≥ 10mg/L (100 mg/dl), with an abnormal serum FLC ratio. 3. Newly diagnosed participants must be eligible for stem cell transplant at investigator criteria. 4. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 5. Participant must be ≥ 18 years of age 6. Participant must have adequate organ function, defined as follows: System Laboratory Values Hematologic Absolute neutrophil count (ANC) ≥1.5 X 109/L Hemoglobin ≥8.0 g/dL Platelets ≥75 x 109/L for subjects in whom \<50% of bone marrow nucleated cells are plasma cells; otherwise platelet count \>50 × 109/L Calcium corrected serum calcium \<14 mg/dL (\<3.5 mmol/L); or free ionized calcium \<6.5 mg/dL (\<1.6 mmol/L); Hepatic Total bilirubin ≤1.5X ULN (Isolated bilirubin ≥1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%) ALT ≤2.5 X ULN AST ≤2.5 X ULN Renal eGFRa ≥30 mL/min/ 1.73 m2 Spot urine (albumin/creatinine ratios (spot urine) \<500 mg/g (56 mg/mmol) 7. Female participants: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: * Is not a woman of childbearing potential (WOCBP) OR * Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of \<1% per year), preferably with low user dependency, during the intervention period and for at least 4 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention. A WOCBP must have a negative highly sensitive serum pregnancy test (as required by local regulations) within 72 hours before the first dose of study intervention and agree to use a highly effective method of contraception during the study and for 4 months after the last dose of belantamab mafodotin. Additional requirements for pregnancy testing during and after study intervention The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with a nearly undetected pregnancy. Nonchildbearing potential is defined as follows (by other than medical reasons): * ≥45 years of age and has not had menses for \>1 year * Patients who have been amenorrhoeic for \<2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure. 8. Male participants: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 6 months: * Refrain from donating sperm PLUS either: * Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR * Must agree to use contraception/barrier as detailed below: Agree to use a male condom and female partner to use an additional highly effective contraceptive method with a failure rate of \<1% per year as when having sexual intercourse with a woman of childbearing potential (including pregnant females). All prior treatment-related toxicities (defined by National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.0 (must be ≤ Grade 1 at the time of enrolment except for alopecia). 9. Participant must be able to understand the study procedures and agree to participate in the study by providing written informed consent.
Exclusion criteria
Patients that present any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of deaths | Throughout the study period. Approximately 48 months | Number of patients that are exitus after start of the study treatment |
| Incidence of adverse events (AEs) | Throughout the study period. Approximately 48 months | Number of patients experiencing AEs, either treatment or non-treatment related, classified according to severity and graded according to NCTCAE V4.0 |
| Incidence of analytical alterations | Throughout the study period. Approximately 48 months | Changes in laboratory analytes from the hematology and blood chemistry panel after start of the study experimental treatment |
| Incidence of ocular events | Throughout the study period. Approximately 48 months | Number of patients experiencing ocular alterations after start of the study experimental treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | Throughout the study period. Approximately 48 months | The percentage of participants with a confirmed partial response (PR) or better (PR, Very good partial response (VGPR), Complete response (CR), stringent complete response (sCR)). Assessed Q4W during induction, three months after ASCT, after consolidation, q4W during maintenance until PD, unacceptable toxicity, death, withdrawal of consent, loss to follow-up or end of the study. |
| Complete Response Rate (CRR) | Throughout the study period. Approximately 48 months | The percentage of participants with a confirmed complete response (CR) or better (stringent complete response (CR, sCR)). Assessed Q4W during induction, three months after ASCT, after consolidation, q4W during maintenance until PD, unacceptable toxicity, death, withdrawal of consent, loss to follow-up or end of the study. |
| Minimal Residual Disease (MRD) negativity rate | Throughout the study period. Approximately 48 months | The percentage of participants who are MRD negative by next-generation flow cytometry (NGF). MRD will be evaluated after each phase of treatment (induction, autologous stem cell transplant, consolidation and once a year during maintenance). If there is suspect of CR at any time different of those previously specified, the MRD should be evaluated at the suspicion of CR. Assessed Q4W during induction, three months after ASCT, after consolidation, q4W during maintenance until PD, unacceptable toxicity, death, withdrawal of consent, loss to follow-up or end of the study. |
| Time to Response (TTR) | Throughout the study period. Approximately 48 months | The time from the date of inclusion and the first documented evidence of response (PR or better) among participants who achieve confirmed PR or better. |
| Duration of Response (DoR) | Throughout the study period. Approximately 48 months | The time from first documented evidence of PR or better until progressive disease (PD) or death due to PD among participants who achieved PR or better. |
| Progression-Free Survival (PFS) | Throughout the study period. Approximately 48 months | The time from the date of inclusion until the earliest date of documented disease progression or death due to any cause. |
| Progression-Free Survival 2 (PFS2) | Throughout the study period. Approximately 48 months | The time from inclusion to disease progression after initiation of new anti-cancer therapy or death from any cause, whichever is earlier. If disease progression after new anti-cancer therapy cannot be measured, a PFS event is defined as the date of discontinuation of new anti-cancer therapy, or death from any cause, whichever is earlier. |
| Overall Survival (OS) | Throughout the study period. Approximately 48 months | Defined as the time from the date of inclusion until the date of death due to any cause. |
| Efficiency of hematopoietic stem cell collection | After cycle 4 of induction, 4 months after inclusion. | Number of CD34 cells collected after 2 induction cycles of treatment of belantamab mafodotin + 4 induction cycles of treatment of VRd. |
Countries
Spain
Contacts
STUDY_CHAIRMaria Victoria Mateos Manteca, M.D.; Ph.D.
Hospital Universitario de Salamanca (Salamanca)
STUDY_CHAIRJesus San Miguel Izquierdo, M.D.; Ph.D.
Clínica Universidad de Navarra (Pamplona)
Outcome results
None listed