Multiple Myeloma
Conditions
Keywords
Refractory Multiple Myeloma, Relapsed Multiple Myeloma, Melphalan flufenamide (Melflufen), Pomalidomide, Dexamethasone
Brief summary
This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with RRMM following 2-4 lines of prior therapy and who were refractory to lenalidomide in the last line of therapy as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide. Patients received either melflufen+dex or pomalidomide+dex.
Detailed description
This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with RRMM following 2-4 lines of prior therapy and who were refractory to lenalidomide in the last line of therapy as demonstrated by disease progression on or within 60 days of completion of the last dose of lenalidomide. Patients were randomized to either one of two arms: Arm A: Melphalan flufenamide (Melflufen) 40 mg on Day 1 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle. Arm B: Pomalidomide 4 mg daily on Days 1 to 21 and dexamethasone 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle. Patients ≥ 75 years of age received a reduced dose of dexamethasone of 20 mg on Days 1, 8, 15 and 22 for both Arm A and Arm B. Patients were to receive treatment until such time as there was documented disease progression, unacceptable toxicity, or the patient/treating physician determined it was not in the patient's best interest to continue. Dose modifications and delays in therapy may have been implemented based on patient tolerability as detailed in the protocol. In the event of a cycle delay, unrelated to dexamethasone toxicity, it was recommended to continue dexamethasone weekly.
Interventions
Sponsors
Oncopeptides AB
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female, age 18 years or older 2. A prior diagnosis of multiple myeloma with documented disease progression requiring further treatment at time of screening 3. Measurable disease defined as any of the following: * Serum monoclonal protein ≥ 0.5 g/dL by protein electrophoresis. * ≥ 200 mg/24 hours of monoclonal protein in the urine on 24-hour electrophoresis * Serum free light chain ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain ratio 4. Received 2-4 prior lines of therapy, including lenalidomide and a PI, either sequential or in the same line, and is refractory (relapsed and refractory or refractory) to both the last line of therapy and to lenalidomide (≥ 10 mg) administered within 18 months prior to randomization. Refractory to lenalidomide is defined as progression while on lenalidomide therapy or within 60 days of last dose, following at least 2 cycles of lenalidomide with at least 14 doses of lenalidomide per cycle. 5. Life expectancy of ≥ 6 months 6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. 7. Females of child bearing potential (FCBP) must have a negative serum or urine pregnancy test prior to start of treatment. Participants must agree to ongoing pregnancy testing. All patients must be willing to comply with all requirements of the USA pomalidomide Risk Evaluation and Mitigation Strategy (REMS) program or the pomalidomide Pregnancy Prevention Plan (PPP). 8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent. 9. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec Fridericia Formula. 10. The following laboratory results must be met during screening and also immediately before study drug administration on Cycle 1 Day 1: * Absolute neutrophil count (ANC) ≥ 1,000 cells/mm\^3 (1.0 x 10\^9/L) * Platelet count ≥ 75,000 cells/mm\^3 (75 x 10\^9/L) * Hemoglobin ≥ 8.0 g/dl * Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), or patients diagnosed with Gilberts syndrome, that have been reviewed and approved by the medical monitor. * Aspartate transaminase (AST /SGOT) and alanine transaminase (ALT/SGPT) ≤ 3.0 x ULN. * Renal function: Estimated creatinine clearance by Cockcroft-Gault formula ≥ 45 mL/min. 11. Must be able to take antithrombotic prophylaxis. 12. Must have, or be willing to have an acceptable central catheter. (Port a cath, peripherally inserted central catheter \[PICC-line\], or central venous catheter) (Insertion only required if randomized to Arm A).
Exclusion criteria
1. Primary refractory disease (i.e. never responded (≥ MR) to any prior therapy) 2. Evidence of mucosal or internal bleeding or platelet transfusion refractory 3. Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study. 4. Prior exposure to pomalidomide 5. Known intolerance to IMiDs. 6. Known active infection requiring parenteral or oral anti-infective treatment within 14 days of randomization. 7. Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active surveillance. 8. Pregnant or breast-feeding females 9. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation 10. Known human immunodeficiency virus or active hepatitis C viral infection 11. Active hepatitis B viral infection (defined as HBsAg+). * Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-HBs+, Anti-HBc-). * Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) may be enrolled at the discretion of the investigator after consideration of risk of reactivation. 12. Concurrent symptomatic amyloidosis or plasma cell leukemia 13. POEMS syndrome 14. Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to randomization. IMiDs, PIs and or corticosteroids within 2 weeks prior to randomization. Other investigational therapies and monoclonal antibodies within 4 weeks of randomization. Prednisone up to but no more than 10 mg orally q.d. or its equivalent for symptom management of comorbid conditions is permitted but dose should be stable for at least 7 days prior to randomization 15. Residual side effects to previous therapy \> grade 1 prior to randomization (Alopecia any grade and/or neuropathy grade 2 without pain are permitted) 16. Prior peripheral stem cell transplant within 12 weeks of randomization 17. Prior allogeneic stem cell transplantation with active graft-versus-host-disease. 18. Prior major surgical procedure or radiation therapy within 4 weeks of the randomization 19. Known intolerance to steroid therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | From date of randomization until first evidence of confirmed disease progression or death due to any cause (whichever occurred first), up to the data cutoff date of 03 Feb 2021 (ie, assessed up to approximately 43 months). | Progression Free Survival defined as the duration in months from randomization until first evidence of confirmed disease progression, as assessed by the Independent Review Committee (IRC) according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). Disease progression was defined according to the IMWG-URC as progressive disease or death due to any cause, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | From randomization until best response achieved before confirmed disease progression or death due to any cause, up to data cutoff of 03 Feb 2021 (ie, assessed up to approx. 43 months). Median time to best response: Arm A=2.1 months and Arm B=2.0 months | ORR defined as the proportion of patients for whom the best overall confirmed response is stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR), as assessed by IRC. |
| Duration of Response (DOR) | From first documentation of a confirmed response to first evidence of confirmed disease progression or death due to any cause, up to the data cutoff date of 03 Feb 2021 (ie, assessed up to approximately 43 months). | DOR defined as the duration in months from first documentation of a confirmed response to first evidence of confirmed disease progression or death due to any cause. |
| Overall Survival (OS) | From date of randomization until up to 24 months following confirmed disease progression or initiation of subsequent therapy, up to the data cutoff date of 03 Feb 2023 (ie, assessed up to approximately 67 months). | OS defined as the time in months from randomization to date of death due to any cause. Patients who were still alive at end of study, or lost to follow up, were censored at the last day the patient was known to be alive. |
| Safety and Tolerability: Number of Patients With Treatment-emergent Adverse Events (TEAEs), Including Clinical Laboratory and Vital Signs Abnormalities, as Assessed by CTCAE v4.0 | From start of dosing until 30 days after the last dose of study treatment, up to the data cutoff date of 03 Feb 2023 (ie, assessed up to approximately 67 months). Median duration of study treatment was 25.2 and 22.1 weeks for Arm A and B, respectively. | Number of patients with TEAEs, including clinical laboratory and vital signs abnormalities, as assessed by CTCAE v4.0 are presented. No formal statistical analysis was performed for safety endpoints. |
Countries
Austria, Belgium, Czechia, Denmark, Estonia, France, Greece, Hungary, Israel, Italy, Lithuania, Netherlands, Norway, Poland, Romania, Russia, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
The recruitment was performed from specialized clinics' own patient pool at 115 different treatment sites in the US, Europe and Asia (20 different countries). The first patient was recruited in 12-Jun-2017 and the last patient 25-Aug-2020.
Pre-assignment details
246 patients were randomized to treatment Arm A, 249 patients to treatment Arm B (FAS). Of the 495 randomized patients, 228 patients in Arm A received treatment and 246 patients in Arm B received treatment (SAF). The protocol had pre-defined treatment criteria for specific laboratory values, and if the patient's values deteriorated between screening and C1D1, treatment could not be initiated. In total, 664 patients were screened, 495 randomized, 474 treated, 21 randomized but not treated.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Melflufen+Dexamethasone Melflufen 40 mg i.v. on Day 1 and dexamethasone 40 mg (20 mg for patients ≥ 75 years of age) on Days 1, 8, 15 and 22 of each 28-day cycle. Patients were to be treated until confirmed progression, unacceptable toxicity, or the patient or investigator decided it was not in the patient's best interest to continue.
Melflufen: Intravenous infusion
Dexamethasone: Oral tablets | 246 |
| Arm B: Pomalidomide+Dexamethasone Pomalidomide 4 mg orally daily on Days 1 to 21 and dexamethasone 40 mg (20 mg for patients ≥ 75 years of age) on Days 1, 8, 15 and 22 of each 28-day cycle. Patients were to be treated until confirmed progression, unacceptable toxicity, or the patient or investigator decided it was not in the patient's best interest to continue.
Pomalidomide: Oral capsules
Dexamethasone: Oral tablets | 249 |
| Total | 495 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 49 | 40 |
| Overall Study | Lack of Efficacy | 6 | 8 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 21 | 9 |
| Overall Study | Progressive Disease | 130 | 170 |
| Overall Study | Randomized But Not Treated | 18 | 3 |
| Overall Study | Study Terminated by Sponsor | 5 | 11 |
| Overall Study | Withdrawal by Subject | 17 | 7 |
Baseline characteristics
| Characteristic | Arm A: Melflufen+Dexamethasone | Arm B: Pomalidomide+Dexamethasone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 150 Participants | 164 Participants | 314 Participants |
| Age, Categorical Between 18 and 65 years | 96 Participants | 85 Participants | 181 Participants |
| Age, Continuous | 68 years | 68 years | 68 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 5 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 232 Participants | 237 Participants | 469 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 7 Participants | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 13 Participants | 21 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 4 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 10 Participants | 20 Participants |
| Race (NIH/OMB) White | 224 Participants | 222 Participants | 446 Participants |
| Region of Enrollment Austria | 1 participants | 2 participants | 3 participants |
| Region of Enrollment Belgium | 3 participants | 2 participants | 5 participants |
| Region of Enrollment Czechia | 29 participants | 30 participants | 59 participants |
| Region of Enrollment Denmark | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Estonia | 3 participants | 1 participants | 4 participants |
| Region of Enrollment France | 9 participants | 10 participants | 19 participants |
| Region of Enrollment Greece | 23 participants | 23 participants | 46 participants |
| Region of Enrollment Hungary | 17 participants | 14 participants | 31 participants |
| Region of Enrollment Israel | 7 participants | 7 participants | 14 participants |
| Region of Enrollment Italy | 16 participants | 14 participants | 30 participants |
| Region of Enrollment Lithuania | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Netherlands | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Norway | 14 participants | 19 participants | 33 participants |
| Region of Enrollment Poland | 23 participants | 24 participants | 47 participants |
| Region of Enrollment Romania | 10 participants | 10 participants | 20 participants |
| Region of Enrollment Russia | 40 participants | 39 participants | 79 participants |
| Region of Enrollment South Korea | 7 participants | 8 participants | 15 participants |
| Region of Enrollment Spain | 22 participants | 20 participants | 42 participants |
| Region of Enrollment Taiwan | 1 participants | 4 participants | 5 participants |
| Region of Enrollment United Kingdom | 5 participants | 5 participants | 10 participants |
| Region of Enrollment United States | 11 participants | 15 participants | 26 participants |
| Sex: Female, Male Female | 107 Participants | 109 Participants | 216 Participants |
| Sex: Female, Male Male | 139 Participants | 140 Participants | 279 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 180 / 246 | 169 / 249 |
| other Total, other adverse events | 227 / 228 | 243 / 246 |
| serious Total, serious adverse events | 99 / 228 | 124 / 246 |
Outcome results
Primary
Progression Free Survival (PFS)
Progression Free Survival defined as the duration in months from randomization until first evidence of confirmed disease progression, as assessed by the Independent Review Committee (IRC) according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC). Disease progression was defined according to the IMWG-URC as progressive disease or death due to any cause, whichever occurs first.
Time frame: From date of randomization until first evidence of confirmed disease progression or death due to any cause (whichever occurred first), up to the data cutoff date of 03 Feb 2021 (ie, assessed up to approximately 43 months).
Population: All randomized patients (Full Analysis Set as per protocol) were included into the primary outcome measure analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Melflufen+Dexamethasone | Progression Free Survival (PFS) | 6.83 months |
| Arm B: Pomalidomide+Dexamethasone | Progression Free Survival (PFS) | 4.93 months |
p-value: 0.0311Log Rank
Secondary
Duration of Response (DOR)
DOR defined as the duration in months from first documentation of a confirmed response to first evidence of confirmed disease progression or death due to any cause.
Time frame: From first documentation of a confirmed response to first evidence of confirmed disease progression or death due to any cause, up to the data cutoff date of 03 Feb 2021 (ie, assessed up to approximately 43 months).
Population: Full Analysis Set (all patients randomized to either Arm A or Arm B).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Melflufen+Dexamethasone | Duration of Response (DOR) | 11.17 months |
| Arm B: Pomalidomide+Dexamethasone | Duration of Response (DOR) | 11.07 months |
Secondary
Overall Response Rate (ORR)
ORR defined as the proportion of patients for whom the best overall confirmed response is stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR), as assessed by IRC.
Time frame: From randomization until best response achieved before confirmed disease progression or death due to any cause, up to data cutoff of 03 Feb 2021 (ie, assessed up to approx. 43 months). Median time to best response: Arm A=2.1 months and Arm B=2.0 months
Population: Full Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Melflufen+Dexamethasone | Overall Response Rate (ORR) | 80 Participants |
| Arm B: Pomalidomide+Dexamethasone | Overall Response Rate (ORR) | 67 Participants |
Secondary
Overall Survival (OS)
OS defined as the time in months from randomization to date of death due to any cause. Patients who were still alive at end of study, or lost to follow up, were censored at the last day the patient was known to be alive.
Time frame: From date of randomization until up to 24 months following confirmed disease progression or initiation of subsequent therapy, up to the data cutoff date of 03 Feb 2023 (ie, assessed up to approximately 67 months).
Population: Full Analysis Set (all patients randomized to either Arm A or Arm B).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Melflufen+Dexamethasone | Overall Survival (OS) | 20.24 Months |
| Arm B: Pomalidomide+Dexamethasone | Overall Survival (OS) | 23.98 Months |
Secondary
Safety and Tolerability: Number of Patients With Treatment-emergent Adverse Events (TEAEs), Including Clinical Laboratory and Vital Signs Abnormalities, as Assessed by CTCAE v4.0
Number of patients with TEAEs, including clinical laboratory and vital signs abnormalities, as assessed by CTCAE v4.0 are presented. No formal statistical analysis was performed for safety endpoints.
Time frame: From start of dosing until 30 days after the last dose of study treatment, up to the data cutoff date of 03 Feb 2023 (ie, assessed up to approximately 67 months). Median duration of study treatment was 25.2 and 22.1 weeks for Arm A and B, respectively.
Population: Safety Analysis Set (all patients that have received at least one dose of study drug in either Arm A or Arm B).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Melflufen+Dexamethasone | Safety and Tolerability: Number of Patients With Treatment-emergent Adverse Events (TEAEs), Including Clinical Laboratory and Vital Signs Abnormalities, as Assessed by CTCAE v4.0 | 227 Participants |
| Arm B: Pomalidomide+Dexamethasone | Safety and Tolerability: Number of Patients With Treatment-emergent Adverse Events (TEAEs), Including Clinical Laboratory and Vital Signs Abnormalities, as Assessed by CTCAE v4.0 | 243 Participants |