Relapsed Multiple Myeloma, Relapsed-Refractory Multiple Myeloma
Conditions
Brief summary
This was a randomized, controlled, open-label, Phase 3 multicenter study which enrolled patients with Relapsed-Refractory Multiple Myeloma (RRMM) who were either double refractory to an Immunomodulatory Drug (IMiD) and a Proteasome Inhibitor (PI) (regardless of the number of prior lines of therapy), or had received at least 3 prior lines of therapy including an IMiD and a PI. Patients received treatment with melflufen+dexamethasone+daratumumab or daratumumab until documented progressive disease, unacceptable toxicity, or patient/treating physician decision. Patients in the daratumumab treatment arm had the option to receive treatment with melflufen+dexamethasone+daratumumab after confirmed progressive disease.
Interventions
DRUGMelflufen
Powder for solution for i.v. infusion
DRUGDexamethasone
Oral tablets
DRUGDaratumumab
Solution for s.c. injection
Sponsors
Oncopeptides AB
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Independent Review Committee was planned to be blinded to treatment assignment. Due to the early termination, the response assessments were only done by investigators, not by an independent review committee.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A prior diagnosis of multiple myeloma with documented disease progression after the last line of therapy * Double refractory to an IMiD and a PI (regardless of the number of prior lines of therapy) or have received at least 3 prior lines of therapy including an IMiD and a PI * Prior treatment with daratumumab or another anti-CD38 antibody may be allowed under certain circumstances: * Achieved at least partial response (PR) and not refractory to an anti-CD38 antibody * At least 6 months since the last dose of anti-CD38 antibody * Not discontinued anti-CD38 antibody treatment due to related Grade ≥ 3 toxicity * Male and female of childbearing potential agree to use contraception during the treatment period and at least 3 months after the last dose
Exclusion criteria
* Primary refractory disease (i.e., never responded with at least Minimal Response to any prior therapy for multiple myeloma) * Prior treatment with CD38 CAR-T cell therapy or CD38/CD3 bispecific antibodies * Any medical condition that may interfere with safety or participation in this study * 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 * Known or suspected amyloidosis, plasma cell leukemia, or POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) * Known central nervous system (CNS) or meningeal involvement of myeloma * Prior stem cell transplant (autologous and/or allogenic) within 6 months of initiation of therapy or prior allogeneic stem cell transplantation with active graft-versus-host-disease * Prior treatment with melflufen
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | From the date of randomization until the end of study (approximately 12 months). | Time from the date of randomization to the date of first documentation of confirmed progressive disease (PD) or death due to any cause, whichever occurred first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | From the date of randomization until the end of study (approximately 12 months). | Time from the first evidence of confirmed assessment of sCR, CR, VGPR or PR to first confirmed disease progression, or death due to any cause. DOR is defined only for patients with a confirmed PR or better. |
| Best Response | From the date of randomization until the end of study (approximately 12 months). | Proportion of patients with sCR, CR, VGPR, PR, Minimal Response (MR), Stable Disease (SD), PD, or non-evaluable (NE). |
| Clinical Benefit Rate (CBR) | From the date of randomization until the end of study (approximately 12 months). | The proportion of patients who achieve a best confirmed response of sCR, CR, VGPR, PR, or MR. |
| Duration of Clinical Benefit (DOCB) | From the date of randomization until the end of study (approximately 12 months). | Time from first evidence of confirmed assessment of sCR, CR, VGPR, PR, or MR to first confirmed disease progression, or to death due to any cause. DOCB is defined only for patients with a confirmed MR or better. |
| Overall Response Rate (ORR) | From the date of randomization until the end of study (approximately 12 months). | Proportion of patients who achieve a best-confirmed response of stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR). |
| Time to Progression (TTP) | From the date of randomization until the end of study (approximately 12 months). | Time from randomization to the date of the first documented confirmed PD |
| Time to Next Treatment (TTNT) | From the date of randomization until the end of study (approximately 12 months). | Time from randomization to the date of next anti-myeloma treatment or until death. |
| Overall Survival (OS) | From the date of randomization until the end of study (approximately 12 months). | Time from randomization to death due to any cause. |
| Time to Response (TTR) | From the date of randomization until the end of study (approximately 12 months). | Time from randomization to the date of the first documented confirmed response in a patient who has responded with ≥PR. |
Countries
Bulgaria, Czechia, Georgia, Germany, Greece, Norway, Poland, Russia, Serbia, Spain, Ukraine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Melflufen+Dexamethasone+Daratumumab) Treatment was given in 28-day cycles in an outpatient treatment setting.
* Melflufen 30 mg intravenous (i.v.) infusion on Day 1 of each cycle
* Dexamethasone 40 mg per oral (p.o.) weekly (20 mg p.o. weekly if ≥75 years)
* Daratumumab 1800 mg subcutaneously (s.c.) on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7 | 27 |
| Arm B (Daratumumab) Treatment was given in 28-day cycles in an outpatient treatment setting.
• Daratumumab 1800 mg s.c. on Days 1, 8, 15, and 22 in Cycles 1 and 2, on Days 1 and 15 in Cycles 3 to 6, and on Day 1 from Cycle 7 | 27 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Arm A/Arm B Treatment | Adverse Event | 0 | 3 |
| Arm A/Arm B Treatment | Failed Criteria for Treatment Initiation | 4 | 1 |
| Arm A/Arm B Treatment | Other | 1 | 0 |
| Arm A/Arm B Treatment | Patient Request | 1 | 0 |
| Arm A/Arm B Treatment | Physician Decision | 1 | 1 |
| Arm A/Arm B Treatment | Progressive Disease | 3 | 12 |
| Arm A/Arm B Treatment | Study Terminated by Sponsor | 17 | 10 |
| Crossover (Arm B) | Adverse Event | 0 | 1 |
| Crossover (Arm B) | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Arm A (Melflufen+Dexamethasone+Daratumumab) | Arm B (Daratumumab) | Total |
|---|---|---|---|
| Age, Continuous | 64.5 years | 66.7 years | 65.6 years |
| Age, Customized <65 | 12 Participants | 8 Participants | 20 Participants |
| Age, Customized 65 - ≤75 | 13 Participants | 16 Participants | 29 Participants |
| Age, Customized >75 | 2 Participants | 3 Participants | 5 Participants |
| Eastern Cooperative Oncology Group (ECOG) score score = 0 | 8 Participants | 6 Participants | 14 Participants |
| Eastern Cooperative Oncology Group (ECOG) score score = 1 | 18 Participants | 15 Participants | 33 Participants |
| Eastern Cooperative Oncology Group (ECOG) score score = 2 | 1 Participants | 6 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 27 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 170.4 cm | 167.0 cm | 168.7 cm |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 27 Participants | 54 Participants |
| Sex: Female, Male Female | 11 Participants | 10 Participants | 21 Participants |
| Sex: Female, Male Male | 16 Participants | 17 Participants | 33 Participants |
| Weight | 79.46 kg | 78.75 kg | 79.1 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 22 | 3 / 26 | 1 / 2 |
| other Total, other adverse events | 21 / 22 | 22 / 26 | 2 / 2 |
| serious Total, serious adverse events | 6 / 22 | 12 / 26 | 1 / 2 |
Outcome results
Primary
Progression Free Survival (PFS)
Time from the date of randomization to the date of first documentation of confirmed progressive disease (PD) or death due to any cause, whichever occurred first.
Time frame: From the date of randomization until the end of study (approximately 12 months).
Population: Analysis was performed using the Full Analysis Set (FAS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Progression Free Survival (PFS) | NA months |
| Arm B (Daratumumab) | Progression Free Survival (PFS) | 4.86 months |
p-value: =0.003295% CI: [0.052, 0.65]Log Rank
Secondary
Best Response
Proportion of patients with sCR, CR, VGPR, PR, Minimal Response (MR), Stable Disease (SD), PD, or non-evaluable (NE).
Time frame: From the date of randomization until the end of study (approximately 12 months).
Population: Analysis was performed using the Full Analysis Set (FAS).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Best Response | Partial Response (PR) | 11 Participants |
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Best Response | Stable Disease (SD) | 3 Participants |
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Best Response | Very Good Partial Response (VGPR) | 4 Participants |
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Best Response | Progressive Disease (PD) | 1 Participants |
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Best Response | Minimal Response (MR) | 3 Participants |
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Best Response | Not Evaluable (NE) | 4 Participants |
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Best Response | Complete Response (CR) | 1 Participants |
| Arm B (Daratumumab) | Best Response | Not Evaluable (NE) | 4 Participants |
| Arm B (Daratumumab) | Best Response | Complete Response (CR) | 0 Participants |
| Arm B (Daratumumab) | Best Response | Very Good Partial Response (VGPR) | 3 Participants |
| Arm B (Daratumumab) | Best Response | Partial Response (PR) | 5 Participants |
| Arm B (Daratumumab) | Best Response | Minimal Response (MR) | 5 Participants |
| Arm B (Daratumumab) | Best Response | Stable Disease (SD) | 5 Participants |
| Arm B (Daratumumab) | Best Response | Progressive Disease (PD) | 5 Participants |
Secondary
Clinical Benefit Rate (CBR)
The proportion of patients who achieve a best confirmed response of sCR, CR, VGPR, PR, or MR.
Time frame: From the date of randomization until the end of study (approximately 12 months).
Population: Analysis was performed using the Full Analysis Set (FAS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Clinical Benefit Rate (CBR) | 70.4 percentage of patients |
| Arm B (Daratumumab) | Clinical Benefit Rate (CBR) | 48.1 percentage of patients |
p-value: 0.0997Cochran-Mantel-Haenszel
Secondary
Duration of Clinical Benefit (DOCB)
Time from first evidence of confirmed assessment of sCR, CR, VGPR, PR, or MR to first confirmed disease progression, or to death due to any cause. DOCB is defined only for patients with a confirmed MR or better.
Time frame: From the date of randomization until the end of study (approximately 12 months).
Population: Analysis was performed using the Full Analysis Set (FAS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Duration of Clinical Benefit (DOCB) | NA months |
| Arm B (Daratumumab) | Duration of Clinical Benefit (DOCB) | NA months |
p-value: 0.01695% CI: [0.013, 0.96]Log Rank
Secondary
Duration of Response (DOR)
Time from the first evidence of confirmed assessment of sCR, CR, VGPR or PR to first confirmed disease progression, or death due to any cause. DOR is defined only for patients with a confirmed PR or better.
Time frame: From the date of randomization until the end of study (approximately 12 months).
Population: Analysis was performed using the Full Analysis Set (FAS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Duration of Response (DOR) | NA months |
| Arm B (Daratumumab) | Duration of Response (DOR) | NA months |
p-value: 0.52595% CI: [0.026, 6.693]Log Rank
Secondary
Overall Response Rate (ORR)
Proportion of patients who achieve a best-confirmed response of stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), or Partial Response (PR).
Time frame: From the date of randomization until the end of study (approximately 12 months).
Population: Analysis was performed using the Full Analysis Set (FAS).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Overall Response Rate (ORR) | 59.3 percentage of patients |
| Arm B (Daratumumab) | Overall Response Rate (ORR) | 29.6 percentage of patients |
p-value: 0.03Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS)
Time from randomization to death due to any cause.
Time frame: From the date of randomization until the end of study (approximately 12 months).
Population: Analysis was performed using the Full Analysis Set (FAS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Overall Survival (OS) | 11.04 months |
| Arm B (Daratumumab) | Overall Survival (OS) | NA months |
p-value: 0.372195% CI: [0.086, 2.569]Log Rank
Secondary
Time to Next Treatment (TTNT)
Time from randomization to the date of next anti-myeloma treatment or until death.
Time frame: From the date of randomization until the end of study (approximately 12 months).
Population: Analysis was performed using the Full Analysis Set (FAS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Time to Next Treatment (TTNT) | 11.04 months |
| Arm B (Daratumumab) | Time to Next Treatment (TTNT) | NA months |
p-value: 0.038495% CI: [0.047, 1.056]Log Rank
Secondary
Time to Progression (TTP)
Time from randomization to the date of the first documented confirmed PD
Time frame: From the date of randomization until the end of study (approximately 12 months).
Population: Analysis was performed using the Full Analysis Set (FAS).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Time to Progression (TTP) | NA months |
| Arm B (Daratumumab) | Time to Progression (TTP) | NA months |
p-value: 0.018795% CI: [0.063, 0.846]Log Rank
Secondary
Time to Response (TTR)
Time from randomization to the date of the first documented confirmed response in a patient who has responded with ≥PR.
Time frame: From the date of randomization until the end of study (approximately 12 months).
Population: Analysis was performed using the Full Analysis Set (FAS).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm A (Melflufen+Dexamethasone+Daratumumab) | Time to Response (TTR) | 1.8 months | Standard Deviation 1 |
| Arm B (Daratumumab) | Time to Response (TTR) | 1.8 months | Standard Deviation 1.1 |