Multiple Myeloma
Conditions
Keywords
Newly diagnosed, multiple myeloma, myeloma, bendamustine, Treanda, carfilzomib, dexamethasone, phase I, phase II, dose escalation, transplant, non-transplant, plasma cell, Kyprolis
Brief summary
This study is designed to define dose-limiting toxicity and determine preliminary evidence of efficacy of carfilzomib (CFZ) in combination with bendamustine and dexamethasone for patients with newly diagnosed multiple myeloma (MM).
Detailed description
Multiple myeloma (MM) is a malignant plasma cell disorder resulting in approximately 11,000 deaths in the United States each year. It is estimated that between 60,000-80,000 people are currently under treatment for refractory or relapsed MM. Prognosis and survival have improved over the last 20 years, but the disease is still universally fatal despite efforts to develop new and more effective chemotherapeutic regimens. Therefore, new regimens need to be developed for patients prior to peripheral blood stem cell transplant and for those unable to tolerate the toxicity of transplant. An IRB-approved long-term retrospective chart review study (IRB-AAAU4389) was conducted to collect data for Outcome Measures relating to long-term analysis (up to 6.5 years).
Interventions
DRUGBendamustine
Bendamustine will be administered IV on days 1 and 2 with dose escalation up to 90 mg/m2 of each 28-day cycle. Dose escalation is as follows: -1 \| 60 mg/m2 1. \| 70 mg/m2 2. \| 70 mg/m2 3. \| 90 mg/m2 4. \| 90mg/m2 5. \| 90 mg/m2
DRUGCarfilzomib
Carfilzomib will be administered IV on Days 1, 2, 8, 9, 15, and 16 every 28 days. Dose Escalation is as follows: -1 \| 27 mg/m2 1. \| 27 mg/m2 2. \| 36 mg/m2 3. \| 36 mg/m2 4. \| 45 mg/m2 5. \| 56 mg/m2
DRUGDexamethasone
Dexamethasone will be administered PO or IV, 20 mg, on 1, 2, 8, 9, 15, 16 and 22, 23 of each 28-day cycle.
Sponsors
Suzanne Lentzsch, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years. 2. Life expectancy ≥ 3 months. 3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. 4. Adequate hepatic function. 5. Sufficient Absolute neutrophil count (ANC) within 14 days prior to randomization. 6. Sufficient Hemoglobin within 14 days prior to randomization (subjects may be receiving red blood cell (RBC) transfusions in accordance with institutional guidelines). 7. Sufficient platelet count 14 days prior to randomization. 8. Creatinine Clearance ≥ 30 mL/minute within 7 days prior to randomization. 9. Left Ventricular Ejection Fraction ≥ 40%. 10. Written informed consent in accordance with federal, local, and institutional guidelines. 11. Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to practice contraception. 12. Male subjects must agree to practice contraception. 13. Patients must have histologically or cytologically confirmed symptomatic multiple myeloma (MM). Patients should not have previously been treated. 14. Prior kyphoplasty, vertebroplasty, local radiation therapy for symptomatic bone lesions (e.g., uncontrolled pain or high risk of pathologic fracture) are permitted. 15. Patients are allowed up to two cycles of high dose steroids if needed for symptomatic disease before study enrollment.
Exclusion criteria
1. Patients who have had chemotherapy for Multiple Myeloma. Exception: local radiation therapy for symptomatic bone lesions (e.g., uncontrolled pain or high risk of pathologic fracture). 2. Patients currently receiving high dose systemic steroids for treatment of Multiple Myeloma in excess of 320mg total dose of dexamethasone or equivalent, patients who received an investigational agent within 5 half-lives of the agent. 3. Patients with non-measurable Multiple Myeloma or primary plasma cell leukemia. 4. Pregnant or lactating females. 5. Major surgery within 21 days prior to enrollment. 6. Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to enrollment. 7. Known human immunodeficiency virus (HIV) infection. 8. Known active hepatitis B or C infection. 9. Unstable angina or myocardial infarction within 4 months prior to enrollment. 10. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment. 11. Uncontrolled, non-hematologic malignancy requiring active treatment. 12. Patients with known brain metastases (treated or not) will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. 13. Significant neuropathy within 14 days prior to randomization. 14. Known history of allergy to Captisol, or to other agents in the study. 15. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment. 16. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrollment. 17. Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Carfilzomib in Combination With Bendamustine and Dexamethasone | 6 months | MTD defined as the highest dose at which ≤20% of participants experience dose-limiting toxicity (DLT), to define the recommended phase II dose. DLT were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute version 4.0. An AE was considered a DLT if it occurred in cycle 1, was deemed related to study treatment, and was one of peripheral neuropathy ≥grade 2, any non-hematologic AE ≥ grade 3, neutropenia grade 4 lasting ≥7 days or with fever, thrombocytopenia grade 4 lasting ≥7 days or with bleeding, or any AE requiring a dose reduction during cycle 1 or a delay in the start of cycle 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Next Treatment (TTNT) | Up to 6.5 years | The TTNT is measured from the date of initiation of treatment to the start date of the next treatment regimen. |
| Progression Free Survival (PFS) | Up to 6.5 Years | PFS is defined as the duration of time from start of study treatment to time of progression or death, whichever occurs first. |
| Overall Response Rate (ORR) | 2 years | ORR defined as the number of participants demonstrating complete response or partial response. Complete response defined as complete disappearance of an M-protein and no evidence of MM in the bone marrow. Partial response defined as ≥50% reduction in the level of the serum monoclonal paraprotein, reduction in 24-hour M-protein either by greater than or equal to 90% or to \<200 mg, ≥50% reduction in size of soft tissue plasmacytoma (by radiography or clinical examination), no increase in the number or size of lytic bone lesions. |
| Overall Survival (OS) Rate | Up to 6.5 Years | The percentage of people who are still alive. |
| Number of Adverse Events (AEs) | 30 Days Post Last Dose, Up to approximately 9 months | Total number of AEs observed. |
| Time to Best Response | 2 years | Time to the best response recorded. |
Countries
United States
Participant flow
Pre-assignment details
23 participants signed a consent form; 2 were screen fails and 1 was removed from the study prior to the study start and did not receive the study interventions.
Participants by arm
| Arm | Count |
|---|---|
| CFZ With Bendamustine and Dexamethasone First participant received: CFZ 27mg/m\^2, Bendamustine 70mg/m\^2, Dexamethasone 20mg; Second participant received: CFZ 36mg/m\^2, Bendamustine 70mg/m\^2, Dexamethasone 20mg; Third participant received: CFZ 36mg/m\^2, Bendamustine 90mg/m\^2, Dexamethasone 20mg; Fourth participant received: CFZ 45mg/m\^2, Bendamustine 90mg/m\^2, Dexamethasone 20mg; Fifth participant and all other participants received: CFZ 56mg/m\^2, Bendamustine 90mg/m\^2, Dexamethasone 20mg.
Data was collected and analyzed as one arm for this single-arm study. Additionally, presented as one arm to protect the confidentiality of the first four participants. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Dose Level 1 | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | CFZ With Bendamustine and Dexamethasone |
|---|---|
| Age, Continuous | 65 years |
| Race/Ethnicity, Customized Hispanic | 7 Participants |
| Race/Ethnicity, Customized Non-Hispanic | 13 Participants |
| Region of Enrollment United States | 20 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 20 |
| other Total, other adverse events | 20 / 20 |
| serious Total, serious adverse events | 7 / 20 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Carfilzomib in Combination With Bendamustine and Dexamethasone
MTD defined as the highest dose at which ≤20% of participants experience dose-limiting toxicity (DLT), to define the recommended phase II dose. DLT were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute version 4.0. An AE was considered a DLT if it occurred in cycle 1, was deemed related to study treatment, and was one of peripheral neuropathy ≥grade 2, any non-hematologic AE ≥ grade 3, neutropenia grade 4 lasting ≥7 days or with fever, thrombocytopenia grade 4 lasting ≥7 days or with bleeding, or any AE requiring a dose reduction during cycle 1 or a delay in the start of cycle 2.
Time frame: 6 months
Population: A total of 19 out of 19 participants were analyzed when evaluating the maximum tolerated dose. Participants who received dose level 5 continued to be evaluated for dose limiting toxicities.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CFZ With Bendamustine and Dexamethasone | Maximum Tolerated Dose (MTD) of Carfilzomib in Combination With Bendamustine and Dexamethasone | 56 mg/m^2 |
Secondary
Number of Adverse Events (AEs)
Total number of AEs observed.
Time frame: 30 Days Post Last Dose, Up to approximately 9 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CFZ With Bendamustine and Dexamethasone | Number of Adverse Events (AEs) | 106 Adverse Events |
Secondary
Overall Response Rate (ORR)
ORR defined as the number of participants demonstrating complete response or partial response. Complete response defined as complete disappearance of an M-protein and no evidence of MM in the bone marrow. Partial response defined as ≥50% reduction in the level of the serum monoclonal paraprotein, reduction in 24-hour M-protein either by greater than or equal to 90% or to \<200 mg, ≥50% reduction in size of soft tissue plasmacytoma (by radiography or clinical examination), no increase in the number or size of lytic bone lesions.
Time frame: 2 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CFZ With Bendamustine and Dexamethasone | Overall Response Rate (ORR) | 19 participants |
Secondary
Overall Survival (OS) Rate
The percentage of people who are still alive.
Time frame: Up to 6.5 Years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CFZ With Bendamustine and Dexamethasone | Overall Survival (OS) Rate | 17 Participants |
Secondary
Progression Free Survival (PFS)
PFS is defined as the duration of time from start of study treatment to time of progression or death, whichever occurs first.
Time frame: Up to 6.5 Years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CFZ With Bendamustine and Dexamethasone | Progression Free Survival (PFS) | 77 Months |
Secondary
Time to Best Response
Time to the best response recorded.
Time frame: 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CFZ With Bendamustine and Dexamethasone | Time to Best Response | 10.23 Months |
Secondary
Time to Next Treatment (TTNT)
The TTNT is measured from the date of initiation of treatment to the start date of the next treatment regimen.
Time frame: Up to 6.5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CFZ With Bendamustine and Dexamethasone | Time to Next Treatment (TTNT) | 77.0 months |