Multiple Myeloma
Conditions
Brief summary
A) Phase 1: To determine the maximal tolerated dose (MTD) of lenalidomide that can be safely added to high-dose melphalan prior to autologous stem cell transplantation (ASCT). B) Phase 2: To determine whether the addition of high-dose lenalidomide to ASCT followed by maintenance standard-dose lenalidomide improves the response rate and duration of response for relapsed multiple myeloma (RMM).
Detailed description
Experimental: Phase 1 Subjects will dose escalate lenalidomide in a series of subjects in a 3+3 design through 6 dose levels of lenalidomide (as per modified Fibonacci escalation) to determine the maximal tolerated dose (MTD)of lenalidomide prior to ASCT. Planned dose levels of lenalidomide in Phase 1 portion of study: Dose Level/ Lenalidomide Dose / Schedule -1: 25mg daily x 5 days 1. 25mg twice daily x 5 days 2. 25mg qAM, 50mq qPM x 5 days 3. 50mg qAM, 75mg qPM x 5 days 4. 75mg qAM, 100mg qPM x 5 days 5. 100mg qAM, 150mg qPM x 5 days 6. 150mg qAM, 200mg qPM x 5 days Experimental: Phase 2 The MTD determine for lenalidomide in the phase 1 portion of this study will be used in the transplant phase of the phase 2 portion. In the transplant phase of the study, all participants will receive oral lenalidomide at the pre-determined dose level for phase 1 and MTD for phase 2 for 5 days (designated as days -5 to -1). On days-2 and -1, all patients will receive 100mg/m2 of intravenous melphalan once daily for a total of 2 doses (200mg/m2total). After a period of 24-72 hours has elapsed from the last melphalan dose (designated as Day 0) each patient will receive infusion of at least 2.0 x 106/kg of autologous CD34+ stem cells. Maintenance lenalidomide will begin at Day +100 at a dose of 25 mg/day, orally for 1-21 days followed by a 7-day rest period (28 day cycles).
Interventions
DRUGlenalidomide
daily dose dependent on dose-escalation schedule
DRUGmelphalan
100 mg/m2 given Days -2 and -1
Sponsors
Weill Medical College of Cornell University
Celgene
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically or cytologically confirmed relapsed, primary refractory, or relapsed and refractory multiple myeloma. * Patients must have measurable disease as defined by the International Uniform Response Criteria,defined as any of the following: * serum M-protein of \> = 500mg/dL * urine M-protein of \> = 200mg/ 24 hours * involved free light chain \> = 10mg/dL provided serum free light chain ratio is abnormal * Patients must have received at least one prior line of therapy. * Age \> = 18 years. * Life expectancy of greater than 12 weeks. * ECOG performance status \< = 2. * All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist. * Patients must have normal organ and marrow function as defined below: * ANC \> = 1,000/uL * platelets \> = 50,000/uL * total bilirubin \< = 1.5 X upper limit of normal * AST(SGOT)/ALT(SGPT) \< = 2.5 X upper limit of normal * Cardiac Ejection Fraction \> = 45 % * Creatinine clearance \> 60 cc/min * Patients must have an adequate number of CD34+ stem cells collected to allow for transplantation. This number is defined as ≥ 2 x 106 CD34+ cells / kg body weight. If not previously collected and stored, the patient must be willing to undergo stem cell mobilization and collection as per standard practice. * The effects of lenalidomide on the developing human fetus at the recommended therapeutic dose are unknown; however, it has been shown to be teratogenic other primates. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. The treating physician will follow the adverse reporting guidelines as outlined in further detail below for pregnancies. * Lenalidomide has been shown to carry a risk of thromboembolic events, especially when used in combination with either corticosteroids or alkylating chemotherapeutic agents. All patients who participate in this study must be willing and able to tolerate prophylactic anticoagulation with low-molecular weight heparin (LMWH) for the required dates in treatment protocol. Patients also must be able to tolerate low-dose aspirin, 81 mg daily, during the maintenance phase of the treatment protocol. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Patients who have had myeloma therapy within 14 days prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier. Patients may have received bisphosphonate therapy as part of routine myeloma care at any time prior to study entry. * Patients may not be receiving any other investigational agents. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to lenalidomide (including thalidomide) or melphalan. * Known positive for HIV or infectious hepatitis, type B or C. * Uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Pregnant and lactating women are excluded from the study because the risks to an unborn fetus or potential risks in nursing infants are unknown. * History of thrombosis or thromboembolic event within last 60 days prior to study entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Lenalidomide That Can be Added to Melphalan | 12 months | The primary endpoint for the phase 1 portion of this study is to determine the maximum tolerated dose of lenalidomide that can be added to melphalan. |
| Duration of Overall Response (DoR) | Until disease progression, death, or for a maximum of 3 years, whichever occurs first | The primary endpoint for the phase 2 portion of this study is to determine the duration of overall response (DoR). The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Until disease progression or a maximum of 3 years, whichever occurs first | Overall response rate is the number of patients with complete response and partial response. Response is defined by the International Uniform Response Criteria for Multiple Myeloma (IURC) |
| Overall Survival | Until death or date of last contact with the subject | Overall survival is defined as the interval between the day of transplantation (Day 0) and date of death. If the date of death is uncertain, the date of last contact with the subject will be used. |
| Mean Functional Assessment of of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Score | Cycle 6, day 1, at approximately 4.5 months | quality of life will be evaluated and scored using the questionnaire from the bone marrow transplant subscale of the Functional Assessment of Cancer Therapy available from w ww.facit.org. The FACT-BMT is a 50 item questionnaire that measures five dimensions of quality of life in bone marrow transplant patients, including physical well-being, social and family well-being, emotional well-being, functional well-being, and additional concerns. It is scored on a 5 point Likert scale. Total scores range from 0 to 148, with a higher score indicating higher quality of life. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORRoger Pearse, MD
Weill Medical College of Cornell University
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 Dose Level 1 Oral lenalidomide 25mg twice daily x 5 days (designated as days -5 to -1).
On days-2 and -1, all patients will receive 100mg/m2 of intravenous melphalan once daily for a total of 2 doses (200mg/m2total). After a period of 24-72 hours has elapsed from the last melphalan dose (designated as Day 0) each patient will receive infusion of at least 2.0 x 106/kg of autologous CD34+ stem cells.
Maintenance lenalidomide will begin at Day +100 at a dose of 25 mg/day, orally for 1-21 days followed by a 7-day rest period (28 day cycles).
lenalidomide: daily dose dependent on dose-escalation schedule
melphalan: 100 mg/m2 given Days -2 and -1 | 2 |
| Phase 1 Dose Level 2 Oral lenalidomide 25mg qAM, 50mq qPM x 5 days (designated as days -5 to -1).
On days-2 and -1, all patients will receive 100mg/m2 of intravenous melphalan once daily for a total of 2 doses (200mg/m2total). After a period of 24-72 hours has elapsed from the last melphalan dose (designated as Day 0) each patient will receive infusion of at least 2.0 x 106/kg of autologous CD34+ stem cells.
Maintenance lenalidomide will begin at Day +100 at a dose of 25 mg/day, orally for 1-21 days followed by a 7-day rest period (28 day cycles).
lenalidomide: daily dose dependent on dose-escalation schedule
melphalan: 100 mg/m2 given Days -2 and -1 | 4 |
| Phase 1 Dose Level 3 Oral lenalidomide 50mg qAM, 75mg qPM x 5 days (designated as days -5 to -1).
On days-2 and -1, all patients will receive 100mg/m2 of intravenous melphalan once daily for a total of 2 doses (200mg/m2total). After a period of 24-72 hours has elapsed from the last melphalan dose (designated as Day 0) each patient will receive infusion of at least 2.0 x 106/kg of autologous CD34+ stem cells.
Maintenance lenalidomide will begin at Day +100 at a dose of 25 mg/day, orally for 1-21 days followed by a 7-day rest period (28 day cycles).
lenalidomide: daily dose dependent on dose-escalation schedule
melphalan: 100 mg/m2 given Days -2 and -1 | 3 |
| Phase 1 Dose Level 4 Oral lenalidomide 75mg qAM, 100mg qPM x 5 days (designated as days -5 to -1).
On days-2 and -1, all patients will receive 100mg/m2 of intravenous melphalan once daily for a total of 2 doses (200mg/m2total). After a period of 24-72 hours has elapsed from the last melphalan dose (designated as Day 0) each patient will receive infusion of at least 2.0 x 106/kg of autologous CD34+ stem cells.
Maintenance lenalidomide will begin at Day +100 at a dose of 25 mg/day, orally for 1-21 days followed by a 7-day rest period (28 day cycles).
lenalidomide: daily dose dependent on dose-escalation schedule
melphalan: 100 mg/m2 given Days -2 and -1 | 4 |
| Phase 1 Dose Level 5 Oral lenalidomide 100mg qAM, 150mg qPM x 5 days (designated as days -5 to -1).
On days-2 and -1, all patients will receive 100mg/m2 of intravenous melphalan once daily for a total of 2 doses (200mg/m2total). After a period of 24-72 hours has elapsed from the last melphalan dose (designated as Day 0) each patient will receive infusion of at least 2.0 x 106/kg of autologous CD34+ stem cells.
Maintenance lenalidomide will begin at Day +100 at a dose of 25 mg/day, orally for 1-21 days followed by a 7-day rest period (28 day cycles).
lenalidomide: daily dose dependent on dose-escalation schedule
melphalan: 100 mg/m2 given Days -2 and -1 | 6 |
| Phase 1 Dose Level 6 Oral lenalidomide 150mg qAM, 200mg qPM x 5 days (designated as days -5 to -1).
On days-2 and -1, all patients will receive 100mg/m2 of intravenous melphalan once daily for a total of 2 doses (200mg/m2total). After a period of 24-72 hours has elapsed from the last melphalan dose (designated as Day 0) each patient will receive infusion of at least 2.0 x 106/kg of autologous CD34+ stem cells.
Maintenance lenalidomide will begin at Day +100 at a dose of 25 mg/day, orally for 1-21 days followed by a 7-day rest period (28 day cycles).
lenalidomide: daily dose dependent on dose-escalation schedule
melphalan: 100 mg/m2 given Days -2 and -1 | 3 |
| Phase 2 MTD Phase 2 MTD, oral lenalidomide 150mg qAM, 200mg qPM x 5 days (designated as days -5 to -1).
On days-2 and -1, all patients will receive 100mg/m2 of intravenous melphalan once daily for a total of 2 doses (200mg/m2total). After a period of 24-72 hours has elapsed from the last melphalan dose (designated as Day 0) each patient will receive infusion of at least 2.0 x 106/kg of autologous CD34+ stem cells.
Maintenance lenalidomide will begin at Day +100 at a dose of 25 mg/day, orally for 1-21 days followed by a 7-day rest period (28 day cycles).
lenalidomide: daily dose dependent on dose-escalation schedule
melphalan: 100 mg/m2 given Days -2 and -1 | 30 |
| Total | 52 |
Baseline characteristics
| Characteristic | Phase 1 Dose Level 1 | Phase 1 Dose Level 2 | Phase 1 Dose Level 3 | Phase 1 Dose Level 4 | Phase 1 Dose Level 5 | Phase 1 Dose Level 6 | Phase 2 MTD | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 11 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 5 Participants | 2 Participants | 19 Participants | 34 Participants |
| Immunoglobulin Isotype IgA Kappa | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants | 6 Participants |
| Immunoglobulin Isotype IgA Lambda | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 5 Participants |
| Immunoglobulin Isotype IgD Kappa | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Immunoglobulin Isotype IgG Kappa | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 12 Participants | 16 Participants |
| Immunoglobulin Isotype IgG Lambda | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 7 Participants | 12 Participants |
| Immunoglobulin Isotype Kappa Free light Chain | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 3 Participants | 1 Participants | 3 Participants | 10 Participants |
| Immunoglobulin Isotype Lambda Free light Chain | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 7 Participants | 12 Participants |
| Race (NIH/OMB) White | 0 Participants | 3 Participants | 1 Participants | 3 Participants | 5 Participants | 3 Participants | 17 Participants | 32 Participants |
| Region of Enrollment United States | 2 participants | 4 participants | 3 participants | 4 participants | 6 participants | 3 participants | 30 participants | 52 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 0 Participants | 12 Participants | 22 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 3 Participants | 3 Participants | 18 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 4 | 0 / 3 | 0 / 4 | 0 / 6 | 0 / 3 | 0 / 30 |
| other Total, other adverse events | 1 / 2 | 4 / 4 | 3 / 3 | 3 / 4 | 6 / 6 | 3 / 3 | 29 / 30 |
| serious Total, serious adverse events | 1 / 2 | 2 / 4 | 1 / 3 | 2 / 4 | 3 / 6 | 1 / 3 | 8 / 30 |
Outcome results
Primary
Duration of Overall Response (DoR)
The primary endpoint for the phase 2 portion of this study is to determine the duration of overall response (DoR). The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
Time frame: Until disease progression, death, or for a maximum of 3 years, whichever occurs first
Population: This outcome measure only assesses Phase 2 participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Phase 1 Participants | Duration of Overall Response (DoR) | VGPR | 10 participants |
| All Phase 1 Participants | Duration of Overall Response (DoR) | PR | 4 participants |
| All Phase 1 Participants | Duration of Overall Response (DoR) | SD | 1 participants |
| All Phase 1 Participants | Duration of Overall Response (DoR) | PD | 0 participants |
| All Phase 1 Participants | Duration of Overall Response (DoR) | sCR | 7 participants |
| All Phase 1 Participants | Duration of Overall Response (DoR) | CR | 6 participants |
Primary
Maximum Tolerated Dose (MTD) of Lenalidomide That Can be Added to Melphalan
The primary endpoint for the phase 1 portion of this study is to determine the maximum tolerated dose of lenalidomide that can be added to melphalan.
Time frame: 12 months
Population: This outcome measure only assesses Phase 1 participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Phase 1 Participants | Maximum Tolerated Dose (MTD) of Lenalidomide That Can be Added to Melphalan | NA mg/day |
Secondary
Mean Functional Assessment of of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Score
quality of life will be evaluated and scored using the questionnaire from the bone marrow transplant subscale of the Functional Assessment of Cancer Therapy available from w ww.facit.org. The FACT-BMT is a 50 item questionnaire that measures five dimensions of quality of life in bone marrow transplant patients, including physical well-being, social and family well-being, emotional well-being, functional well-being, and additional concerns. It is scored on a 5 point Likert scale. Total scores range from 0 to 148, with a higher score indicating higher quality of life.
Time frame: Cycle 6, day 1, at approximately 4.5 months
Population: Subjects from whom data were not collected were excluded from analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| All Phase 1 Participants | Mean Functional Assessment of of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Score | 85.28 score on a scale |
| Phase 1 Dose Level 2 | Mean Functional Assessment of of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Score | 69.3 score on a scale |
| Phase 1 Dose Level 3 | Mean Functional Assessment of of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Score | 81.5 score on a scale |
| Phase 1 Dose Level 4 | Mean Functional Assessment of of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Score | 70.13 score on a scale |
| Phase 1 Dose Level 5 | Mean Functional Assessment of of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Score | 80.14 score on a scale |
| Phase 1 Dose Level 6 | Mean Functional Assessment of of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Score | 79.33 score on a scale |
| Phase 2 Expansion | Mean Functional Assessment of of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Score | 74.68 score on a scale |
Secondary
Overall Response Rate
Overall response rate is the number of patients with complete response and partial response. Response is defined by the International Uniform Response Criteria for Multiple Myeloma (IURC)
Time frame: Until disease progression or a maximum of 3 years, whichever occurs first
Secondary
Overall Survival
Overall survival is defined as the interval between the day of transplantation (Day 0) and date of death. If the date of death is uncertain, the date of last contact with the subject will be used.
Time frame: Until death or date of last contact with the subject