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Randomized Phase III Trial of Bortezomib, Lenalidomide and Dexamethasone (VRd) Versus Carfilzomib, Lenalidomide, Dexamethasone (CRd) Followed by Limited or Indefinite Lenalidomide Maintenance in Patients With Newly Diagnosed Symptomatic Multiple Myeloma


Phase 3
18 Years
N/A
Not Enrolling
Both
Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

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Trial Information

Randomized Phase III Trial of Bortezomib, Lenalidomide and Dexamethasone (VRd) Versus Carfilzomib, Lenalidomide, Dexamethasone (CRd) Followed by Limited or Indefinite Lenalidomide Maintenance in Patients With Newly Diagnosed Symptomatic Multiple Myeloma


PRIMARY OBJECTIVES:

I. To compare the overall survival between two strategies of lenalidomide maintenance
following induction with a proteasome inhibitor-IMiD (lenalidomide) combination: limited
duration of maintenance (24 months) versus indefinite maintenance therapy until disease
progression.

SECONDARY OBJECTIVES:

I. To compare the progression-free survival between two strategies of lenalidomide
maintenance following induction with a proteasome inhibitor-IMiD combination: limited
duration of maintenance (24 months) or indefinite maintenance therapy until disease
progression.

II. To compare progression-free survival between bortezomib, lenalidomide, and dexamethasone
(VRd) and carfilzomib, lenalidomide, and dexamethasone (CRd) induction followed by
lenalidomide maintenance in patients with newly diagnosed symptomatic multiple myeloma.

III. To compare induction rates of response between VRd and CRd arms. IV. To evaluate time
to progression, duration of response and overall survival between VRd and CRd induction
therapy.

V. To compare induction rates of toxicity between VRd and CRd arms. VI. To evaluate toxicity
during lenalidomide maintenance.

TERTIARY OBJECTIVES:

I. To compare the short and long-term health-related quality of life impact between two
strategies of lenalidomide maintenance following induction with a proteasome inhibitor-IMiD
combination: limited duration of maintenance (24 months) versus indefinite maintenance
therapy until disease progression.

II. To compare the impact on health-related quality of life between VRd and CRd induction
therapy.

III. To evaluate the association between early induction response and change in
health-related quality of life.

IV. To describe changes in health-related quality of life during the induction, active
maintenance and observation phases.

V. To evaluate correlation between treatment adherence during maintenance and health-related
quality of life.

VI. To compare induction minimal residual disease negativity rates between VRd and CRd arms.

VII. To compare minimal residual disease negativity rates between two strategies of
lenalidomide maintenance following induction with a proteasome inhibitor-IMiD combination:
limited duration of maintenance (24 months) versus indefinite maintenance therapy until
disease progression.

VIII. To describe changes in minimal residual disease during the induction, active
maintenance and observation phases and explore association with response.

IX. To evaluate gene expression profiles of tumor cells at baseline among standard risk
patients and explore the development of a prognostic gene expression signature for standard
risk myeloma.

X. To evaluate changes in gene expression profiles of tumor cells following treatment and
elucidate response and resistance mechanisms.

OUTLINE:

INDUCTION: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive bortezomib subcutaneously (SC) or intravenously (IV) on days 1, 4,
8, and 11 of courses 1-8 and days 1 and 8 of courses 9-12; lenalidomide orally (PO) daily on
days 1-14; and dexamethasone PO daily on days 1, 2, 4, 5, 8, 9, 11, and 12 of courses 1-8
and days 1, 2, 8, and 9 of courses 9-12. Treatment repeats every 3 weeks for 12 courses in
the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16;
lenalidomide PO daily on days 1-21; and dexamethasone PO on days 1, 8, 15, and 22. Treatment
repeats every 4 weeks for 9 courses in the absence of disease progression or unacceptable
toxicity.

MAINTENANCE: After completion of induction therapy, patients are then randomized to 1 of 2
maintenance treatment arms.

ARM C: Patients receive lenalidomide PO daily on days 1-21. Treatment repeats every 4 weeks
for 24 courses in the absences of disease progression or unacceptable toxicity.

ARM D: Patients receive lenalidomide PO daily on days 1-21. Courses repeat every 4 weeks in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and then annually for 10 years.


Inclusion Criteria:



- STEP I: Patients must be diagnosed with symptomatic standard-risk multiple myeloma
(SR-MM) as defined by all of the following:

- No evidence of t(4;14), t(14;16),t(14;20), or deletion 17p on fluorescent in
situ hybridization (FISH)

- Standard risk gene expression profile (GEP)70 signature (only if GEP has been
done and results are available)

- Serum lactate dehydrogenase (LDH) =< 2 x upper limit of normal (ULN)

- No more than 20% circulating plasma cells on white blood cell (WBC) differential
or 2,000 plasma cells/microliter of peripheral blood

- STEP I: Patients must have measurable or evaluable disease as defined by having one
or more of the following:

- >= 1g/dL monoclonal protein (M-protein) on serum protein electrophoresis

- >= 200 mg/24 hrs of monoclonal protein on a 24 hour urine protein
electrophoresis

- Involved free light chain >= 10 mg/dL AND abnormal serum immunoglobulin kappa to
lambda free light chain ratio (< 0.26 or > 1.65)

- Monoclonal bone marrow plasmacytosis >= 30% (evaluable disease)

- Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and
serum free light chain (FLC) assay, or bone marrow biopsy and or aspirate are
required to be performed within 28 days prior to randomization

- NOTE: UPEP (on a 24-hour collection) is required, no substitute method is
acceptable; urine must be followed monthly if the baseline urine M-spike is
>= 200 mg/24 hr; please note that if both serum and urine M-components are
present, both must be followed in order to evaluate response

- NOTE: The serum free light chain test is required to be done if the patient
does not have measurable disease in the serum or urine; measurable disease
in the serum is defined as having a serum M-spike >= 1 g/dL; measurable
disease in the urine is defined as having a urine M-spike >= 200mg/24 hr

- STEP I: Hemoglobin >= 8 g/dL

- STEP I: Untransfused platelet count >= 75,000 cells/mm^3

- STEP I: Absolute neutrophil count >= 1000 cells/mm^3

- STEP I: Calculated creatinine clearance >= 30 mL/min

- STEP I: Bilirubin =< 1.5 mg/dL

- STEP I: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT])
and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST])
< 2.5 times the upper limit of normal

- STEP I: Patients must have received no more than one cycle (4 weeks or less) of prior
chemotherapy and no more than 160mg of prior dexamethasone for treatment of
symptomatic myeloma; they should not have been exposed to lenalidomide, bortezomib or
carfilzomib for treatment of symptomatic myeloma; prior radiation therapy to
symptomatic lesions is allowed provided 14 days have elapsed from the completion of
radiation therapy

- STEP I: Prior systemic glucocorticoid use for the treatment of non-malignant
disorders is permitted; prior or concurrent topical or localized glucocorticoid
therapy to treat non-malignant comorbid disorders is permitted; note: concurrent use
after registration on the study should be restricted to the equivalent of prednisone
10 mg per day

- STEP I: Patients must not have active, uncontrolled seizure disorder; patients must
have had no seizures in the last 6 months

- STEP I: Patients must not have uncontrolled intercurrent illness including
uncontrolled hypertension, symptomatic congestive heart failure, unstable angina,
uncontrolled cardiac arrhythmia, uncontrolled psychiatric illness or social situation
that would limit compliance with the study, or a prior history of Stevens Johnson
Syndrome

- STEP I: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
(PS 3 allowed if secondary to pain)

- STEP I: Patients with monoclonal gammopathy of undetermined significance or
asymptomatic multiple myeloma are not eligible

- STEP I: Patients must not have grade 2 or higher peripheral neuropathy by Common
Terminology Criteria for Adverse Events (CTCAE) 4.0

- STEP I: Patients must not have active, uncontrolled infection

- STEP I: Patients may have a history of current or previous deep vein thrombosis or
pulmonary embolism but must be willing to take some form of anti-coagulation as
prophylaxis if they are not currently on full-dose anticoagulation

- STEP I: Patients should not have New York Heart Association classification III or IV
heart failure or myocardial infarction within the previous 6 months

- STEP I: Patients with a history of prior malignancy are eligible provided they were
treated with curative intent and do not require active therapy (currently treated
basal cell, squamous cell carcinoma of the skin, or carcinoma "insitu" of the cervix
or breast are not excluded)

- STEP I: 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 prior to
and again within 24 hours of starting lenalidomide 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; all patients
must be counseled at a minimum of every 28 days about pregnancy precautions and risks
of fetal exposure

- STEP I: Sexually active males must be willing to use a condom (even if they have
undergone a prior vasectomy) while having intercourse, while taking lenalidomide and
for 4 weeks after stopping treatment

- STEP I: The following patients will be excluded:

- Pregnant women

- Nursing women

- STEP I: Human immunodeficiency virus (HIV) infection is not excluded; known HIV
positive patients must meet the following criteria:

- Cluster of differentiation (CD(4 cell count >= 350/mm^3

- No history of acquired immune deficiency syndrome (AIDS)-related illness

- Not currently prescribed zidovudine or stavudine

- STEP I: Patient enrolling to this study must agree to register to the mandatory
RevAssist program, and be willing and able to comply with the requirements of
RevAssist

- STEP I: Patients must be willing to provide biological samples as required by the
study

- STEP II: Patients must not have experienced progression on step 1 induction therapy

- STEP II: Step 2 registration must be within 28 days of completing step 1 therapy

- STEP II: Patients must not have received any non-protocol therapy outside of the
assigned induction therapy

- STEP II: ECOG performance status 0, 1, or 2 (PS 3 allowed if secondary to pain)

- STEP II: Any adverse event related to step 1 therapy must have resolved to grade 2 or
less

- STEP II: Hemoglobin >= 8 g/dL

- STEP II: Platelet count >= 75,000 cells/mm^3

- STEP II: Absolute neutrophil count >= 1000 cells/mm^3

- STEP II: Calculated creatinine clearance >= 30 mL/min

- STEP II: Bilirubin =< 1.5 mg/dL

- STEP II: SGPT (ALT) and SGOT (AST) < 2.5 times the upper limit of normal

- STEP II: FCBP must have a negative serum or urine pregnancy test with a sensitivity
of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours of
starting lenalidomide 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; all patients must be counseled at a minimum
of every 28 days about pregnancy precautions and risks of fetal exposure

- STEP II: Sexually active males must be willing to use a condom (even if they have
undergone a prior vasectomy) while having intercourse, while taking lenalidomide and
for 4 weeks after stopping treatment

- STEP II: The following patients will be excluded:

- Pregnant women

- Nursing women

- STEP II: Patient enrolling to this study must agree to register to the mandatory
RevAssist program and be willing and able to comply with the requirements of
RevAssist

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall survival for the maintenance analysis

Outcome Description:

The Kaplan-Meier (KM) method will be used to describe the overall survival function by arm.

Outcome Time Frame:

From the maintenance randomization to death due to any cause or, censored at the date last known alive, assessed up to 15 years

Safety Issue:

No

Principal Investigator

Shaji Kumar

Investigator Role:

Principal Investigator

Investigator Affiliation:

Eastern Cooperative Oncology Group

Authority:

United States: Federal Government

Study ID:

E1A11

NCT ID:

NCT01863550

Start Date:

November 2013

Completion Date:

Related Keywords:

  • Stage I Multiple Myeloma
  • Stage II Multiple Myeloma
  • Stage III Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

Name

Location

Eastern Cooperative Oncology GroupBoston, Massachusetts  02215