Bortezomib or Carfilzomib With Lenalidomide and Dexamethasone in Treating Patients With Newly Diagnosed Multiple Myeloma

PRIMARY OBJECTIVES:

I. To compare the overall survival between two strategies of lenalidomide maintenance
following induction with a proteasome inhibitor? immunomodulatory drug (IMiD) combination:
limited duration of maintenance (24 months) versus 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.

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

IV. To compare induction rates of toxicity between VRd and CRd arms. V. To evaluate toxicity
during lenalidomide maintenance. VI. To compare minimal residual disease (MRD) negative rates
between VRd and CRd arms at end of induction therapy.

TERTIARY OBJECTIVES:

I. To compare the short and long-term health-related quality of life impact between the two
strategies of lenalidomide maintenance.

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 MRD negative rates between the two strategies of lenalidomide maintenance.

VII. To compare MRD negative rates between VRd and CRd arms during induction therapy.

VIII. To examine patterns of change in MRD levels over time and examine conversion from
detectable to MRD negative status.

IX. To evaluate agreement and association between International Myeloma Working Group (IMWG)
and MRD based disease-free status.

X. To describe the mutational profile of newly diagnosed multiple myeloma. XI. To identify
mutations associated with resistance to VRd and CRd induction therapy.

XI. To identify expression profiles associated with MRD negative status with each induction
therapy.

XII. To determine the ability of MRD status at induction end to predict short-term and
long-term overall and progression-free survival.

XIII. To determine the effects of tobacco, operationalized as combustible tobacco (1a), other
forms of tobacco (1b), and environmental tobacco exposure (ETS) (1c) on provider-reported
cancer-treatment toxicity (adverse events [both clinical and hematologic] and dose
modifications).

XIV. To determine the effects of tobacco on patient-reported physical symptoms and
psychological symptoms.

XV. To examine quitting behaviors and behavioral counseling/support and cessation medication
utilization.

XVI. To explore the effect of tobacco use and exposure on treatment duration, relative dose
intensity, and therapeutic benefit.

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 (or completion of at least 6 courses in
Arm A but stopped early due to unacceptable toxicity, or at least 4 courses in Arm B but
stopped early due to unacceptable toxicity), 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 (except gene expression profile [GEP]70
status if unknown):

- No evidence of t(14;16) by fluorescence in situ hybridization (FISH) testing on
bone marrow or not available

- No evidence of t(14:20) by FISH testing on bone marrow or not available

- No evidence of deletion 17p by FISH testing on bone marrow

- FISH should be from within 90 days of registration

- NOTE: If the FISH result states that no immunoglobulin heavy chain (IgH)
abnormality is present, both t(14;16) and t(14;20) can be considered
negative; in addition, if the patient has a t(11;14) or t(4;14)
translocation present, they can be considered negative for t(14;16) and
t(14;20); if testing for t(14;16) or t(14;20) could not be performed for
lack of sufficient material or non-availability of the probe in the test
panel, patients can be enrolled on the study

- Standard Risk GEP70 signature within the past 90 days (only if GEP has been done
and results are available)

- NOTE: GEP testing is NOT a requirement for the study; if the test has been
done, patients found to have a GEP70 status of high-risk will not be
eligible

- Serum lactate dehydrogenase (LDH) =< 2 x upper limit of normal (ULN) within the
past 28 days

- No more than 20% circulating plasma cells on peripheral blood smear differential
or 2,000 plasma cells/microliter on white blood cell (WBC) differential of
peripheral blood within the past 90 days

- NOTE: This is NOT the plasma cell % from the marrow aspirate

- STEP I: Patients must have measurable or evaluable disease as defined by having one or
more of the following, obtained within 28 days prior to randomization:

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

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

- Involved free light chain >= 10 mg/dL or >= 100 mg/L 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 are required to be performed within 28 days
prior to randomization; a bone marrow biopsy and/or aspirate is required within
28 days if bone marrow is being followed for response

- 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 >= 200 mg/24 hr

- STEP I: Hemoglobin >= 8 g/dL (obtained within 28 days prior to randomization)

- STEP I: Untransfused platelet count >= 75,000 cells/mm^3 (obtained within 28 days
prior to randomization)

- STEP I: Absolute neutrophil count >= 1000 cells/mm^3 (obtained within 28 days prior to
randomization)

- STEP I: Calculated creatinine clearance >= 30 mL/min (obtained within 28 days prior to
randomization)

- STEP I: Bilirubin =< 1.5 mg/dL (obtained within 28 days prior to randomization)

- 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 (obtained within 28 days prior to randomization)

- STEP I: Patients must have received no more than one cycle (4 weeks or less) of prior
chemotherapy and no more than 160 mg of prior dexamethasone (or equivalent dose of
prednisone) 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 there are no residual
toxicity related to radiation and blood counts that meet the study requirements

- 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

- 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 0, 1, or 2
(performance status [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 ?in situ? 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 throughout the entire
duration of study treatment, and for 28 days after the last dose of lenalidomide; FCBP
must also agree to ongoing pregnancy testing; all patients must be counseled at a
minimum of every 28 days about pregnancy precautions and risks of fetal exposure;
female subjects must agree to use contraception or abstinence for 30 days after last
dose of carfilzomib

- A female of childbearing potential is any woman, regardless of sexual orientation
or whether they have undergone tubal ligation, who meets the following criteria:
1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months

- 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 28 days after stopping lenalidomide; male subjects must also agree to abstain from
donating blood, semen, or sperm during study participation and for at least 28 days
after discontinuation from lenalidomide; male subjects must be willing to use condoms
for 90 days after discontinuation of carfilzomib

- 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 II: Patients must have complete induction without experiencing progression or
patients must have received at least 6 cycles on Arm A and 4 cycles on Arm B but
stopped induction therapy due to adverse events

- STEP II: Step 2 registration must be within 6 weeks of completing step 1 therapy

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

- 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 (within 28 days prior to randomization to Step II)

- STEP II: Platelet count >= 75,000 cells/mm^3 (within 28 days prior to randomization to
Step II)

- STEP II: Absolute neutrophil count >= 1000 cells/mm^3 (within 28 days prior to
randomization to Step II)

- STEP II: Calculated creatinine clearance >= 30 mL/min (within 28 days prior to
randomization to Step II)

- STEP II: Bilirubin =< 1.5 mg/dL (within 28 days prior to randomization to Step II)

- STEP II: SGPT (ALT) and SGOT (AST) < 2.5 times the upper limit of normal (within 28
days prior to randomization to Step II)

- STEP II: 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 throughout the entire
duration of study treatment, and for 28 days after the last dose of lenalidomide; FCBP
must also agree to ongoing pregnancy testing; all patients must be counseled at a
minimum of every 28 days about pregnancy precautions and risks of fetal exposure

- A female of childbearing potential is any woman, regardless of sexual orientation
or whether they have undergone tubal ligation, who meets the following criteria:
1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months

- 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 28 days after stopping lenalidomide; male subjects must also agree to abstain from
donating blood, semen, or sperm during study participation and for at least 28 days
after discontinuation from lenalidomide; males must agree to use contraception and
agree to not donate sperm for at least 90 days after the last day of carfilzomib

- 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