| Eligibility |
Inclusion Criteria:
1. Newly diagnosed patients with histologically confirmed Multiple Myeloma (MM) based on
the IMWG diagnostic criteria and measurable disease within the past 4 weeks (or past 8
weeks if patient received pre-study MM therapy) based on one of the following:
- Serum monoclonal protein = 1.0 g/dL
- Urine monoclonal protein = 200 mg/24 hour
- Involved serum immunoglobulin free light chain = 10 mg/dL and abnormal
kappa/lambda ratio.
2. Evidence of underlying end organ damage and/or myeloma defining event attributed to
underlying plasma cell proliferative disorder meeting at least one of the following
(Note: Myeloma defining event does not need to be based on repeat testing done at
screening, if previous pathology, radiology, etc., confirm diagnosis of myeloma per
IMWG)
- Hypercalcemia: serum calcium >0.25 mmol/L (> 1 mg/dL) above upper limit of normal
or = 2.75 mmol/L (11 mg/dL)
- Anemia: hemoglobin value <10 g/dL or > 2 g/dL below lower limit of normal
- Bone disease: = 1 lytic lesions on skeletal X-ray, CT, or Positron Emission
Tomography (PET)-C. For patients with 1 lytic lesion, bone marrow should
demonstrate =10% clonal plasma cells
- Clonal bone marrow plasma cell percentage =60%
- Involved/un-involved serum free light chain ratio =100 and involved free light
chain
=100 mg/L.
- > 1 focal lesion on magnetic resonance imaging study (lesion must be >5 mm) in
size
- For patients with 1 lytic lesion, bone marrow should demonstrate =10% clonal
plasma cells
3. Creatinine Clearance (CrCl) = 60 ml/min. CrCl can be measured or estimated using
Cockcroft-Gault method, Modification of Diet in Renal Disease (MDRD), or Chronic
Kidney Disease Epidemiology Collaboration (CKD-EPI) formulae
4. Age = 18 years at the time of signing the informed consent documentation. Age limit of
= 75 years.
5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
6. Absolute neutrophil count (ANC) = 1.0 K/microliter (uL), hemoglobin = 8 g/dL, and
platelet count = 75 K/uL, unless if cytopenias are deemed to be due disease at
discretion of clinical investigator. Transfusions and growth factors are permissible.
7. Adequate hepatic function, with bilirubin < 1.5 x the pper Limit of Normal (ULN), and
Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) < 3.0 x ULN.
8. All study participants must be able to tolerate one of the following
thromboprophylactic strategies: aspirin, oral facto Xa inhibitors, low molecular
weight heparin, warfarin (coumadin), or alternative anti-coagulant.
9. All study participants must be registered into the mandatory electronic REMS (eREMS)
program and be willing and able to comply with the requirements of Risk Evaluation
Management and Safety (REMS).
10. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide
for Cycle 1 (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.
A female of childbearing potential is a sexually mature female who: 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).
Exclusion Criteria:
1. Patients receiving >1 cycle of prior treatment or concurrent systemic treatment for
multiple myeloma:
- Treatment of hypercalcemia or spinal cord compression or aggressively progressing
myeloma with current or prior corticosteroids is permitted
- Bone targeting agents are permitted
- Concurrent or prior treatment with corticosteroids for indications other than
multiple myeloma is permitted
- Prior treatment with radiotherapy is permitted
- Prior MM treatments, such as Immunomodulating Drugs (IMIDs) or non-MM drugs in
clinical trials for smoldering myeloma is permitted with a washout period of 2
weeks from last dose. Smoldering patients previously treated with carfilzomib are
excluded.
- Patients with measurable disease who received up to one cycle of any therapy
within 60 days with a washout period of 2 weeks from last dose (on a trial or
outside a trial) are eligible (Note: Measurable disease is defined as one or more
of the following: Serum monoclonal protein = 1.0 g/dL, Urine monoclonal protein =
200 mg/24 hour and/ or Involved serum immunoglobulin free light chain = 10 mg/dL
AND abnormal kappa/lambda ratio)
2. Prior or current exposure to any of the following:
- To daratumumab or other anti- Cluster of Differentiation (CD) -38 therapies
(unless a re-treatment study)
- Exposure to an investigational drug (including investigational vaccine) or
invasive investigational medical device for any indication within 4 weeks or 5
pharmacokinetic half-lives, whichever is longer.
- Focal radiation therapy within 14 days prior to randomization with the exception
of palliative radiotherapy for symptomatic management but not on measurable
extramedullary plasmacytoma.
3. Patients with plasma cell leukemia
4. Patients with Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin
changes syndrome (POEMS syndrome)
5. Patients with amyloidosis
6. Patients with known Chronic Obstructive Pulmonary Disorder (COPD) with a forced
expiratory volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing
is required for subjects suspected of having COPD, and subjects must be excluded if
FEV1 <50% of predicted normal.
7. Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma
of any classification. Note that participants who currently have controlled
intermittent asthma or controlled mild persistent asthma are allowed to participate in
the study.
8. Pregnant or lactating females. Because there is a potential risk for AEs in nursing
infants secondary to treatment of the mother with carfilzomib in combination with
lenalidomide, pregnant or lactating females are excluded from study participation.
These potential risks may also apply to other agents used in this study.
9. Uncontrolled hypertension (i.e., systolic blood pressure (BP) >160 mmHg, diastolic BP
> 100 mmHg)
10. Uncontrolled diabetes (i.e., two independent glucose readings >200 mg/dL)
11. Active hepatitis B or C infection
12. Subject is:
- Seropositive for human immunodeficiency virus (HIV)
- Seropositive for hepatitis B (defined by a positive test for hepatitis B surface
antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg
negative but positive for antibodies to hepatitis B core (HBc) antigen [anti-HBc]
and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened
using real-time polymerase chain reaction (RT-PCR) measurement of hepatitis B
virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION:
Subjects with serologic findings suggestive of HBV vaccination (anti-HBs
positivity as the only serologic marker) AND a known history of prior HBV
vaccination do not need to be tested for HBV DNA by PCR.
- Seropositive for hepatitis C (except in the setting of a sustained virologic
response (SVR), defined as aviremia at least 12 weeks after completion of
antiviral therapy).
- Patients with active Coronavirus Disease of 2019 (COVID-19) infection are not to
be enrolled until 10 days have passed from the initial positive test, and the
patient is symptom-free. COVID-19 vaccinations following national guidelines
(i.e., CDC) are encouraged; however, the series should be completed prior to the
first day of study treatment. If this is not possible, every effort should be
made to administer vaccines at a time when patient is not scheduled to receive
study treatment (e.g., "off-weeks").
13. Clinically significant cardiac disease, including:
- Myocardial infarction within 6 months before randomization, or unstable or
uncontrolled disease/condition related to or affection cardiac function (e.g.,
unstable angina, congestive heart failure, New York Heart Association (NYHA)
Class III-IV) or a left ventricular ejection fraction of <40%.
- Uncontrolled cardiac arrhythmia
- Intolerance to hydration due to pre-existing pulmonary or cardiac impairment.
14. Pulmonary hypertension
15. Has refractory gastrointestinal (GI) disease with refractory nausea/vomiting,
inflammatory bowel disease, or bowel resection that would prevent absorption of oral
agents
16. Uncontrolled intercurrent illness including but not limited to active infection or
psychiatric illness/social situations that would compromise compliance with study
requirements
17. Significant neuropathy = Grade 3 or Grade 2 neuropathy with pain at baseline
18. Contraindication to any concomitant medication, including antivirals or
anticoagulation
19. Major surgery within 3 weeks prior to first dose
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