Aggressive Smoldering Curative Approach Evaluating Novel Therapies and Transplant

This study is a multi-center phase 2 study of carfilzomib, lenalidomide, daratumumab, and
dexamethasone in subjects with high-risk smoldering multiple myeloma (SMM). Myeloma remains
incurable with the current approaches. The typical natural history of myeloma is one of
repeated relapses, accompanied by genetic evolution and development of new abnormalities,
which are often responsible for drug resistance. The presence of a precursor phase of
smoldering myeloma, and the ability to identify those at the highest risk of progression,
sets the stage to examine the possibility that we can cure the disease through early
intervention. In order to potentially achieve this, we need to develop a highly effective
combination that includes the most active drugs from different classes. Carfilzomib in
combination with lenalidomide and dexamethasone results in high response rates and deep
responses in subjects with newly diagnosed myeloma. Daratumumab in combination with
lenalidomide results in high response rates in relapsed refractory disease. All these drugs
are well tolerated and subjects are able to stay on them long term as a maintenance
treatment. The combination of the carfilzomib, lenalidomide, daratumumab and dexamethasone
presents the potential to enhance the effectiveness of the regimens. We hypothesize that this
combination will lead to deep response including a higher proportion of minimal residual
disease (MRD) negative disease among those with high risk smoldering myeloma and may
translate into cure or long term disease quiescence.

Inclusion Criteria:

- Age 18 years and ≤ 80 years

- High risk smoldering myeloma, which is untreated, as defined by: Serum M spike > 3
gm/dL AND an involved to uninvolved free light chain (FLC) ratio > 8 AND bone marrow
PC% > 10%

- The following laboratory values obtained 14 days prior to registration.

- Calculated creatinine clearance (using Cockcroft-Gault equation below)* ≥ 30 mL/min

- Absolute neutrophil count (ANC) ≥ 1000/mm3

- Platelet count ≥ 75000/mm3

- Hemoglobin ≥8.0 g/dL

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

- alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN

- left ventricular ejection fraction (LVEF) ≥ 40%

- Prior therapy for the treatment of solitary plasmacytoma is permitted, but >7 days
should have elapsed from the last day of radiation. Note: Prior therapy with
clarithromycin, dehydroepiandrosterone (DHEA), anakinra, pamidronate or zoledronic
acid is permitted. Any additional agents not listed must be approved by the Principal
Investigator.

- Measurable disease as defined by at least one of the following:

- Serum monoclonal protein ≥ 1.0 g/dL (see Section 11.1 for definition)

- >200 mg of monoclonal protein in the urine on 24 hour electrophoresis

- Serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin
kappa to lambda free light chain ratio.

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 (Appendix
VII)

- Previously untreated.

- Provide informed written consent.

- Negative pregnancy test done ≤7 days prior to cycle 1 day 1, for women of childbearing
potential only.

- All study participants must be registered into the mandatory Revlimid Risk Evaluation
and Mitigation Strategy (REMS®) program and be willing and able to comply with the
requirements of the REMS® program.

- Females of reproductive potential must adhere to the scheduled pregnancy testing as
required in the Revlimid REMS® program.

- Willing to follow strict birth control measures as outlined in the protocol.

Female subjects: If they are of childbearing potential, agree to one of the following:

- Practice 2 effective methods of contraception, at the same time, from the time of
signing the informed consent form through 90 days after the last dose of trial drug,
AND must also adhere to the guidelines of any treatment-specific pregnancy prevention
program, if applicable, OR

- Agree to practice true abstinence when this is in line with the preferred and usual
lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of
contraception.)

Male subjects: even if surgically sterilized (i.e., status post-vasectomy), must agree to
one of the following:

- Agree to practice effective barrier contraception during the entire trial treatment
period and through 90 days after the last dose of trial drug, OR

- Must also adhere to the guidelines of any treatment-specific pregnancy prevention
program, if applicable, OR

- Agree to practice true abstinence when this is in line with the preferred and usual
lifestyle of the subject. (Periodic abstinence (e.g., calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of
contraception).

- Willing to return to enrolling institution for follow-up during the Active
Treatment Phase of the trial.

- Male subjects must agree not to donate sperm for at least 90 days after the last
dose of study treatment.

- Willing to provide samples for planned research

- Life expectancy > 6 months

- Able to take aspirin (325 mg) daily as prophylactic anticoagulation. Subjects
intolerant to aspirin may use warfarin or low dose molecular weight heparin.

Exclusion Criteria:

- monoclonal gammopathy of undetermined significance (MGUS), standard risk smoldering
myeloma, symptomatic myeloma, or light chain amyloidosis with organ involvement.

- Diagnosed or treated for another malignancy ≤ 2 years before trial enrollment or
previously diagnosed with another malignancy and have any evidence of residual
disease. NOTE: Subjects with nonmelanoma skin cancer or carcinoma in situ of any type
are not excluded if they have undergone complete resection.

- If any of the following exist at screening, subject will not be eligible for trial
because this trial involves an investigational agent whose genotoxic, mutagenic and
teratogenic effects on the developing fetus and newborn are unknown:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception (per protocol)

- Other co-morbidity which would interfere with subject's ability to participate in
trial, e.g. uncontrolled infection, uncompensated heart or lung disease.

- Other concurrent chemotherapy, or any ancillary therapy considered investigational.
NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and
are thus allowed while on protocol treatment.

- Peripheral neuropathy ≥ Grade 3 on clinical examination or grade 2 with pain within 30
days prior to C1D1.

- Major surgery ≤14 days prior to C1D1.

- Evidence of current uncontrolled cardiovascular conditions, including hypertension,
cardiac arrhythmias, congestive heart failure, unstable angina, or myocardial
infarction within the past 6 months. Note: Prior to trial entry, any ECG abnormality
at screening must be documented by the investigator as not medically relevant.

- New York Heart Association (NYHA) II, III, IV heart failure

- Known human immunodeficiency virus (HIV) positive.

- Known hepatitis B surface antigen-positive status, or known or suspected active
hepatitis C infection.

- Any medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol.

- Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal
antibodies or human proteins, or their excipients (refer to respective package inserts
or Investigator's Brochure), or known sensitivity to mammalian-derived products. Known
allergies, hypersensitivity, or intolerance to trial drugs.

- Inability to comply with protocol/procedures.