DARA RVD For High Risk SMM

Inclusion Criteria:

• Age ≥ 18 years.

• Must meet criteria of high-risk smoldering MM as described with one of the belowcriteria:

• Bone marrow clonal plasma cells ≥10% and any one or more of the following:

• Serum M protein ≥3.0 gm/dL

• Immunoparesis with reduction of two uninvolved immunoglobulin isotypes

• Serum involved/uninvolved free light chain ratio ≥8 (but less than 100)

• Free Light Chain Smoldering Myeloma patients are not excluded

• Progressive increase in M protein level (Evolving type of SMM)*** Increasein serum monoclonal protein by ≥10% on two successive evaluations within a 6-month period

• Bone marrow clonal plasma cells 50-60%

• Abnormal plasma cell immunophenotype (≥95% of bone marrow plasma cells areclonal) and reduction of one or more uninvolved immunoglobulin isotypes

• High Risk FISH defined as any one or several of the following: t(4;14),t(14;16), t(14;20), del 17p or 1q gain

• MRI with diffuse abnormalities or 1 focal lesion (≥5mm)

• PET-CT with one focal lesion (≥5mm) with increased uptake withoutunderlying osteolytic bone destruction

• OR High-risk per IMWG/Mayo 2018 "20-2-20" Criteria (at least 2 of thefollowing)

• Bone marrow plasmacytosis ≥20%

• ≥ 2g/dl M protein

• 20 involved: uninvolved serum free light chain ratio

• No evidence of CRAB criteria* or new criteria of active MM which including thefollowing:

• Increased calcium levels: Corrected serum calcium >0.25 mmol/L(>1mg/dL) abovethe upper limit of normal or >2.75 mmol/L (>11mg/dL);

• Renal insufficiency (attributable to myeloma);

• Anemia (Hgb 2g/dL below the lower limit of normal or <10g/dL);

• Bone lesions (lytic lesions or generalized osteoporosis with compressionfractures)

• No evidence of the following new criteria for active MM including thefollowing:

• Bone marrow plasma cells >60%

• Serum involved/uninvolved FLC ratio ≥100

• MRI with more than one focal lesion

• Participants with CRAB criteria that are attributable to conditions other thanthe disease under study may be eligible after discussion with the SponsorInvestigator

• ECOG Performance Status (PS) 0, 1, or 2 (Appendix A)

• The following laboratory values obtained ≤ 28 days prior to registration:

• ANC ≥1000/ µL

• PLT ≥ 50,000/ µL

• Total bilirubin ≤ 2.0 mg/dL (If total is elevated check direct and if normalpatient is eligible.)

• AST≤ 3 x institutional upper limit of normal (ULN)

• ALT ≤ 3 x institutional upper limit of normal (ULN)

• Estimated creatinine clearance≥ 60mL/min or a creatinine ≤ 2.2 mg/dL

• Voluntary written informed consent before performance of any study-related procedurenot part of normal medical care, with the understanding that consent may bewithdrawn by the subject at any time without prejudice to future medical care.

• Females of childbearing potential* must have a negative serum or urine pregnancytest with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filledwithin 7 days as required by Revlimid REMS®) and must either commit to continuedabstinence from heterosexual intercourse or begin TWO acceptable methods of birthcontrol, one highly effective method and one additional effective method AT THE SAMETIME, at least 28 days before she starts taking lenalidomide.

-- A female of childbearing potential is a sexually mature female who: has notundergone a hysterectomy (the surgical removal of the uterus) or bilateraloophorectomy (the surgical removal of both ovaries) or has not been naturallypostmenopausal (amenorrhea following cancer therapy does not rule out childbearingpotential) for at least 24 consecutive months (i.e., has had menses at any timeduring the preceding 24 consecutive months)

• All study participants must be registered into the mandatory Revlimid REMS® programand be willing and able to comply with the requirements of the REMS® program.

• Females of child-bearing potential must adhere to the scheduled pregnancy testing asrequired in the Revlimid REMS® program.

• Men must agree to use a latex condom during sexual contact with a female ofchildbearing potential even if they have had a successful vasectomy

• Detectable clonality sequence by next generation sequencing using clonoSEQ assay toallow for minimal residual disease measurement

• Ability to understand and the willingness to sign a written informed consent.

Exclusion Criteria:

• Symptomatic Multiple Myeloma or any evidence of CRAB criteria, including presence ofmyeloma defining events (MDE). Any prior therapy for active Myeloma should also beexcluded. Prior therapy for smoldering myeloma is not an exclusion criterion.Bisphosphonates are not excluded

• Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapyconsidered investigational. Prior therapy with bisphosphonate is allowed. Priorradiation therapy to a solitary plasmacytoma is allowed. Prior clinical trials ortherapy for smoldering MM or MGUS are allowed but should be discussed with thePrincipal Investigator.

• Serious medical or psychiatric illness likely to interfere with participation inthis clinical study.

• Diagnosed or treated for another malignancy within 2 years of enrollment, with theexception of complete resection of basal cell carcinoma or squamous cell carcinomaof the skin, an in-situ malignancy, or low-risk prostate cancer after curativetherapy.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements.

• Pregnant or nursing women will be excluded from the study because lenalidomide is anagent with the potential for teratogenic or abortifacient effects.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to daratumumab, bortezomib, lenalidomide, or hyaluronidase

• Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) or SARS-CoV-2 (COVID-19).

• Patients who are seropositive because of hepatitis B virus vaccine areeligible.

• Patients who are positive for SARS-COV-2 antibody, HIV1 and 2 antibody,hepatitis B core antibody or hepatitis B surface antigen must have a negativepolymerase chain reaction (PCR) result before enrollment. Those who are PCRpositive will be excluded.

• Subject has known chronic obstructive pulmonary disease (COPD) or severe, persistentasthma with a Forced Expiratory Volume in 1 second (FEV1) < 50% of predicted normal.

• Note that PFT/FEV1 testing is required at screening for patients suspected ofhaving COPD or severe, persistent asthma or are suspected of having thoseconditions or other respiratory impairment