ON 123300 (Narazaciclib) and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Able to provide a signed Written Informed Consent: Voluntary written consent must begiven before performance of any study-related procedure not part of standard medicalcare

• Male or female patients ≥18 years

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• Symptomatic MM having progressed on ≥2 prior line of therapies - including 1proteasome inhibitor (bortezomib, carfilzomib etc.), 1 immunomodulatory drug (lenalidomide, pomalidomide, thalidomide etc.), and 1 CD38 targeting monoclonalantibody (daratumumab, isatuximab) either as monotherapy or in combination.Refractoriness (progression while on therapy or ≤60 days after discontinuation oftherapy) to prior line of therapy is not required.

• Subjects who received BCMA-targeted immune-effector therapies like CAR-T cellsand/or bispecific antibodies prior can be enrolled provided they are ≥60 days out ofthe treatment.

• Subjects must not be candidates for treatment regimens known to provide clinicalbenefit to be eligible for this study.

• Subjects must have measurable disease defined by at least 1 of the following 4measurements:

• Serum M-protein > 0.5 g/dL or Urine M-protein > 200 mg/24 hours

• Light chain MM without measurable disease in serum or urine: Serumimmunoglobulin free light chain assay: involved free light chain level >10mg/dL (> 100 mg/L) provided the serum free light chain ratio is abnormal

• For oligo/non-secretory myeloma, measurable by standard imaging (PET/CT or MRI) ± bone marrow biopsy if myeloma biomarkers are inconclusive or non-contributory

• Able to swallow and absorb oral medication

• All previous therapies for cancer, including radiotherapy, major surgery andinvestigational therapies discontinued for ≥ 14 days before study entry, and allacute effects of any prior therapy resolved to baseline severity or Grade ≤ 1 CommonTerminology Criteria for Adverse Events (CTCAE v5.0) excluding alopecia or fatigue.

• Adequate organ or marrow function

• CrCl (Cockcroft-Gault equation) ≥ 45ml/min

• ALT/AST ≤2 times upper limit of normal

• Total bilirubin ≤2 times upper limit of normal (<3 x ULN for congenitalhyperbilirubinemia states like Gilbert Syndrome)

• Corrected serum calcium ≤12.5mg/dL or free ionized calcium ≤6.5mg/dL

• ANC ≥1 x 109/L (prior growth factor permitted but must be without support 7days before screening test)

• Hemoglobin ≥8g/dL (without blood transfusion in 7 days prior to test,recombinant erythropoietin permitted)

• Platelets ≥50 x 109/L

• No active infections (including but not limited to HIV, Hepatitis B, Hepatitis C,tuberculosis) or chronic health conditions which may interfere in the study in theopinion of the investigator.

• HIV: undetectable HIV viral load and CD4 counts >200 for >6 months on continuousantiretroviral therapy may be screened.

• Hepatitis B: If HbcAb positive and HBV PCR-, may be screened

• Hepatitis C: if completed anti-viral therapy and in sustained virological response >6 months, may be screened

• Tuberculosis: Quantiferon or skin prick test positive but with negative chestimaging

• (CXR or CT) and asymptomatic, may be screened

• Note: A line of therapy consists of ≥1 complete cycle of a single agent, a regimenconsisting of a

• combination of several drugs, or a planned sequential therapy of various regimens3.

• A treatment is considered a new line of therapy if any one of the following threeconditions are met:

• Start of a new line of treatment after discontinuation of a previous line: if thetreatment regimen is discontinued for any reason, and a different regimen isstarted, it should be considered a new line of therapy. A regimen is considered tohave been discontinued if all the drugs in that given regimen have been stopped. Theregimen is not considered to have been discontinued if some of the drugs of theregiment, but not all, have been discontinued.

• The unplanned addition or substitution of one or more drugs in an existing regimen:Unplanned addition of a new drug, or switching to a different drug, or combinationof drugs due to any reason, is considered a new line of therapy.

• Stem cell transplant (SCT): In patients undergoing >1 SCT, except in the case of aplanned tandem SCT with a predefined interval such as 3 months, each SCT (autologousor allogeneic, should be considered a new line of therapy, regardless of whether theconditioning regime used is the same or different.

Exclusion Criteria:

• Active plasma cell leukemia at screening (>5% plasma cells by standarddifferential), Waldenstroms macroglobulinemia, PEOMS syndrome (polyneuropathy,organomegaly, endocrinopathy, monoclonal protein and skin changes), known active orprior CNS involvement or exhibits meningeal signs (extradural skull or spinal masscausing extrinsic mass effect is not excluded) or clinically significantamyloidosis.

• History of allogeneic hematopoietic cell transplantation (HCT), or other cellulartherapy product, within 60 days.

• Inability to tolerate oral medication, presence of poorly controlledgastrointestinal disease, or dysfunction that could affect study drug absorptionincluding but not limited to:

• Diarrhea > Grade 1, based on the NCI CTCAE grading, in the absence ofantidiarrheals.

• Known GI disease or GI procedure that could interfere with the oral absorptionor tolerance of study drug, including difficulty swallowing.

• Following cardiac conditions:

• New York Heart Association (NYHA) stage III or IV congestive heart failure

• myocardial infarction or coronary artery bypass graft (CABG) <6 months prior toenrollment

• History of clinically significant ventricular arrhythmia or unexplained syncopenot believed to be vasovagal in nature or due to dehydration

• History of severe nonischemic cardiomyopathy e. Impaired cardiac function (LVEF <45%) as assessed by echocardiogram or multi gated acquisition (MUGA) scan.

• Stroke or seizure within 6 months of enrollment

• Are at risk for Torsades de pointes (TdP): Patients who have a marked baselineprolongation of QT/QTc interval (eg, repeated demonstration of a QTc interval >470msec) using Fredericia's QT correction formula, or who have a history of additionalrisk factors for TdP (eg, heart failure, hypokalemia, family history of Long QTSyndrome), or who are currently taking medications that prolong the QT/QTc interval.

• Are currently taking or within 5 half-lives of taking strong inducers and inhibitorsof cytochrome P450 enzyme (CYP) 2C8 and CYP3A4.

• Have had major surgery within 14 days prior to screening to allow for postoperativehealing of the surgical wound and site(s).

• Have received recent (within 28 days prior to screening) live attenuated vaccines.

• Active pregnancy or breastfeeding females

• Known chronic alcohol or drug abuse

• Lack of capacity to sign consent and/or participate in the trial

• Any other condition deemed by the investigator to make the patient a poor candidatefor clinical trial and/or treatment with investigational agents.

• Any altered mental status or any psychiatric condition that would interfere with theunderstanding of the informed consent or limit compliance with study requirements.

• Prior or concurrent malignancy, except for the following:

• Adequately treated non-melanoma skin cancer (basal cell or squamous cell skincarcinoma) ≥1 year

• Cervical carcinoma in situ adequately treated ≥1 year

• Adequately treated Stage I or II cancer from which the subject is currently incomplete remission ≥2 years

• Any other cancer from which the subject has been disease-free for ≥ 3 years

• Males or females of childbearing potential who do not agree to practice 2highly effective methods of contraception. Highly effective method ofcontraception has a failure rate of less than 1% per year when usedconsistently and correctly, and agree to remain on a highly effective method ofcontraception from the time of signing the informed consent form through 90days after the last dose of study drug. For women, examples of highly effectivecontraceptives include A) user independent methods: 1. implantable progesteroneonly hormonal contraception 2. intrauterine device/intrauterine hormonereleasing system 3. vasectomized partner B) user dependent methods: 1. combinedestrogen and protestor hormonal contraception (oral intravaginal ortransdermal) 2. progesterone only hormone contraception (oral or injectable).For men, highly effective barrier method of contraception include - condom withspermicidal foam/gel/film/cream/suppository from the time of signing the ICFuntil 90 days after receiving the last dose of treatment. Intercourse with apregnant woman must involve the use a condom. Women and men must agree not todonate eggs or sperm while on the study drug or up to 90 days after the lastdose of drug.

• Uncontrolled, untreated or active infections, including but not limited to HIV,Hepatitis B, Hepatitis C, tuberculosis.