Pre-transplant Purging and Post-transplant MRD-guided Maintenance Therapy with Elranatamab in Patients with High-risk Multiple Myeloma

Inclusion Criteria:

1. Transplant eligible patients with newly diagnosed multiple myeloma (NDMM).

2. High-risk multiple myeloma*

3. Participants with disease response ≥ PR to induction therapy

4. Age ≥ 18 and ≤ 75. Non-English-speaking participants are eligible.

5. Karnofsky performance status ≥70 (Appendix A).

6. Adequate liver function (total bilirubin ≤1.5X ULN; ALT ≤2.5 X ULN)

7. Estimated creatinine clearance ≥40 mL/min. Creatinine clearance may be calculatedusing Cockcroft-Gault, estimated glomerular filtration rate (Modification of Diet inRenal Disease [MDRD]), or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula). *

8. Participant agrees to not donate blood while taking lenalidomide and for 28 daysafter stopping lenalidomide.

9. Participant agrees to enroll in the lenalidomide REMS program.

10. Women of child-bearing potential (WOCPB) must abstain from heterosexual intercourseor agree to use a contraceptive method that is highly effective (with a failure rateof <1% per year), preferably with low user dependency (as described in Appendix B),plus one additional effective method at least 28 days before starting therapy,during the intervention period, at least 28 days after the last dose of lenalidomideand at least 4 months after the last dose of elranatamab, and agrees not to donateeggs (ova, oocytes) for reproduction during this period. The investigator shouldevaluate the effectiveness of the contraceptive method in relation to the first doseof the study intervention. A WOCBP must have a negative highly sensitive serumpregnancy test (as required by local regulations) within 10-14 days and also within 24 hours before the first dose of the study intervention. Non Nonchildbearing potential is defined as follows (by other than medical reasons):

• ≥ 45 years of age and has not had menses for >1 year.

• Participants who have been amenorrhoeic for <2 years without a history of ahysterectomy and oophorectomy must have a follicle-stimulating hormone value inthe postmenopausal range upon screening evaluation.

• Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation.

11. Male participant agrees to contraceptive use that should be consistent withinstitutional guidelines regarding the methods of contraception for thoseparticipating in clinical studies.

• Male participants are eligible to participate if they agree to the followingduring the intervention period and for 1 (for lenalidomide) to 4 (forelranatamab) months after the last dose of study treatment to allow forclearance of any altered sperm: - Refrain from donating sperm during treatment (including dose interruptions) and for 4 weeks after their last dose oflenalidomide and 4 months after the last dose of elranatamab. PLUS, either:

• Be abstinent from heterosexual intercourse as their preferred and usuallifestyle (abstinent on a long term and persistent basis) and agree to remainabstinent. OR

• Must agree to use contraception/barrier as detailed in Appendix B. *Definitionof high-risk and ultra-high-risk MM15:

• High-risk MM:o Presence of a high-risk chromosomal abnormality (HRCA) including: 17p13deletion; t(4;14); t(14;16); t(14;20); Gain or amplification 1q by FISH.

• Ultra-high-risk MM

• Presence of ≥2 HRCA.

Exclusion Criteria:

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to elranatamab or other agents used in study.

• Drug interactions (Prohibited unless considered medically necessary): a. At projected clinical doses, TMDD (target mediated drug disposition) ofelranatamab is expected. If concomitant medication alters target expression, it canpotentially impact the PK of elranatamab. Drugs like anti-thymocyte globulin (ATG)can deplete T-cells and can potentially impact the PK of drugs targeting CD3. b.Elranatamab has been shown to increase T-cell activation and induce cytokineproduction (including IL-2, IL-6, IL-10, TNF-alpha and IFN-gamma). Cytokines havebeen shown to modulate expression of CYP enzymes and transporters, therefore,elranatamab can potentially affect CYP enzyme and transporter expression levels, andconsequently modulate the clearance of concomitant medications that are substratesfor these enzymes or transporters. When administering elranatamab, it is importantto exercise caution with concomitant medications, especially those that aresensitive substrates of the cytochrome P450 (CYP) enzyme system and have a narrowtherapeutic index. Increased exposure of CYP substrates is more likely to occurafter the first dose of elranatamab on Day 1 and up to 14 days after the 32 mg doseon Day 4 and during and after CRS. Examples of such medications includecyclosporine. During this critical window, it's imperative to closely monitor thetoxicity or concentrations of these concomitant drugs. If necessary, doseadjustments for these co-administered drugs should be considered to ensure patientsafety. c. Cytochrome P450 (CYP) enzyme system is responsible for the metabolism ofa vast number of drugs. Below are examples of drugs metabolized by specific CYPenzymes that could be impacted if elranatamab alters the activity or expression ofthese enzymes. Exercise caution when using these drugs: i. CYP2C9 substrates:

1.

• Warfarin

2.

• Phenytoin

3.

• Celecoxib

4.

• Losartan ii. CYP3A4 substrates:

1.

• Statins: simvastatin, atorvastatin, lovastatin

2.

• Calcineurin inhibitors: cyclosporine, tacrolimus

3.

• Antiretroviral drugs: ritonavir, saquinavir, nelfinavir

4.

• Benzodiazepines: diazepam, alprazolam

5.

• Calcium channel blockers: nifedipine, verapamil, diltiazem

6.

• Macrolide antibiotics: erythromycin, clarithromycin iii. CYP2D6 substrates:

1.

• Antipsychotics: aripiprazole, risperidone, haloperidol

2.

• Tricyclic antidepressants: amitriptyline, nortriptyline, imipramine

3.

• Beta-blockers: metoprolol, propranolol, carvedilol

4.

• Codeine

5.

• Tamoxifen iv. CYP1A2 substrates:

1.

• Theophylline 2. - Fluvoxamine 3. - Clozapine v. CYP2C19 substrates:

1.

• Omeprazole

2.

• Citalopram

3.

• Diazepam d. For participants on digoxin, monitor digoxin plasma levelsperiodically with the concomitant use of lenalidomide. Refer to lenalidomideUSPI for additional information.

• History of progressive disease at any time before starting maintenance.

• Participants with non-secretory MM (no measurable disease on electrophoresis andimmunofixation). Participants with a measurable disease on PET scan or bone marrowwill be eligible.

• Participants with Waldenströms macroglobulinemia.

• Participants with POEMS syndrome.

• Participants with smoldering MM (IMWG criteria)

• Participants with plasma cell leukemia.

• Participants with standard-risk MM.

• Participants with relapsed and/or refractory MM.

• Participant must not have presence of active renal condition (infection,requirement for dialysis or any other condition that could affect participant'ssafety). Participants with isolated proteinuria resulting from MM are eligible,provided they fulfil inclusion criteria.

• Participant must not have current unstable liver or biliary disease defined by thepresence of ascites, encephalopathy, coagulopathy, esophageal or gastric varices,persistent jaundice, or cirrhosis. Note: Stable non-cirrhotic chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliaryinvolvement of malignancy is acceptable if otherwise meets entry criteria.

• Uncontrolled and active pulmonary disease.

• Participant must not have used an investigational drug or approved systemicanti-myeloma therapy (including systemic steroids) within 14 days or fivehalf-lives, whichever is shorter, preceding the first dose of study drug.

• Participant must not have any evidence of active mucosal or internal bleeding.

• Participant must not have an uncontrolled infection.

• Participant must not have evidence of cardiovascular risk, including any of thefollowing:

• Evidence of current clinically significant uncontrolled arrhythmias, includingclinically significant ECG abnormalities such as 2nd degree (Mobitz Type II) or 3rd degree atrioventricular (AV) block.

• History of myocardial infarction, acute coronary syndromes (including unstableangina), coronary angioplasty, or stenting or bypass grafting within three (3)months of screening.

• Class III or IV heart failure as defined by the New York Heart Associationfunctional classification system.16

• Uncontrolled hypertension (blood pressure that remains above goal despite theconcurrent use of three antihypertensive drug classes). • Participant must nothave known HIV infection. • Participant must not have active Hepatitis B and/orC infection. • Participant must not have invasive malignancies other thandisease under study, unless the second malignancy has been medically stable forat least 2 years and, in the opinion of the principal investigators, will notaffect the evaluation of the effects of clinical trial treatments on thecurrently targeted malignancy. Participants with curatively treatednon-melanoma skin cancer may be enrolled without a 2-year restriction. •Participants must not be pregnant or lactating. • Patients with cognitiveimpairments and/or any serious unstable pre-existing medical condition orpsychiatric disorder that can interfere with safety or with obtaining informedconsent or compliance with study procedures.