1. ≥18 years of age
2. Documented diagnosis of MM according to IMWG diagnostic criteria
3. Measurable disease at Screening as defined by any of the following:
• Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level ≥200 mg/24 hours; or
• Light chain MM in whom only measurable disease is by serum free light chain (FLC) levels: Serum Ig free light chain ≥10 mg/dL and abnormal serum Ig kappa/lambda FLC ratio.
4. Not considered for high-dose chemotherapy with ASCT due to:
• Ineligible due to advanced age; or
• Ineligible due to presence of comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with ASCT; or
• Deferral of high-dose chemotherapy with ASCT as initial treatment.
5. Eastern Cooperative Oncology Group Performance Status grade of 0 or 1.
6. Clinical laboratory values meeting the following criteria during the Screening Phase:
• Hemoglobin ≥ 8.0 g/dL (≥5 mmol/L), recombinant human erythropoietin use is permitted
• Platelets ≥75×109/L
• Absolute Lymphocyte Count ≥0.3 ×109/L
• Absolute Neutrophil Count (ANC) ≥ 1.0 ×109/L (prior growth factor support is permitted but must be without support in the 7 days prior to the laboratory test)
• Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤3.0 × upper limit of normal (ULN)
• Estimated Glomerular Filtration Rate ≥ 40 mL/min/1.73 m2 based upon Modified Diet in Renal Disease formula (MDRD-4) calculation or a 24-hour urine collection.
• Total bilirubin ≤2.0 × ULN; except in participants with congenital hyperbilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤2.0 × ULN is required)
7. A woman of childbearing potential (WOCBP) must have 2 negative highly sensitive serum or urine pregnancy test (β-human chorionic gonadotropin) tests prior to starting VRd and must agree to further testing during the study.
8. When a woman is of childbearing potential, the participant must commit either to
abstaining continuously from heterosexual intercourse or agree to practice 2 methods of
reliable birth control simultaneously, ie, one highly effective method of contraception (failure rate of <1% per year when used consistently and correctly; see examples below) and one other effective method (ie, male latex or synthetic condom, diaphragm, or cervical cap). The participant must agree to remain on both methods of birth control, without interruption, from the time of signing the informed consent or for at least 4 weeks before therapy (whichever is earlier) until at least 4 weeks following the last dose of lenalidomide, 3 months after receiving the last dose of bortezomib, or 1 year after receiving the conditioning regimen (cyclophosphamide and fludarabine) or 1 year after receiving cilta-cel infusion (whichever is later). Reliable contraception is indicated even where there has been a history of infertility, unless it is due to hysterectomy. Women of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed.
9. A man must commit either to abstaining continuously from heterosexual intercourse or a man
• Who is sexually active with a WOCBP or a pregnant woman must agree to use a barrier method of contraception (eg, latex or synthetic condom with spermicidal foam /gel /film /cream /suppository), without interruption, from the time of signing the informed consent form (ICF) or for at least 4 weeks before therapy (whichever is earlier) until at least 4 weeks after the last dose of lenalidomide, 3 months after the last dose of bortezomib, 1 year after receiving the conditioning regimen (cyclophosphamide and fludarabine) or 1 year after receiving cilta-cel infusion (whichever is later), even if they have undergone a successful vasectomy.
• Should agree to practice contraception according to and for the time frame specified in the global REVLIMID pregnancy prevention program or equivalent local REVLIMID pregnancy prevention program, whichever is more stringent.
10. Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively, during the study and until at least 4 weeks after the last dose of lenalidomide, 3 months after the last dose of bortezomib, 1 year after receiving the conditioning regimen (cyclophosphamide and fludarabine), or 1 year after receiving cilta-cel infusion (whichever is later).
11. Participant must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard-of-care for the participant’s disease.
12. Willing and able to adhere to the prohibitions and lifestyle restrictions specified in this protocol.

1. Frailty index of ≥ 2 according to Myeloma Geriatric Assessment score.
2. Active malignancies (ie, progressing or requiring treatment change in the last 24 months) other than the disease being treated under study. The only allowed exceptions are:
• non-muscle invasive bladder cancer treated within the last 24 months that is considered completely cured.
• skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered completely cured.
• non-invasive cervical cancer treated within the last 24 months that is considered completely cured.
• localized prostate cancer (N0M0):
o with a Gleason score of ≤6, treated within the last 24 months or untreated and under surveillance,
o with a Gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence,or
o history of localized prostate cancer and receiving androgen deprivation therapy and considered to have a very low risk of recurrence.
• breast cancer: adequately treated lobular carcinoma in situ or ductal carcinoma in situ, or history of localized breast cancer and receiving antihormonal agents and considered to have a very low risk of recurrence.
• malignancy that is considered cured with minimal risk of recurrence.
3. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCICTCAE) Version 5.
4. The following cardiac conditions:
• New York Heart Association Stage III or IV congestive heart failure
• Myocardial infarction or coronary artery bypass graft ≤ 6 months prior to enrollment
• History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration
• History of severe non-ischemic cardiomyopathy
• Screening 12-lead ECG showing a baseline corrected Prolonged corrected QT interval (QTc) >470 msec (for women) and >450 msec (for men), as assessed by 12-lead ECG, except in participants with a pacemaker.
• Impaired cardiac function (left ventricular ejection fraction <45%) as assessed by echocardiogram or multiple-gated acquisition (MUGA) scan 5. Known active, or prior history of central nervous system (CNS) involvement or exhibits clinical signs of meningeal involvement of MM. 6. Stroke or seizure within 6 months of signing ICF. 7. Plasma cell leukemia at the time of screening (>2.0 x 109/L plasma cells by standard differential), Waldenstrom’s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), or primary amyloid light-chain amyloidosis.
8. Seropositive for human immunodeficiency virus (HIV).
9. Vaccinated with live, attenuated vaccine within 4 weeks prior to first dose of VRd.
10. Hepatitis B infection. In the event the infection status is unclear, quantitative levels are necessary to determine the infection status.
11. Hepatitis C infection defined as (anti-hepatitis C virus [HCV] antibody positive or detectable HCV-RNA) or known to have a history of hepatitis C.
12. Participant must not require continuous supplemental oxygen.
13. Contraindications, known life-threatening allergies, hypersensitivity, or intolerance to any of the study treatments, including cyclophosphamide or fludarabine (if known) or any of their excipients, including boron, mannitol, dimethyl sulfoxide (refer to Investigator’s Brochure or local product prescribing information for complete lists of excipients).
14. Serious underlying medical condition, such as:
• Evidence of active viral or bacterial infection requiring systemic antimicrobial therapy, or uncontrolled systemic fungal infection
• Active autoimmune disease
• Overt clinical evidence of dementia or altered mental status
• Any history of Parkinson’s disease or other neurodegenerative disorder
15. Prior treatment with CAR-T therapy directed at any target.
16. Any therapy that is targeted to BCMA.
17.1 Any prior therapy for MM or smoldering myeloma other than a short course of corticosteroids (not to exceed 40 mg of dexamethasone, or equivalent per day for a maximum of 4 days, total of 160 mg dexamethasone or equivalent, or maximum 1 cycle of VRd therapy prior to enrollment, in a dosing regimen that is consistent with the protocol regimen for VRd induction (including dose modifications consistent with protocol guidelines.
17.2 Radiation therapy for treatment of plasmacytoma within 14 days before enrollment (palliative radiation for pain control secondary to lytic lesion is allowed within 14 days of enrollment). However, if the radiation portal covered ≤5% of the bone marrow reserve, the subject is eligible irrespective of the end date of radiation therapy.
18. Received a strong cytochrome P450 (CYP) 3A4 inducer within 5 half-lives prior to VRd induction therapy.
19. Received an investigational treatment (including investigational vaccines) or used an invasive investigational medical device within 15 days prior to VRd induction therapy or is currently enrolled in an investigational study.
20. Major operations or surgical procedures within 2 weeks prior to VRd induction therapy, or has surgery planned during the study or within 2 weeks after study treatment administration. (Note: participants with planned surgical procedures to be conducted under local anesthesia may participate.)
21. Any issue that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
22. Pregnant or breast-feeding, or planning to become pregnant while enrolled in this study and until at least 4 weeks after the last dose of lenalidomide, 3 months after the last dose of bortezomib, 1 year after receiving the conditioning regimen (cyclophosphamide and fludarabine) or 1 year after receiving cilta-cel infusion (whichever is later).
23. Plans to father a child while enrolled in this study until at least 4 weeks after the last dose of lenalidomide, 3 months after the last dose of bortezomib, 1 year after receiving the conditioning regimen (cyclophosphamide and fludarabine) or 1 year after receiving cilta-cel infusion (whichever is later).

Hôpital Maisonneuve-Rosemont (CIUSSS de l’Est-de-l’Ile-de-Montréal)

– Richard LeBlanc (richard.leblanc.med2@ssss.gouv.qc.ca)
– Marie-Pier Lecours-Cyr (mplecours-cyr.hmr@ssss.gouv.qc.ca)