Horizon Two: A multi-arm trial for high-risk newly diagnosed multiple myeloma

Inclusion Criteria:

* Voluntarily agree to participate by giving written informed consent

  -≥18 years of age
* Symptomatic and transplant eligible newly diagnosed multiple myeloma histologically confirmed per IMWG criteria that is high-risk as defined by at least one of the following:

  * Del(17p) (CCF ≥ 20%, by analyses conducted on CD138-positive/purified cells) and/or TP53 mutation assessed by NGS
  * One of these translocations-t(4;14) or t(14;16) or t(14;20)-co-occurring with +1q and/or del(1p32)
  * Monoallelic del(1p32) along with +1q, or biallelic del(1p32)
  * High β2M (≥5.5 mg/dL) with normal creatinine (\<1.2 mg/dL)
  * Presence of extra-medullary disease non-contiguous with bone at diagnosis (by PET-CT or Whole Body MRI)
  * Primary plasma cell leukemia (circulating plasma cells \> 5% at diagnosis)
* No more than 2 cycles of NCCN listed induction therapy for multiple myeloma
* Measurable disease, per IMWG criteria, at time of diagnosis defined as one of the following:

  * Serum M-protein at diagnosis ≥ 0.5g/dL (0.3 g/dL or above if IgA subtype)
  * Urine M-protein ≥ 200 mg/24hours
  * Serum free light chain difference \> 100 mg/L
  * Plasmacytoma ≥ 2cm
  * Bone marrow involvement ≥ 30%
* ECOG performance status of 0-2
* Adequate organ function, as indicated by the following laboratory values:

  * Adequate hematological function, defined as ANC ≥ 1000/µL, platelet count ≥ 75,000/µL, and hemoglobin ≥ 8 g/dL (transfusion and/or growth factor support is allowed for hematologic parameters as long as the investigator deems the patient otherwise fit for screening)
  * Adequate hepatic function, defined as total bilirubin level ≤ 1.5 x institutional upper limit of normal (IULN) except in participants with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤1.5 x IULN is required), AST ≤ 2.5 x IULN, and ALT ≤ 2.5 x IULN
  * Adequate renal function, defined as calculated creatinine clearance ≥ 30 mL/min per institutional standard (assessment method should be recorded, measured or C-G acceptable)
* Persons of childbearing potential must have a negative serum pregnancy test at screening (within 72 hours of first dose of trial medication). Non-childbearing potential for a person assigned as female at birth is defined as 1 of the following:

  --≥ 45 years of age and has not had menses for \>1 year
  * Amenorrheic for \> 2 years without a hysterectomy and/or oophorectomy and follicle-stimulating hormone value in the postmenopausal range upon pretrial (screening) evaluation
  * Status is post-hysterectomy, -oophorectomy, or -tubal ligation
* Persons of childbearing potential must be willing to use highly effective contraceptive measures during sexual contact with a person assigned as male at birth starting with the Screening visit through 90 days after last dose of trial medication.

  --Note: Abstinence is acceptable if this is the established and preferred contraception for the participant.
* Persons assigned as male at birth with a partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the trial starting with the Screening visit through 90 days after the last dose of trial medication is received. Persons assigned as male at birth with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.

  --Note: Abstinence is acceptable if this is the established and preferred contraception method for the participant.
* Known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using New York Heart Association Functional Classification. To be eligible for this trial, participants should be Class 2 or better. Class 2 is defined as slight limitation of physical activity, in which ordinary physical activity leads to fatigue, palpitation, or dyspnea; the person is comfortable at rest.
* Prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessments of the investigational arms are eligible for this trial.
* Known HIV infection and on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
* Evidence of chronic hepatitis B virus (HBV) infection must have an undetectable HBV viral load on suppressive therapy, if indicated.
* History of hepatitis C virus (HCV) infection must have been treated and cured. For patients with known HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
* Willing and able to comply with the requirements of the protocol.

Exclusion Criteria:

* Major concurrent illness or organ dysfunction including but not limited to the following:

  * POEMS syndrome
  * Symptomatic major organ involvement AL amyloidosis
* History of allergy or known hypersensitivity to any of the trial therapies or any of their excipients, or contraindication to any of the trial therapies as outlined in the local prescribing information (e.g., United States Prescribing Information \[USPI\])
* Complete spinal cord compression or CNS involvement
* Known leptomeningeal disease
* Allogeneic tissue/solid organ transplant recipients with chronic GVHD requiring steroid equivalent dose of \> 20 mg prednisone
* Active infection requiring treatment
* History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
* Psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial
* Legally incapacitated or has limited legal capacity
* Persons who are pregnant or breastfeeding