This is a Phase Ib/II study with the primary purpose of the Phase Ib part being to estimate the MTD and/or recommended phase 2 dose (RP2D) of the combination of LGH447 and BYL719 when administered orally to adult patients with relapsed and refractory multiple myeloma. Once the MTD and/or RP2D is determined for the combination of LGH447 and BYL719, additional patients will be enrolled in the Phase II part to determine whether the combination of LGH447 and BYL719 exhibits improved anti-multiple myeloma activity compared to single agent LGH447. This trial never made it to the Phase II part of the this trial.

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2

• Patients with a confirmed diagnosis of multiple myeloma who have received two or more lines of therapy and are refractory to their most recent line of therapy, as defined as relapse while on therapy or within 60 days from their last line of therapy. If patient has not received either an immunomodulatory drug (IMID) or proteasome inhibitor as a prior therapy then Investigator must notify Novartis prior to the patient enrollment. Patients who have received a prior bone marrow transplant and otherwise meet the inclusion criteria are eligible for this study

• For patients in the Phase II portion of the study, must have measurable disease defined by at least 1 of the following 3 measurements:

  • Serum M-protein ≥ 0.5 g/dL
  • Urine M-protein ≥ 200 mg/24 hours OR
  • Serum free light chain (FLC) > 100 mg/L of involved FLC

• All patients must be willing to undergo a mandatory bone marrow aspirate and/or biopsy at baseline for the assessment of biomarker/pharmacodynamics and disease status

Exclusion Criteria:

• Systemic antineoplastic therapy (including unconjugated therapeutic antibodies and toxin immunoconjugates) or any experimental therapy within 14 days or 5 half-lives, whichever is shorter, before the first dose of either study drug
• Radiotherapy within 14 days before the first dose of either study drug except localized radiation therapy for lytic bone lesions and plasmacytomas
• Major surgery within 2 weeks before the first dose of either study drug
• Ongoing therapy with chronic or high dose corticosteroids. Low dose steroids (i.e. prednisone ≤ 10 mg or an equivalent steroid dose), inhaled and topical steroids are permitted
• Patients who are currently receiving treatment with a prohibited medication that cannot be discontinued at least one week prior to the start of treatment:
• Narrow Therapeutic index substrates, strong inhibitors and strong inducers of CYP3A4
• Strong Inhibitors of CYP2D6
• Narrow therapeutic index substrates of CYP2C8, CYP2C9, CYP2C19 and CYP2D6
• Any of the following clinical laboratory results during screening (i.e., within 28 days before the first dose of either study drug):
• Absolute neutrophil count (ANC) < 1,000/mm3 without growth factor support within 7 days prior to testing
• Platelet count < 75,000 mm3 without transfusion support within 7 days prior to testing
• Bilirubin > 1.5 times the upper limit of the normal range (ULN).
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 times the ULN.
• Calculated creatinine clearance < 30 ml/min according to Cockcroft-Gault equation
• Corrected QT interval (QTc) of > 450 milliseconds (ms) in males and > 470 milliseconds (ms) in females on baseline electrocardiogram (ECG) (using Fridericia [QTcF] corrected QT interval