A Trial Evaluating Efficacy & Safety of RVD +/- Panobinostat in Transplant Eligible, Newly Diagnosed Multiple Myeloma (NDMM)

• Revlimid (Drug), also known as lenalidomide: Revlimid was used with dexamethasone to treat patients with multiple myeloma
• Velcade (Drug), also known as bortezomib: Velcade was a proteasome inhibitor indicated for treatment of patients with multiple myeloma
• dexamethasone (Drug), also known as Decadron: Dexamethasone was a steroid used to treat patients with multiple myeloma.
• Farydak (Drug), also known as panobinostat, LBH589: FARYDAK® (panobinostat) capsules was a prescription medicine used, in combination with bortezomib and dexamethasone, to treat adults with a type of cancer called multiple myeloma after at least 2 other types of treatment have been tried.

Primary outcomes

• Near Complete Response (nCR)/CR Rate of the Combination of Panobinostat With Bortezomib, Lenalidomide and Dexamethasone (P-RVD) vs RVD in Newly Diagnosed Multiple Myeloma Patients [84 days]

Secondary outcomes

• Minimal Residual Disease (MRD) Negativity (mCR) After 4 Cycles of Induction by Next Gen Sequencing [Month 3]: MRD negativity by Clonal Sequencing (ClonoSEQTM) assay (Adaptive Biotechnologies)
• Best Overall Response Rate (ORR) and MRD Negativity After ASCT and Maintenance [Month 3 up to end of study, approximately 3 years.]: ORR (CR + PR) and MRD negativity after ASCT and maintenance
• Depth of Response by International Myeloma Working Group (IMWG) Criteria [Day 22 up to end of study, approximately 3 years]: Rate of Very Good Partial Response (VGPR), Complete Response (CR) and Stringent Complete Response (sCR)
• Duration of Response [From measurable response to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years.]
• Overall Survival [3 years after the last patient is enrolled to the study]
• Progression Free Survival [3 years after the last patient is enrolled to the study]

Sex: All, ages: 18 Years to 74 Years

Key Inclusion Criteria:

* Patient newly diagnosed with multiple myeloma, based on following IMWG 2014 definition (Rajkumar et al 2014):
* Clonal bone marrow plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following myeloma defining events:
* Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder
* Any one or more of the following biomarkers of malignancy:

  1. Clonal bone marrow plasma cell percentage ≥ 60%
  2. Involved: uninvolved serum free light chain ratio ≥ 100
  3. >1 focal lesions on MRI studies
* Patient with measurable disease defined by at least 1 of the following conditions present at screening:
* Serum M-protein by Protein Electrophoresis (PEP) ≥ 1.0 g/dL (≥ 10 g/L).
* Urine M-protein by PEP ≥ 200 mg/24 hours. Involved serum free light chain level ≥ 10 mg/dL (≥ 100 mg/L), provided that the serum free light chain ratio is abnormal.
* Patient eligible for autologous stem cell transplantation based on the investigator's clinical judgment.
* Patient with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2
* Patient's age ≥ 18 and <75 years at time of signing the informed consent
* Patient provided written informed consent prior to any screening procedures
* Women of childbearing potential (WOCBP) with a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline

Key Exclusion Criteria:

Patients eligible for this study must not meet any of the following criteria:

* Any concomitant anti-cancer therapy (other than bortezomib/lenalidomide/dexamethasone; bisphosphonates are permitted only if commenced prior to the start of screening period)
* Unresolved diarrhea ≥ CTCAE grade 2 or presence of medical condition associated with chronic diarrhea (such as irritable bowel syndrome, inflammatory bowel disease).
* Allogeneic stem cell transplant recipient presenting with graft versus host disease either active or requiring immunosuppression
* Patient shown intolerance to bortezomib or to dexamethasone or components of these drugs or has any contraindication to one or the other drug, following locally applicable prescribing information
* Patient with rade ≥ 2 peripheral neuropathy or grade 1 peripheral neuropathy with pain on clinical examination at screening
* Patient received prior treatment with DAC inhibitors including Panobinostat
* Patient needing valproic acid for any medical condition during the study or within 5 days prior to first administration of panobinostat/study treatment.
* Patient taking any anti-cancer therapy concomitantly (bisphosphonates are permitted only if commenced prior to the start of screening period)
* Patient who received:

  1. prior anti-myeloma chemotherapy or medication including Immunomodulator (IMiDs) and Dex ≤ 3 weeks prior to start of study.
  2. experimental therapy or biologic immunotherapy including monoclonal antibodies ≤ 4 weeks prior to start of study.
  3. prior radiation therapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior start of study.
* Patient has not recovered from all therapy-related toxicities associated with above listed treatments to < grade 2 CTCAE.
* Patient undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy to < grade 2 CTCAE
* Patients with evidence of mucosal or internal bleeding
* Clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 month prior to screening)
* Inability to determine the Fridericia's Correction Formula (QTc) F interval
* Patient with an impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat (e.g. ulcerative disease, uncontrolled nausea, vomiting, malabsorption syndrome, obstruction, or stomach and/or small bowel resection)
* Sexually active males unless they use a condom during intercourse while taking the drug during treatment, and for 6 months after stopping treatment
* Pregnant or nursing (lactating) women.

Participant flow

Outcome results

• Near Complete Response (nCR)/CR Rate of the Combination of Panobinostat With Bortezomib, Lenalidomide and Dexamethasone (P-RVD) vs RVD in Newly Diagnosed Multiple Myeloma Patients (Primary)
• Minimal Residual Disease (MRD) Negativity (mCR) After 4 Cycles of Induction by Next Gen Sequencing (Secondary)
• Best Overall Response Rate (ORR) and MRD Negativity After ASCT and Maintenance (Secondary)
• Depth of Response by International Myeloma Working Group (IMWG) Criteria (Secondary)
• Duration of Response (Secondary)
• Overall Survival (Secondary)
• Progression Free Survival (Secondary)

Adverse events

Time frame: Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 1 year.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: This study was terminated prematurely. The reason for study termination was not related to challenges linked to efficacy or safety data but instead, had faced unanticipated challenges with enrollment.

• Study Protocol (PDF, 2016-01-19)
• Statistical Analysis Plan (PDF, 2017-02-09)

• Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals