Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis

PRIMARY OBJECTIVES:

I. To evaluate non-relapse mortality (NRM) up to day +100.

SECONDARY OBJECTIVES:

I. To evaluate non-relapse mortality (NRM) up to day +365. II. To evaluate the incidence of acute graft versus host disease (GVHD) and chronic GVHD up to day +365 post-transplant.

III. To evaluate the overall survival and disease free survival up to 1 year. IV. To evaluate clinical response and molecular response (complete response and partial response) up to 1 year.

OUTLINE:

Participants receive busulfan intravenously (IV) over 2 hours and fludarabine IV over 30 minutes on days -5 to -2. Participants undergo hematopoietic cell transplantation (HSCT) on day 0. Participants then receive cyclophosphamide IV over 60 minutes on days 3 and 4.

After completion of study treatment, participants are followed up for 1 year.

• Busulfan (Drug), also known as 1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508: Given IV
• Cyclophosphamide (Drug), also known as (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719: Given IV
• Fludarabine (Drug), also known as Fluradosa: Given IV
• Hematopoietic Cell Transplantation (Procedure), also known as HCT, Hematopoietic Stem Cell Transplantation, HSCT, stem cell transplantation: Undergo HSCT
• Laboratory Biomarker Analysis (Other): Correlative studies

Primary outcomes

• Non-relapse Mortality (NRM) at Day 100 [Up to day 100]: NRM is defined as death due to GVHD, infections, sepsis, organ (lung, liver, kidney) toxicity. Death from underlying disease (i.e. progression or relapse) is not considered NRM.

Secondary outcomes

• Non-relapse Mortality (NRM) at Day 365 [Up to day 365]: NRM is defined as death due to GVHD, infections, sepsis, organ (lung, liver, kidney) toxicity. Death from underlying disease (i.e. progression or relapse) is not considered NRM.
• Incidence of Acute Graft Versus Host Disease (GVHD) [Up to day 365]: Cases of acute graft versus host disease (GVHD) will be diagnosed by the treating physician and will be reported as a count of participants with acute GVHD.
• Incidence of Chronic GVHD [Up to day 365]: Chronic GVHD will be assessed based on criteria established by the National Institutes of Health Consensus Development Project in 2005, and recently updated in 2014. This will be reported as a count of participants diagnosed with chronic GVHD
• Overall Survival at One Year [Up to 1 year]: Overall survival is defined as the number of participants remaining alive up to one year following stem cell transplant.
• Disease Free Survival at One Year [Up to 1 year]: Disease free survival is defined as an absence of disease relapse or progression up to one year following stem cell transplant.
• Number of Participants With Different Clinical Responses [Up to 1 year]: Clinical Responses were determined by disease-specific criteria taking into account multiple clinical and molecular markers. Multiple Myeloma (MM) response was determined using International Myeloma Working Group (IMWG) consensus criteria for response. Participants with MM had either Stringent Complete Response (sCR) or Very Good Partial Response (VGPR). Myelofibrosis (MF) response was determined using International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus criteria. Participants with MF had either Complete Response (CR) or Stable Disease (SD) (also referred to in the protocol as no response).
• Number of Participants With Minimal Residual Disease (MRD) Response [Up to 1 year]: After bone marrow transplant, bone marrow was collected every 3-6 months (as clinically indicated per treating investigator) for up to one year after bone marrow transplant. Bone marrow was evaluated by a clinical pathologist for any evidence of multiple myeloma (MM) or myelofibrosis (MF). Evidence of MM or MF in the bone marrow is referred to as minimal residual disease (MRD). A participant with evidence of MRD is MRD-positive. A participant with no evidence of MRD is MRD-negative, which is considered an MRD response. This outcome reports the number participants with MRD responses any time between bone marrow transplant up to one year of follow-up.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Participants must have one of the following diagnoses of multiple myeloma (MM) or primary/secondary myelofibrosis (MF)
* Participants must have histologically documented multiple myeloma (MM)

  * Participants in early relapse (less than 24 months from initiation of systemic anti-myeloma therapy which may include single or planned tandem autologous transplant) after primary therapy that included and autologous HSCT; OR
  * Later stage; OR
  * High risk factors defined by the presence of any one of the following detected at any time prior to enrollment: deletion of chromosome 13 by conventional cytogenetics, hypodiploidy, abnormality in chromosome 1 (1q amplification or 1p deletion), t(4;14), t(14;16), t(14;20) or deletion of 17p by fluorescence in situ hybridization (FISH) or conventional karyotyping; high risk criteria based on commercially available gene expression profiling; OR
  * Extramedullary disease, plasma cell leukemia or high lactate dehydrogenase (LDH)
* Participants must have histologically documented myelofibrosis (MF)

  * Participants with Dynamic International Prognostic Scoring System (DIPSS) plus intermediate stage 2 or higher risk MF; OR
  * Subset of intermediate stage 1 participants; defined by:

    * Poor-risk molecular profile (triple negative: JAK2, CALR, MPL); OR
    * Presence of any of the following mutations: ASXL1, SRSF2, EZH2, IDH1/2; OR
    * Severe thrombocytopenia, severe anemia, high peripheral blood blasts percentage; OR
    * Unfavorable cytogenetic abnormalities (rearrangements of chromosome 5 or 7 or >= 3 abnormalities
* Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines
* DONOR: A related donor - fully matched
* DONOR: A related donor - haploidentical
* DONOR: An unrelated donor - fully matched
* DONOR: An unrelated donor -9/10 matched

Exclusion Criteria:

* Cardiac-left ventricular ejection fraction < 40%, symptomatic coronary artery disease, or uncontrolled arrhythmias
* Pulmonary-forced expiratory volume at one second (FEV1) or diffusion capacity of lung for carbon dioxide (DLCO) < 40% or history of chronic use of supplemental oxygen. Temporary use of supplemental oxygen at the time of screening or registration is allowed if the investigator feels that the underlying cause of requiring oxygen is reversible by the time treatment begins.
* Renal-calculated or measured glomerular filtration rate (GFR) < 30 ml/min, dialysis-dependent, or history of renal transplant
* Hepatic-bilirubin > 2 X upper limit of normal (ULN)
* Alanine aminotransferase (ALT) > 2.5 X ULN or cirrhosis
* Participants with active or uncontrolled bacterial, viral, or fungal infections requiring systemic therapy
* Pregnant women, nursing mothers or women of child-bearing potential who are unwilling to use medically accepted methods of contraception
* Male and female subjects not willing to agree to medically accepted methods of contraception

Participant flow

Outcome results

• Non-relapse Mortality (NRM) at Day 100 (Primary), Count of participants, Participants: All Participants - Treatment 1
• Non-relapse Mortality (NRM) at Day 365 (Secondary), Count of participants, Participants: All Participants - Treatment 2
• Incidence of Acute Graft Versus Host Disease (GVHD) (Secondary), Count of participants, Participants: All Particpants - Treatment 2
• Incidence of Chronic GVHD (Secondary), Count of participants, Participants: All Particpants - Treatment 1
• Overall Survival at One Year (Secondary), Count of participants, Participants: All Particpants - Treatment 3
• Disease Free Survival at One Year (Secondary), Count of participants, Participants: All Particpants - Treatment 3
• Number of Participants With Different Clinical Responses (Secondary), Count of participants, Participants: All Particpants - Treatment 1
• Number of Participants With Minimal Residual Disease (MRD) Response (Secondary), Count of participants, Participants: All Particpants - Treatment 5

Adverse events

Time frame: Adverse Events (AEs) and Serious Adverse Events (SAEs) were collected from Day -6 (6 days prior to stem cell transplant) to day +365 (365 days after stem cell transplant), approximately one year total.

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2019-01-29)

• Catherine Lee, MD, Principal investigator, Huntsman Cancer Institute