Study Description

PRIMARY OBJECTIVE:

I. To determine the efficacy of CC-5013 (lenalidomide) in prolonging time to disease progression in patients with multiple myeloma after autologous stem cell transplant (ASCT).

SECONDARY OBJECTIVES:

I. To determine if CC-5013 will increase the complete response (CR) rate in patients with multiple myeloma following ASCT.

II. To compare the progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma who have undergone ASCT and who then are randomized to either CC-5013 or placebo.

III. To determine the feasibility of long-term administration of CC-5013 to multiple myeloma patients who have undergone ASCT.

OUTLINE:

PERIPHERAL BLOOD STEM CELL (PBSC) MOBILIZATION: Mobilization of autologous PBSC will be performed according to institutional guidelines.

AUTOLOGOUS PBSC TRANSPLANTATION (PBSCT): Patients receive melphalan intravenously (IV) over 30-60 minutes on day -2 or -1 or over 2 days on days -3 and -2 or -2 and -1. Patients undergo autologous PBSCT on day 0.

Patients are then randomized to 1 of 2 maintenance treatment arms. (Note: As of 12/17/09, no more patients will be randomized between lenalidomide and placebo. Patients who have not been randomized as of 12/17/09 will be assigned to lenalidomide.)

ARM I: Beginning between day 100-110, patients receive lenalidomide orally (PO) once daily.

ARM II: Beginning between day 100-110, patients receive placebo (PO) once daily.

In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months thereafter.

Condition or Disease	Intervention/Treatment
DS Stage I Multiple Myeloma DS Stage II Multiple Myeloma DS Stage III Multiple Myeloma Refractory Multiple Myeloma Smoldering Multiple Myeloma	Procedure: Autologous Hematopoietic Stem Cell Transplantation Other: Laboratory Biomarker Analysis Drug: Lenalidomide Drug: Melphalan Procedure: Peripheral Blood Stem Cell Transplantation Other: Placebo Administration

Study Design

Study Type	Interventional
Actual Enrollment	460 participants
Design Allocation	Randomized
Interventional Model	Parallel Assignment
Masking	Double
Primary Purpose	Treatment
Official Title	A Phase III Randomized, Double-Blind Study of Maintenance Therapy With CC-5013 (NSC # 703813) or Placebo Following Autologous Stem Cell Transplantation for Multiple Myeloma
Study Start Date	December 15, 2004
Actual Primary Completion Date	December 31, 2012
Anticipated Study Completion Date	February 22, 2025

Groups and Cohorts

Group/ Cohort	Intervention/ Treatment
Arm I (melphalan, autologous PBSCT, lenalidomide) Beginning between day 100-110, patients receive lenalidomide PO once daily. Treatment continues in the absence of disease progression or unacceptable toxicity.	Procedure: Autologous Hematopoietic Stem Cell Transplantation Undergo autologous PBSCT Other: Laboratory Biomarker Analysis Drug: Lenalidomide Drug: Melphalan Procedure: Peripheral Blood Stem Cell Transplantation
Arm II (melphalan, autologous PBSCT, placebo) Beginning between day 100-110, patients receive placebo PO once daily. Treatment continues in the absence of disease progression or unacceptable toxicity.	Procedure: Autologous Hematopoietic Stem Cell Transplantation Undergo autologous PBSCT Other: Laboratory Biomarker Analysis Drug: Melphalan Procedure: Peripheral Blood Stem Cell Transplantation Other: Placebo Administration

Outcome Measures

Primary Outcome Measures

1. Time to Progression [Duration of study (up to 10years)]
   Time to progression (TTP) was defined as the date of transplant to date of progression or death due to any cause, whichever occurs first. TTP was estimated using the Kaplan Meier method.
   
   Progression was defined per the International Myeloma Working Group definition as one more of the following:
   
   25% increase in serum M-component (absolute increase >= 0.5g/dl)
   
   25% increase in urine M-component (absolute increase >= 200mg/24hour
   
   25% increase in the difference between involved and uninvolved Free Light Chain levels (absolute increase >= 10mg/dl)
   
   25 % increase in bone marrow plasma cell percentage (absolute increase of >=10%)
   
   Definite development of new bone lesion or soft tissue plasmacytomas
   
   Development of hypercalcemia

Secondary Outcome Measures

1. Response to Autologous Hematopoietic Stem-cell Transplant (HSCT) at Day 100 [Day 100]
   Response was defined according to International Myeloma Working Group criteria (2006)
   
   Complete Response: Complete disappearance of M-protein from serum & urine on immunofixation, normalization of Free Light Chain (FLC) ratio & <5% plasma cells in bone marrow (BM)
   
   Partial Response: >= 50% reduction in serum M-Component and/or Urine M-Component >= 90% reduction or <200 mg per 24 hours; or >= 50% decrease in difference between involved and uninvolved FLC levels
   
   Marginal Response: 25-49% reduction in serum M-component & urine M-component by 50-89% which still exceeds 200mg/24hour
   
   Progressive Disease: Defined in primary outcome measure
   
   Stable Disease: Not meeting any of the criteria above

Eligibility Criteria

Ages Eligible for Study	18 Years to 70 Years (Adult, Older Adult)
Sexes Eligible for Study	All
Accepts Healthy Volunteers	No
Inclusion Criteria	Patients must have active multiple myeloma requiring treatment (Durie-Salmon stage >= 1) and have stable disease or be responsive to at least 2 months of any induction therapy; patients with smoldering myeloma are not eligible unless the disease has progressed to >= stage 1 No more than 12 months of any prior therapy, including CC-5013 and thalidomide Within 12 months of initiation of induction therapy No prior progression after initial therapy; in addition, no more than two regimens will be allowed excluding dexamethasone alone No prior peripheral blood, bone marrow, or solid organ transplant Patients must have peripheral blood stem cell collection of >= 2 x 10^6 cluster of differentiation (CD)34+ cells/kg (patient body weight) and preferably 5 x 10^6 cells/kg (patient body weight); stem cells may be collected at any time prior to transplant; peripheral blood stem cell collection may occur before or after registration Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Patients must have diffusing capacity of the lung for carbon monoxide (DLCO) > 50% predicted with no symptomatic pulmonary disease Patients must have left ventricular ejection fraction (LVEF) >= 40% by multi gated acquisition scan (MUGA) or echocardiogram Patients must not have uncontrolled diabetes mellitus Patients must not have an active serious infection Patients must not be human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSag), or hepatitis (Hep) C positive Patients must be non-pregnant and non-nursing; women of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL 10-14 days prior to registration and repeated within 24 hours prior to the first dose of lenalidomide; in addition, women of childbearing potential taking lenalidomide must have a pregnancy test performed by the doctor weekly during the first 4 weeks of treatment, and then every 4 weeks if menses are regular and every 2 weeks if menses are irregular, and then 30 days following the last dose of lenalidomide; women of childbearing potential must either commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control - one highly effective method (intrauterine device [IUD], hormonal, tubal ligation, or partner's vasectomy), and one additional effective method (latex condom, diaphragm, or cervical cap) - at the same time, at least 4 weeks before she begins lenalidomide therapy; "women of childbearing" potential is defined as a sexually mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months; men must agree not to father a child and must use a latex condom during any sexual contact with women of childbearing potential while taking lenalidomide and for 4 weeks after therapy is stopped, even if they have undergone a successful vasectomy Absolute neutrophil count (ANC) >= 1000/uL Platelets >= 100,000/uL Creatinine clearance* >= 40 cc/min To be calculated by method of Cockcroft-Gault or after 24-hour urine collection Creatinine =< 2 mg/dL Total bilirubin =< 2 mg/dL Aspartate aminotransferase (AST) =< 3 x upper limits of normal Alkaline phosphatase =< 3 x upper limits of normal Urine (U)-human chorionic gonadotropin (HCG) or serum HCG negative (if patient of ch
Exclusion Criteria	Patients must have active multiple myeloma requiring treatment (Durie-Salmon stage >= 1) and have stable disease or be responsive to at least 2 months of any induction therapy; patients with smoldering myeloma are not eligible unless the disease has progressed to >= stage 1 No more than 12 months of any prior therapy, including CC-5013 and thalidomide Within 12 months of initiation of induction therapy No prior progression after initial therapy; in addition, no more than two regimens will be allowed excluding dexamethasone alone No prior peripheral blood, bone marrow, or solid organ transplant Patients must have peripheral blood stem cell collection of >= 2 x 10^6 cluster of differentiation (CD)34+ cells/kg (patient body weight) and preferably 5 x 10^6 cells/kg (patient body weight); stem cells may be collected at any time prior to transplant; peripheral blood stem cell collection may occur before or after registration Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Patients must have diffusing capacity of the lung for carbon monoxide (DLCO) > 50% predicted with no symptomatic pulmonary disease Patients must have left ventricular ejection fraction (LVEF) >= 40% by multi gated acquisition scan (MUGA) or echocardiogram Patients must not have uncontrolled diabetes mellitus Patients must not have an active serious infection Patients must not be human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSag), or hepatitis (Hep) C positive Patients must be non-pregnant and non-nursing; women of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL 10-14 days prior to registration and repeated within 24 hours prior to the first dose of lenalidomide; in addition, women of childbearing potential taking lenalidomide must have a pregnancy test performed by the doctor weekly during the first 4 weeks of treatment, and then every 4 weeks if menses are regular and every 2 weeks if menses are irregular, and then 30 days following the last dose of lenalidomide; women of childbearing potential must either commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control - one highly effective method (intrauterine device [IUD], hormonal, tubal ligation, or partner's vasectomy), and one additional effective method (latex condom, diaphragm, or cervical cap) - at the same time, at least 4 weeks before she begins lenalidomide therapy; "women of childbearing" potential is defined as a sexually mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months; men must agree not to father a child and must use a latex condom during any sexual contact with women of childbearing potential while taking lenalidomide and for 4 weeks after therapy is stopped, even if they have undergone a successful vasectomy Absolute neutrophil count (ANC) >= 1000/uL Platelets >= 100,000/uL Creatinine clearance* >= 40 cc/min To be calculated by method of Cockcroft-Gault or after 24-hour urine collection Creatinine =< 2 mg/dL Total bilirubin =< 2 mg/dL Aspartate aminotransferase (AST) =< 3 x upper limits of normal Alkaline phosphatase =< 3 x upper limits of normal Urine (U)-human chorionic gonadotropin (HCG) or serum HCG negative (if patient of childbearing potential)

Contacts and Locations

Sponsors and Collaborators	National Cancer Institute (NCI)
Locations	Mayo Clinic in Arizona | Scottsdale, Arizona, United States, 85259 City of Hope Comprehensive Cancer Center | Duarte, California, United States, 91010 University of California Davis Comprehensive Cancer Center | Sacramento, California, United States, 95817 UC San Diego Medical Center - Hillcrest | San Diego, California, United States, 92103 UCSF Medical Center-Mount Zion | San Francisco, California, United States, 94115 The Medical Center of Aurora | Aurora, Colorado, United States, 80012 Boulder Community Hospital | Boulder, Colorado, United States, 80301 Penrose-Saint Francis Healthcare | Colorado Springs, Colorado, United States, 80907 Porter Adventist Hospital | Denver, Colorado, United States, 80210 Presbyterian - Saint Lukes Medical Center - Health One | Denver, Colorado, United States, 80218 SCL Health Saint Joseph Hospital | Denver, Colorado, United States, 80218 Rose Medical Center | Denver, Colorado, United States, 80220 Western States Cancer Research NCORP | Denver, Colorado, United States, 80222 Swedish Medical Center | Englewood, Colorado, United States, 80113 Saint Mary's Hospital and Regional Medical Center | Grand Junction, Colorado, United States, 81501 Banner North Colorado Medical Center | Greeley, Colorado, United States, 80631 Saint Anthony Hospital | Lakewood, Colorado, United States, 80228 Sky Ridge Medical Center | Lone Tree, Colorado, United States, 80124 Longmont United Hospital | Longmont, Colorado, United States, 80501 Banner McKee Medical Center | Loveland, Colorado, United States, 80539 Saint Mary Corwin Medical Center | Pueblo, Colorado, United States, 81004 North Suburban Medical Center | Thornton, Colorado, United States, 80229 Intermountain Health Lutheran Hospital | Wheat Ridge, Colorado, United States, 80401 Beebe Medical Center | Lewes, Delaware, United States, 19958 Christiana Care Health System-Christiana Hospital | Newark, Delaware, United States, 19718 Saint Francis Hospital - Wilmington | Wilmington, Delaware, United States, 19805 George Washington University Medical Center | Washington, District of Columbia, United States, 20037 University of Florida Health Science Center - Gainesville | Gainesville, Florida, United States, 32610 Mayo Clinic in Florida | Jacksonville, Florida, United States, 32224-9980 University of Miami Miller School of Medicine-Sylvester Cancer Center | Miami, Florida, United States, 33136 Northside Hospital | Atlanta, Georgia, United States, 30342 Augusta University Medical Center | Augusta, Georgia, United States, 30912 Saint Luke's Cancer Institute - Boise | Boise, Idaho, United States, 83712 OSF Saint Joseph Medical Center | Bloomington, Illinois, United States, 61701 Graham Hospital Association | Canton, Illinois, United States, 61520 Memorial Hospital | Carthage, Illinois, United States, 62321 Jesse Brown Veterans Affairs Medical Center | Chicago, Illinois, United States, 60612 University of Illinois | Chicago, Illinois, United States, 60612 University of Chicago Comprehensive Cancer Center | Chicago, Illinois, United States, 60637 Heartland Cancer Research NCORP | Decatur, Illinois, United States, 62526 Eureka Hospital | Eureka, Illinois, United States, 61530 Galesburg Cottage Hospital | Galesburg, Illinois, United States, 61401 Illinois CancerCare-Galesburg | Galesburg, Illinois, United States, 61401 Mason District Hospital | Havana, Illinois, United States, 62644 Hopedale Medical Complex - Hospital | Hopedale, Illinois, United States, 61747 Kewanee Hospital | Kewanee, Illinois, United States, 61443 Mcdonough District Hospital | Macomb, Illinois, United States, 61455 Carle BroMenn Medical Center | Normal, Illinois, United States, 61761 Carle Cancer Institute Normal | Normal, Illinois, United States, 61761 Illinois CancerCare-Ottawa Clinic | Ottawa, Illinois, United States, 61350 Ottawa Regional Hospital and Healthcare Center | Ottawa, Illinois, United States, 61350 OSF Saint Francis Radiation Oncology at Pekin | Pekin, Illinois, United States, 61554 Pekin Hospital | Pekin, Illinois, United States, 61554 Proctor Hospital | Peoria, Illinois, United States, 61614 Illinois CancerCare-Peoria | Peoria, Illinois, United States, 61615 Methodist Medical Center of Illinois | Peoria, Illinois, United States, 61636 OSF Saint Francis Medical Center | Peoria, Illinois, United States, 61637 Illinois Valley Hospital | Peru, Illinois, United States, 61354 Perry Memorial Hospital | Princeton, Illinois, United States, 61356 Saint Margaret's Hospital | Spring Valley, Illinois, United States, 61362 Indiana University/Melvin and Bren Simon Cancer Center | Indianapolis, Indiana, United States, 46202 Providence Medical Center | Kansas City, Kansas, United States, 66112 Lawrence Memorial Hospital | Lawrence, Kansas, United States, 66044 Menorah Medical Center | Overland Park, Kansas, United States, 66209 Radiation Oncology Practice Corporation Southwest | Overland Park, Kansas, United States, 66210 Advent Health - Shawnee Mission Medical Center | Shawnee Mission, Kansas, United States, 66204 Walter Reed National Military Medical Center | Bethesda, Maryland, United States, 20889-5600 Christiana Care - Union Hospital | Elkton, Maryland, United States, 21921 Brigham and Women's Hospital | Boston, Massachusetts, United States, 02115 Dana-Farber Cancer Institute | Boston, Massachusetts, United States, 02215 Lahey Hospital and Medical Center | Burlington, Massachusetts, United States, 01805 University of Minnesota/Masonic Cancer Center | Minneapolis, Minnesota, United States, 55455 Mayo Clinic in Rochester | Rochester, Minnesota, United States, 55905 University of Mississippi Medical Center | Jackson, Mississippi, United States, 39216 Centerpoint Medical Center LLC | Independence, Missouri, United States, 64057 University Health Truman Medical Center | Kansas City, Missouri, United States, 64108 Saint Luke's Hospital of Kansas City | Kansas City, Missouri, United States, 64111 Radiation Oncology Practice Corporation South | Kansas City, Missouri, United States, 64114 Saint Joseph Health Center | Kansas City, Missouri, United States, 64114 North Kansas City Hospital | Kansas City, Missouri, United States, 64116 Research Medical Center | Kansas City, Missouri, United States, 64132 Radiation Oncology Practice Corporation - North | Kansas City, Missouri, United States, 64154 Saint Luke's East - Lee's Summit | Lee's Summit, Missouri, United States, 64086 Liberty Radiation Oncology Center | Liberty, Missouri, United States, 64068 Heartland Regional Medical Center | Saint Joseph, Missouri, United States, 64506 Washington University School of Medicine | Saint Louis, Missouri, United States, 63110 University of Nebraska Medical Center | Omaha, Nebraska, United States, 68198 Cooper Hospital University Medical Center | Camden, New Jersey, United States, 08103 Rutgers Cancer Institute of New Jersey | New Brunswick, New Jersey, United States, 08903 University of New Mexico Cancer Center | Albuquerque, New Mexico, United States, 87106 Montefiore Medical Center-Weiler Hospital | Bronx, New York, United States, 10461 Montefiore Medical Center-Wakefield Campus | Bronx, New York, United States, 10466 Montefiore Medical Center - Moses Campus | Bronx, New York, United States, 10467 Roswell Park Cancer Institute | Buffalo, New York, United States, 14263 Northwell Health NCORP | Lake Success, New York, United States, 11042 North Shore University Hospital | Manhasset, New York, United States, 11030 Long Island Jewish Medical Center | New Hyde Park, New York, United States, 11040 Mount Sinai Hospital | New York, New York, United States, 10029 Memorial Sloan Kettering Cancer Center | New York, New York, United States, 10065 NYP/Weill Cornell Medical Center | New York, New York, United States, 10065 University of Rochester | Rochester, New York, United States, 14642 State University of New York Upstate Medical University | Syracuse, New York, United States, 13210 UNC Lineberger Comprehensive Cancer Center | Chapel Hill, North Carolina, United States, 27599 Carolinas Medical Center/Levine Cancer Institute | Charlotte, North Carolina, United States, 28203 Wake Forest University Health Sciences | Winston-Salem, North Carolina, United States, 27157 The Jewish Hospital | Cincinnati, Ohio, United States, 45236 Case Western Reserve University | Cleveland, Ohio, United States, 44106 MetroHealth Medical Center | Cleveland, Ohio, United States, 44109 Ohio State University Comprehensive Cancer Center | Columbus, Ohio, United States, 43210 Legacy Good Samaritan Hospital and Medical Center | Portland, Oregon, United States, 97210 Providence Portland Medical Center | Portland, Oregon, United States, 97213 Oregon Health and Science University | Portland, Oregon, United States, 97239 Geisinger Medical Center | Danville, Pennsylvania, United States, 17822 Geisinger Medical Center-Cancer Center Hazleton | Hazleton, Pennsylvania, United States, 18201 University of Pennsylvania/Abramson Cancer Center | Philadelphia, Pennsylvania, United States, 19104 Fox Chase Cancer Center | Philadelphia, Pennsylvania, United States, 19111 West Penn Hospital | Pittsburgh, Pennsylvania, United States, 15224 University of Pittsburgh Cancer Institute (UPCI) | Pittsburgh, Pennsylvania, United States, 15232 Geisinger Medical Group | State College, Pennsylvania, United States, 16801 Geisinger Wyoming Valley/Henry Cancer Center | Wilkes-Barre, Pennsylvania, United States, 18711 Saint Francis Hospital | Greenville, South Carolina, United States, 29601 Prisma Health Greenville Memorial Hospital | Greenville, South Carolina, United States, 29605 Prisma Health Cancer Institute - Eastside | Greenville, South Carolina, United States, 29615 Vanderbilt University/Ingram Cancer Center | Nashville, Tennessee, United States, 37232 Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center | Houston, Texas, United States, 77030 Houston Methodist Hospital | Houston, Texas, United States, 77030 M D Anderson Cancer Center | Houston, Texas, United States, 77030 LDS Hospital | Salt Lake City, Utah, United States, 84143 Central Vermont Medical Center/National Life Cancer Treatment | Berlin, Vermont, United States, 05602 University of Vermont and State Agricultural College | Burlington, Vermont, United States, 05405 Virginia Oncology Associates-Hampton | Hampton, Virginia, United States, 23666 Virginia Commonwealth University/Massey Cancer Center | Richmond, Virginia, United States, 23298 University of Washington Medical Center - Montlake | Seattle, Washington, United States, 98195 Saint Mary's Medical Center | Huntington, West Virginia, United States, 25702 Aurora Cancer Care-Glendale | Glendale, Wisconsin, United States, 53212 University of Wisconsin Carbone Cancer Center - University Hospital | Madison, Wisconsin, United States, 53792 Marshfield Medical Center-Marshfield | Marshfield, Wisconsin, United States, 54449 Medical College of Wisconsin | Milwaukee, Wisconsin, United States, 53226 Aspirus Cancer Care - James Beck Cancer Center | Rhinelander, Wisconsin, United States, 54501 Marshfield Medical Center-Rice Lake | Rice Lake, Wisconsin, United States, 54868
Investigators	Principal Investigator: Philip L McCarthy, Alliance for Clinical Trials in Oncology

More Information

Publications

• Holstein SA, Jung SH, Richardson PG, Hofmeister CC, Hurd DD, Hassoun H, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, van Besien K, Gentile TG, Isola L, Maziarz RT, Bashey A, Landau H, Martin T, Qazilbash MH, Rodriguez C, McClune B, Schlossman RL, Smith SE, Hars V, Owzar K, Jiang C, Boyd M, Schultz C, Wilson M, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Linker C, Anderson KC, McCarthy PL. Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial. Lancet Haematol. 2017 Sep;4(9):e431-e442. doi: 10.1016/S2352-3026(17)30140-0. Epub 2017 Aug 17. Erratum In: Lancet Haematol. 2018 Aug;5(8):e332. doi: 10.1016/S2352-3026(18)30114-5. Lancet Haematol. 2018 Dec;5(12):e608. doi: 10.1016/S2352-3026(18)30199-6.

• McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, Van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Qazilbash MH, Levitan D, McClune B, Schlossman R, Hars V, Postiglione J, Jiang C, Bennett E, Barry S, Bressler L, Kelly M, Seiler M, Rosenbaum C, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Anderson KC, Linker C. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1770-81. doi: 10.1056/NEJMoa1114083.

Additional Relevant MeSH Terms

• Multiple Myeloma
• Neoplasms, Plasma Cell
• Smoldering Multiple Myeloma
• Neoplasms by Histologic Type
• Neoplasms
• Hemostatic Disorders
• Vascular Diseases
• Cardiovascular Diseases
• Paraproteinemias
• Blood Protein Disorders
• Hematologic Diseases
• Hemorrhagic Disorders
• Lymphoproliferative Disorders
• Immunoproliferative Disorders
• Immune System Diseases
• Precancerous Conditions
• Hypergammaglobulinemia