Clinical trial NCT02489500
Conditions: AL Amyloidosis
Keywords: AL Amyloidosis Stem Cell Transplantation
Sponsor: Boston Medical Center
Start date: 2015-06-01; Completion date: 2017-04-28
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Standard treatment for AL Amyloidosis is high-dose melphalan and stem cell transplant.

This study will compare the safety and effectiveness of standard treatment with high-dose melphalan and stem cell transplant, compared with investigational bortezomib when used in combination with standard treatment with high-dose melphalan and stem cell transplant for AL amyloidosis.

Detailed description:
This study seeks to enroll patients with AL amyloidosis who have been recommended for standard treatment with high-dose melphalan and stem cell transplant.

Standard treatment for this disease is high-dose melphalan and stem cell transplant.

The purpose of this study is to compare the safety and effectiveness of standard treatment with high-dose melphalan and stem cell transplant, compared with investigational bortezomib when used in combination with standard treatment with high-dose melphalan and stem cell transplant for AL amyloidosis.

Patients enrolled in this study will receive either standard treatment with high-dose melphalan and stem cell transplant, or investigational bortezomib used in combination with standard treatment with high-dose melphalan and stem cell transplant.

Arms: arm 1: Neupogen 16mcg/kg x 4 days Stem cell collection Drug: high dose melphalan 140 or 200 mg/m2 stem cell infusion arm 2: Neupogen 16mcg/kg x 4 days Stem Cell collection drug: high-dose melphalan 140 or 200 mg/m2 drug: Bortezomib 1.0 mg/m2/dose x 4 doses stem cell infusion
Interventions: intervention 1: Bortezomib intervention 2: Melphalan intervention 3: Neupogen intervention 4: Stem Cell Collection intervention 5: Stem cell infusion
Intervention descriptions: intervention 1: Conditioning Regimen:

Drug: Bortezomib: 1.0 mg/m2/dose D -6, D -3, D +1, D + 4 Drug: Melphalan: 70-100 mg/m2/dose D -2, D -1 intervention 2: Conditioning Regimen:

Drug: Melphalan: 70-100 mg/m2/dose D -2, D -1 Stem Cell Transplant: D 0 intervention 3: granulocyte colony-stimulating factor (G-CSF) mobilization 16mcg/kg x 4 days intervention 4: collect at least 2.5 million cluster of differentiation 34 (CD34)+ stem cells intervention 5: infusion of previously collected autologous stem cells

Protocol documents:
Prot_SAP_000.pdf: 
 
 
  
 
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BOSTON MEDICAL CENTER 
 
Phase III trial of high-dose melphalan and stem cell transplantation 
vs high-dose melphalan and Bortezomib and stem cell 
transplantation in patients with AL amyloidosis  
 
 
 
Page 
 
SCHEMA ………………………………………………………………………. 
 
2 
1.0 
OBJECTIVES ………………………………………………………………….. 
3 
 
2.0 
 
BACKGROUND……………………………………………………………….. 
3 
3.0 
 
DRUG INFORMATION……………………………………………………….. 
4 
4.0 
 
ELIGIBILITY CRITERIA……………………………………………………... 
9 
5.0 
 
TREATMENT PLAN………………………………………………………….. 
10 
6.0 
 
DOSAGE MODIFICATIONS………………………………………………..... 
10 
7.0 
 
STUDY CALENDAR…………………………………………………………. 
11 
8.0 
 
OPTIONAL QUESTIONNAIRES…………………….………………………. 
12 
9.0 
 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS……….. 
12 
10.0 
 
STATISTICAL CONSIDERATIONS ………………………………………… 
14 
11.0 
 
REFERENCES ………………………………………………………………... 
14 
PRINCIPAL INVESTIGATOR: 
 
 
 
 
 
Vaishali Sanchorawala, M.D.   
 
 
 
Section of Hematology and Oncology 
 
Boston Medical Center 
 
One Boston Medical Center Place / FGH-1  
Boston, MA  02118 
 
617-638-7017 
 
Vaishali.sanchorawala@bmc.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CO-INVESTIGATORS:  
 
Karen Quillen, MD 
Director of Blood Bank 
Boston Medical Center 
 
One Boston Medical Center Place / Blood Bank 
 
Boston, MA  02118 
 
617-638-7828 
 
Karen.Quillen@bmc.org 
 
Mark Sloan, MD 
Section of Hematology and Oncology 
 
Boston Medical Center 
 
One Boston Medical Center Place / FGH-1  
Boston, MA  02118 
 
617-638-2367 
 
Mark.Sloan@bmc.org 
 
Cindy Varga, MD 
Section of Hematology and Oncology 
 
Boston Medical Center 
 
One Boston Medical Center Place / FGH-1  
Boston, MA  02118 
 
617-638- 6428 
 
Cindy.Varga@bmc.org 
 
 


 
 
  
 
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SCHEMA 
 
 
Stem cell mobilization:   G-CSF mobilization * 
 
 
 
Stem cell collection: 
> 2.5 x 106 CD 34+/kg 
 
 
 
Conditioning regimen: (determined by randomization) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stem cell transplant:   
D 0 
 
 
 
 
 
 
 
 
 
 
 
 
* Plerixafor allowed per institutional guidelines. 
 
 
Arm A: 
Melphalan: 70-100 mg/m2/dose  
D –2, D –1 
 
Arm B: 
Melphalan: 70-100 mg/m2/dose 
D –2, D –1 
 
Bortezomib: 1.0 mg/m2/dose  
D –6, D –3, D +1, D + 4 


 
 
  
 
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1.0  OBJECTIVES 
 
1.1 Primary Objective 
1.1.1 To determine hematologic response of high-dose melphalan and stem cell 
transplantation with the addition of bortezomib to the conditioning regimen 
compared to standard high-dose melphalan and stem cell transplantation 
 
1.2 Secondary Objectives 
1.2.1 To determine the toxicities, overall survival, and organ response of high-dose 
melphalan and stem cell transplantation with the addition of bortezomib to the 
conditioning regimen compared to standard high-dose melphalan and stem cell 
transplantation 
1.2.2 To prospectively examine anxiety, depression, and their potential mediators and 
moderators over the course of high-dose melphalan and stem cell transplantation 
with and without bortezomib  
 
2.0  BACKGROUND 
 
AL amyloidosis is a rare complex multisystem disease related to plasma cell dyscrasia. In 
this disease, clonal plasma cells produce light chains which get mis-folded, and get deposited 
as amyloid fibrils in various organs and tissues leading to organ dysfunction and organ 
failure and death1. Unfortunately, due to its rarity and complexity, there is no standard of care 
for treatment of this rare disease. 
 
High-dose melphalan and stem cell transplantation (HDM/SCT) was initially studied in the 
late 1990s after its success in myeloma at Boston Medical Center and has been an effective 
treatment for selected patients with AL amyloidosis. It has been shown in several reports 
from our center as well as other centers that HDM/SCT can improve survival and lead to 
hematologic and clinical remissions2.  
 
Recently, Boston Medical Center reported on long-term outcome of HDM/SCT in patients 
with AL amyloidosis and the 19-year survival in this report was 25%. Hematologic complete 
response (CR) as defined by the international consensus criteria occurred in 34% at 6 
months; by intention-to-treat analysis. Our experience treating more than 600 patients 
suggests that clinical outcomes following HDM/SCT correlate with the attainment of a CR. 
This report also demonstrates that the median survival of patients who achieve a CR is > 12.8 
years compared to 6 years for those who do not (p<0.001) and that clinical improvement in 
affected organ systems occurs in 2/3 of patients achieving a hematologic CR compared to 
only 1/3 of those who do not (p<0.001). There are similar differences with respect to 
improvements in performance status and quality of life3,4. 
       
Because hematologic CR is such a critical determinant of treatment outcome following 
HDM/SCT, a pilot study was performed to evaluate whether incorporation of bortezomib in 
the conditioning regimen would increase the hematologic CR rates. A synergistic effect 
between bortezomib and melphalan has been demonstrated in vitro and in vivo. Furthermore, 
the toxicity of these two drugs is different. Thus, the combination of bortezomib and HDM 
was a logical approach to study. Ten patients with AL amyloidosis were treated on this study 
and hematologic CR was achieved by 66% of patients; by intention-to-treat analysis. This 
pilot study demonstrated that the addition of Bortezomib to conditioning regimen for 


 
 
  
 
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HDM/SCT produced a high hematologic responses and organ responses without additional 
toxicities5.  
 
Therefore, we propose a randomized phase III clinical trial of HDM/SCT vs addition of 
bortezomib to HDM regimen prior to SCT for patients with AL amyloidosis who are eligible 
to receive stem cell transplantation. This would be a practice changing if phase III trial 
proves HDM-Bor conditioning to be superior to HDM alone conditioning prior to SCT.  
 
We recently completed and closed X05292 clinical trial of 2 cycles of induction with 
bortezomib and dexamethasone followed by HDM-Bortezomib/SCT. Thirty five patients 
with new diagnosis of AL amyloidosis were enrolled in this clinical trial from Jan 2010 to 
Aug 2013. The preliminary data suggests high hematologic responses with high CR rates of 
67% in this clinical trial. However, 2 cycles of induction with twice a week of bortezomib 
and dexamethasone led to dose modifications and without additional benefit in improving 
hematologic responses than pilot study of HDM-Bor/SCT. Therefore, the current trial design 
would exclude the 2 cycles of induction treatment with Bortezomib and dexamethasone.   
 
Currently, there is a phase III randomized clinical trial of MLN 9708 vs physician choice 
treatment for relapsed patients with AL amyloidosis is ongoing, C16011. However, this 
proposed trial would not compete with enrollment on C16011. The eligibility and inclusion 
criteria to participate in both these trials would be different and the subjects relapsing or not 
responding on this proposed clinical trial should be able to enroll on C16011 trial. 
 
While there have been a number of studies prospectively investigating the course of anxiety 
and depression in patients with hematological malignancies undergoing SCT 6,7, there are no 
studies of these kind with AL amyloidosis patients undergoing HDM/SCT. Investigating the 
course of anxiety and depression may be important as studies with heterogeneous cancer and 
SCT regimens have found that elevated depressive symptoms after transplant may be 
associated with decreased survival8,9 and that psychiatric morbidity is associated with longer 
hospitalization duration for SCT. Indeed, only limited research exists for anxiety and 
depression in AL amyloidosis10-12. 
 
 
3.0  DRUG INFORMATION   
 
 
3.1 Bortezomib (Velcade™) 
 
3.1.1 Pharmacology 
Mechanism of Action: Bortezomib is a reversible inhibitor of the chymotrypsin-
like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a 
large 
protein 
complex 
that 
degrades 
ubiquitinated 
proteins. 
The 
ubiquitinproteasome pathway plays an essential role in regulating the intracellular 
concentration of specific proteins, thereby maintaining homeostasis within cells. 
Inhibition of the 26S proteasome prevents this targeted proteolysis, which can 
affect multiple signaling cascades within the cell. This disruption of normal 
homeostatic mechanisms can lead to cell death. 
 
3.1.2 Adverse Effects 
Version 2.5, June 30, 20141 


 
 
  
 
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Adverse Events with Possible Relationship to PS-341 (Bortezomib, Velcade) 
(CTCAE 4.0 Term) 
[n= 2084] 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
CARDIAC DISORDERS 
Heart failure 
GASTROINTESTINAL DISORDERS 
Abdominal pain 
Constipation 
Diarrhea 
Dyspepsia 
Gastrointestinal 
hemorrhage2 
Gastrointestinal 
perforation3 
Ileus 
Nausea 
Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Chills 
Edema limbs 
Fatigue 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fever 
INFECTIONS AND INFESTATIONS 
Infection4 
INVESTIGATIONS 
Neutrophil count 
decreased 
Platelet count decreased 
Weight loss 
METABOLISM AND NUTRITION DISORDERS 
Anorexia 
Dehydration 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
Arthralgia 
Back pain 
Bone pain 
Musculoskeletal and connective 
tissue disorder 
- Other (muscle spasms) 
Myalgia 
Pain in extremity 
NERVOUS SYSTEM DISORDERS 
Dizziness 
Headache 
Leukoencephalopathy 
Neuralgia 
Paresthesia 


 
 
  
 
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Peripheral motor 
neuropathy 
Peripheral sensory 
neuropathy 
Reversible posterior 
leukoencephalopathy 
syndrome 
PSYCHIATRIC DISORDERS 
Anxiety 
Insomnia 
RENAL AND URINARY DISORDERS 
Acute kidney injury 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Adult respiratory distress 
syndrome 
Cough 
Dyspnea 
Pharyngeal mucositis 
Pulmonary hypertension 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Rash maculo-papular 
VASCULAR DISORDERS 
Hypotension 
1 This table will be updated as the toxicity profile of the agent is revised. Updates will be 
distributed to all Principal Investigators at the time of revision.  
2 Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices 
hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-
abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral 
hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, 
and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS 
SOC. 
3 Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, 
Esophageal perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal 
perforation, and Small intestinal perforation under the GASTROINTESTINAL 
DISORDERS SOC. 
4 Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS 
SOC. 
 
Also reported on PS-341 (bortezomib, Velcade) trials but with the relationship to 
PS-341 (bortezomib, Velcade) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (hematocrit low); Blood and lymphatic system disorders - Other 
(lymphadenopathy); Disseminated intravascular coagulation; Febrile neutropenia; 
Hemolytic uremic syndrome; Leukocytosis 
CARDIAC DISORDERS - Acute coronary syndrome; Asystole; Atrial fibrillation; Atrial 
flutter; Atrioventricular block complete; Cardiac arrest; Cardiac disorders - Other (cardiac 
amyloidosis); Cardiac disorders - Other (cardiomegaly); Chest pain - cardiac; Left 
ventricular systolic dysfunction; Mobitz type I; Myocardial infarction; Palpitations; 
Pericardial effusion; Pericardial tamponade; Pericarditis; Right ventricular dysfunction; 
Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia; Ventricular 
arrhythmia; Ventricular fibrillation; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - External ear inflammation; Hearing impaired; 
Tinnitus 
ENDOCRINE DISORDERS – Hypothyroidism 


 
 
  
 
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EYE DISORDERS - Blurred vision; Conjunctivitis; Dry eye; Extraocular muscle paresis; 
Eye disorders - Other (chalazion); Eye disorders – Other (choroidal effusion); Eye 
disorders - Other (conjunctival hemorrhage); Eye disorders - Other (retinal hemorrhage 
with bilateral vision impairment); Keratitis; Watering eyes 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Bloating; Colitis; 
Dry mouth; Duodenal ulcer; Dysphagia; Enterocolitis; Esophagitis; Flatulence; Gastritis; 
Gastroesophageal reflux disease; Gastrointestinal disorders - Other (colonic wall 
thickening); Gastrointestinal disorders - Other (early satiety); Gastrointestinal disorders - 
Other (eructation); Gastrointestinal disorders - Other (ileitis); Gastrointestinal disorders - 
Other (ischemic bowel); Gastrointestinal disorders - Other (mouth/tongue ulceration); 
Gastrointestinal disorders - Other (retching); Gastrointestinal pain; Gingival pain; 
Hemorrhoids; Mucositis oral; Oral pain; Pancreatitis; Small intestinal obstruction; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; 
Flu like symptoms; Gait disturbance; General disorders and administration site conditions 
- Other (catheter related 
complication);General disorders and administration site conditions - Other (hepato-renal 
syndrome); Hypothermia; Injection site reaction; Malaise; Multi-organ failure; Non-cardiac 
chest pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other 
(hepatitis); Hepatobiliary disorders - Other (portal vein thrombosis); Hepatobiliary 
disorders - Other (VOD)  
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Cytokine release 
syndrome 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fall; Fracture; 
Vascular access complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Alanine 
aminotransferase increased; Alkaline phosphatase increased; Aspartate 
aminotransferase increased; Blood bilirubin increased; CD4 lymphocytes decreased; 
CPK increased; Carbon monoxide diffusing capacity decreased; Cardiac troponin I 
increased; Cardiac troponin T increased; Cholesterol high; Creatinine increased; Ejection 
fraction decreased; GGT increased; INR increased; Investigations – Other (albumin); 
Investigations - Other (BUN); Investigations - Other (low chloride); Investigations - Other 
(pancytopenia); Lipase increased; Lymphocyte count decreased; Serum amylase 
increased; Weight gain; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; 
Hyperglycemia; Hyperkalemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; 
Hypoglycemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia; 
Metabolism and nutrition disorders - Other (failure to thrive); Metabolism and nutrition 
disorders - Other (hypoproteinemia); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Avascular 
necrosis; Buttock pain; Chest wall pain; Generalized muscle weakness; Joint range of 
motion decreased; Muscle weakness lower limb; Musculoskeletal and connective tissue 
disorder – Other (cramping); Osteonecrosis of jaw 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Acoustic nerve disorder NOS; Akathisia; Ataxia; 
Cognitive disturbance; Depressed level of consciousness; Dysesthesia; Dysgeusia; 
Dysphasia; Edema cerebral; 
Encephalopathy; Facial muscle weakness; Facial nerve disorder; Hypersomnia; 
Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; Memory impairment; 
Nervous system disorders – Other (autonomic neuropathy); Nervous system disorders - 
Other (Bell's palsy); Nervous system disorders - Other (cranial palsy); Nervous system 
disorders - Other (dysautonomia); Nervous system disorders - Other (L sided facial 
droop); Nervous system disorders - Other (paralysis); Nervous system disorders - Other 
(polyneuropathy); Nervous system disorders - Other (spinal cord compression); Nervous 
system disorders - Other (tongue paralysis); Presyncope; Seizure; Somnolence; Stroke; 
Syncope; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Confusion; Delirium; Depression; Personality 
change; Psychosis 


 
 
  
 
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RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis 
noninfective; Hematuria; Proteinuria; Renal and urinary disorders - Other (bilateral 
hydronephrosis); Renal and urinary disorders - Other (calculus renal); Renal and urinary 
disorders - Other (glomerular nephritis proliferative); Urinary frequency; Urinary 
incontinence; Urinary retention; Urinary tract pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Allergic rhinitis; 
Aspiration; Atelectasis; Bronchopulmonary hemorrhage; Bronchospasm; Epistaxis; 
Hiccups; Hypoxia; Laryngeal edema; Mediastinal hemorrhage; Pharyngolaryngeal pain; 
Pleural effusion; Pleuritic pain; Pneumonitis; Postnasal drip; Pulmonary edema; 
Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (obstructive 
airways disease); Respiratory, thoracic and mediastinal disorders - Other (pleurisy); 
Respiratory, thoracic and mediastinal disorders - Other (respiratory distress); Respiratory, 
thoracic and mediastinal disorders - Other (tachypnea); Tracheal mucositis; Tracheal 
stenosis; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Bullous dermatitis; Dry 
skin; Erythema multiforme; Erythroderma; Hyperhidrosis; Pain of skin; Palmar-plantar 
erythrodysesthesia syndrome; Pruritus; Purpura; Rash acneiform; Skin and 
subcutaneous tissue disorders - Other (angioedema); Skin and subcutaneous tissue 
disorders – Other (leukoclastic vasculitis); Skin and subcutaneous tissue disorders – 
Other (Skin lesion NOS); Urticaria 
VASCULAR DISORDERS - Capillary leak syndrome; Flushing; Hematoma; 
Hypertension; Thromboembolic event; Vascular disorders - Other (trach site); Vasculitis 
Note: PS-341 (bortezomib; Velcade) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other agent, or 
the combination may result in events never previously associated with either agent. 
 
Pregnancy and Lactation: Pregnancy Category D. It is not knownwhether bortezomib is 
excreted in human milk. 
 
Drug Interactions: Closely monitor patients receiving bortezomib in combination with 
strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not 
recommended. Due to potential drug interactions, a complete patient medication list 
should be screened prior to initiation of bortezomib. 
 
3.1.3 Storage & Stability 
Please refer to the current FDA-approved package insert for storage, stability and special 
handling information. 
 
 
3.1.4 
Supply 
VELCADE (bortezomib) for Injection is commercially available.  Each single 
dose vial contains 3.5 mg of bortezomib as a sterile lyophilized powder. Inactive 
ingredient: 35 mg mannitol, USP. 
 
4.0 ELIGIBILITY CRITERIA 
 
1. Histological diagnosis of primary systemic (AL) amyloidosis based on:  
a. Deposition of amyloid material by Congo red stain showing characteristic apple 
green birefringence, AND… 
b. evidence of a clonal plasma cell dyscrasia with monoclonal protein in the serum 
or urine by immunofioxation electrophoresis studies AND/OR abnormal serum 
free light chain assay AND/OR clonal plasma cells in the bone marrow exam 
demonstrated by immunohistochemistry, flow cytometry or in situ hybridization  
AND… 
c. evidence of organ involvement other than carpal tunnel syndrome. Patients with 
senile, secondary, localized, dialysis-related or familial amyloidosis are not 


 
 
  
 
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eligible.  Confirmation of tissue diagnosis at all sites of organ dysfunction is 
encouraged, but not required. 
 
 
2. Patients must be > 18 years of age. 
 
3. Patients must have a performance status of 0-2 by ECOG criteria  
 
4. Patients must have LVEF > 45% by ECHO within 60 days of enrollment 
 
5. Patients with recent (< 6 months) myocardial infarction, congestive heart failure, NYHA 
class III/IV or arrhythmia which are refractory to medical therapy are ineligible.   
 
6. Prior chemotherapy with alkylating agent allowed only if no evidence of Myelodysplastic 
Dysplastic Syndrome (MDS) morphologically or cytogenetically.  Total cumulative dose 
of oral melphalan must be < 300 mg.   Patients should not have received any cytotoxic 
therapy < 4 weeks prior to registration and should have fully recovered from the effects 
of such therapy. 
 
7. Patients must not have overt multiple myeloma (>30% bone marrow plasmacytosis and, 
extensive (>2) lytic lesions and hypercalcemia). 
 
8. No other prior malignancy is allowed except for the following: adequately treated basal 
cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II 
cancer from which the patient is currently in complete remission, or any other cancer 
from which the patient has been disease-free for 5 years. 
 
9. Patients must not be HIV positive. 
 
10. Pulmonary Function Tests must show DLCO > 50%. 
 
11. Pregnant or nursing women may not participate.  Women and men of reproductive 
potential may not participate unless they have agreed to use an effective contraceptive 
method. 
 
12. All patients must be informed of the investigational nature of this study and must sign 
and give written informed consent in accordance with institutional and federal guidelines. 
 
13. Patients must not have known hypersensitivity to bortezomib. 
 
 


 
 
  
 
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5.0  
TREATMENT PLAN 
 
5.1.1 Stem cell mobilization:   
G-CSF alone mobilization 
 
Stem cell collection 
 
> 2.5 x 106 CD 34+/kg 
 
Conditioning regimen: 
 
Randomization: 
 
Arm A 
Melphalan   
70-100 mg/m2/dose D –2, D –1 
 
Arm B 
Melphalan  
70-100 mg/m2/dose D –2, D –1 
         
Bortezomib  
1.0 mg/m2/dose D –6, D –3, D +1, D + 4 
 
Stem cell transplant   D 0 
 
5.5 Criteria for Removal from Protocol Treatment: 
 
5.5.1  Discontinuation of transplant procedure for any reason 
 
5.5.2  Inadequate stem cell collection < 2.5 
 
5.5.3  Complications of stem cell mobilization regimen which are not reversible with 
medical management 
 
5.5.4  Unacceptable toxicity.   
 
5.5.5  The patient may withdraw from the study at any time for any reason. 
 
5.5.6  Development of overt multiple myeloma. 
 
5.5.7  Completion of all protocol therapy. 
 
5.5.8  Determination by the treating physician that further protocol treatment will not be 
in the best interest of the patient. 
 
5.6 All patients will be followed by standard transplant protocol at 6 months, 1 year, then 
annually until death. 
 
6.0  
DOSAGE MODIFICATIONS 
 
N/A 
 


 
 
  
 
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7.0 STUDY CALENDAR 
  
The following testing will be performed per institutional standard for transplant patients. 
REQUIRED STUDIES 
PRE STUDY * 
 Transplant  
F/U # 
PHYSICAL 
 
 
 
History & Physical Exam 
X 
 
X 
Weight & Performance Status 
X 
 
X 
Toxicity Notation 
 
 
X 
 
 
 
 
LABORATORY-Serum 
 
 
 
CBC with Differential  
X 
 
X 
BUN / Serum Creatinine / Glucose 
X 
 
X 
Bili / Alb / Alp / SGOT / SGPT / Amy / TP / LD 
X 
 
X 
AST/ALT/COR/CRP 
X 
 
X 
Na / K / Cl / CO2 / chol / CK / Ca 
X 
 
X 
IRN / Mg / P / Trig / Uric/ TSH 
X 
 
X 
-2 Microglobulin / C-reactive protein 
X 
 
X 
SPEP / GAM / KAPLAM / IFEP 
X 
 
X 
VITB12 / FOL / ESR / RETICB 
X 
 
X 
PTB/ PTT/ DIMER/ INR/ Factor X 
X 
 
X 
FLC 
X 
 
X 
BNP/Tropinin I 
X 
 
X 
Hep B Surface AG, Hep B Core AB, Hep C AB 
X 
 
 
AHIV - 1+2  
X 
 
 
 
 
 
 
LABORATORY-Urine 
 
 
 
UA 
X 
 
X 
UTP24 / UCR24 / UKAP / ULAM 
X 
 
X 
UPEP / UIFEP / TV 
X 
 
X 
 
 
 
 
PATHOLOGY 
 
 
 
BM aspiration / biopsy 
X 
 
X≠ 
Fat aspirate 
X 
 
 
 
 
 
 
X-RAYS AND SCANS 
 
 
 
EKG / CXR 
X 
 
X 
Echocardiogram 
X 
 
X 
PFT’s 
X 
 
 
CPST  
X 
 
 
 
 
 
 
OPTIONAL SUB-STUDY 
 
 
 
Questionnaires▲ 
X▲ 
X▲ 
X▲ 
 
 
 
 
TREATMENT 
 
 
 
High-Dose Melphalan with AuSCT +/- Bortezomib 
 
X 
 
   Testing during treatment should be done per institutional standard and as clinically indicated, including toxicity 
evaluations. The following routine labs should be obtained until neutrophil and platelet engraftment (~14 days) 
Daily: electrolytes, BUN, creatinine, glucose, CBCd; Mon & Thurs: Bili, ALP, GGT, ALT, ALB, Ca, Mg, Phos, 
INR/PTT, clot to blood bank 
#  Follow-up evaluations for disease response will take place at 6 months, one year and annually thereafter. 
*  Tests are recommended for good medical practice and only those listed in the eligibility criteria are required by 
the protocol. 
     If clinically indicated at physician’s discretion 
≠ If needed to evaluate response. 
 
▲  If patient consents to the optional sub-study, questionnaires will be completed at pre-study (any time after consent, 
but prior to mobilization), D-1 (any time between D-2 and D+4), discharge (± 7d), and at 6m follow-up (± 1m). 
See Section 8.0 for questionnaire details. 


 
 
  
 
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8.0 OPTIONAL QUESTIONNAIRES 
 
If the patient consents to the optional sub-study, the following questionnaires will be completed 
at all four time points detailed in Section 7.0: 
 
 Sociodemographic Questionnaire  
o  Patients will be asked to self-report educational attainment and estimated income. 
 State-Trait Anxiety Inventory (STAI-Y)13 
o A 20 item, 4-point measure of state anxiety. It has been shown to reliably assess 
aspects of anxiety symptoms and has been used to diagnose clinical anxiety.  
 Center for Epidemiologic Studies Depression Scale Revised (CES-D) 14 
o A 20 item, 4-point measure of depressive symptoms. It has been shown to reliably 
assess aspects of depressive symptoms.  
 Satisfaction with Life Scale 15 
o A 5 item, 7-point self-report rating scale designed to assess life satisfaction as a 
cognitive domain of subjective wellbeing. 
 Coping Strategy Indicator (CSI)16 
o A 33 item, 3-point self-report rating scale designed to assess 3 basic modes of 
coping. The original version requires patients to identify a stressful event that has 
occurred within the last 6 months and then answer the items based on how they 
coped with their event. In this study, “coping with AL amyloidosis and your stem 
cell transplantation” will be specified as the event.  
 Distress Intolerance Index (DII) 17 
o A 10 item, 5-point self-report scale derived from the Anxiety Sensitivity Index, 
Frustration Discomfort Scale and the Distress Tolerance Scale designed to assess 
the ability withstand negative somatic and emotional states. 
 Medical Outcomes Study (MOS) 36-item Short Form General Health Survey (SF-36)18 
o A 36 item questionnaire that assess 8 scales of health status that can be combined 
into composite scores physical and mental health. SF-36 has good reliability and 
validity in a variety of diseases, and has been suggested to be the most appropriate 
assessment for quality of life for AL amyloidosis4. 
These questionnaires can be completed with the assistance of the study team and interpreter 
services if necessary. Any assistance should be noted. 
 
9.0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
9.1 Primary  
 
9.1.1 Hematologic Response: 
 
CR 
Negative serum and urine immunofixation electrophoresis, normal 
serum free light chain ratio 
 


 
 
  
 
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VGPR dFLC <40 mg/L, dFLC = difference in involved and uninvolved serum 
free light-chain levels 
 
PR 
dFLC reduction >50%, dFLC = difference in involved and uninvolved 
serum free light-chain levels 
 
SD 
Meets neither criteria for CR, VGPR, PR or PD 
 
PD 
From CR, an increase in serum M-protein to > 0.5 g/dL, an increase in 
the urine M-protein to > 200 mg/day, or an increase in the serum 
monoclonal free light chain by > 10 mg/dL (100 mg/L). From VGPR, 
PR or SD, an increase in the serum M-protein from the lowest level by > 
50%, as long as the absolute magnitude of this increase is > 0.5 g/dL; or 
an increase in the urine M-protein from the lowest level by 50%, as long 
as the absolute magnitude of this increase is > 200 mg/day; or an 
increase in the serum or urine monoclonal free light chain by > 50% 
from the lowest level, as long as the absolute magnitude is > 10 mg/dL 
(100 mg/L). 
 
9.2 Secondary 
 
9.2.1 Organ Response: 
 
A subject will be said to have had an organ response in an involved organ if any 
of the following criteria are met: 
 
Kidney: 50% reduction in 24-hour urine protein excretion in the absence of 
progressive renal insufficiency (defined as a 25% increase in serum creatinine, as 
long as that is > to an absolute increase of 0.5 mg/dL). In the case of nephrotic 
syndrome: a decrease in proteinuria to < 1g/24h and an improvement in one of 2 
extrarenal features – normalization of serum albumin or resolution of edema 
and/or discontinuation of diuretics in response to improvement in edema. 
 
Heart: ≥ 2 mm reduction in the interventricular septal (IVS) thickness by 
echocardiogram, improvement of ejection fraction by ≥ 20% (echocardiogram 
must be performed at the same institution), or decrease in 2 NYHA classes 
without increase in diuretic need (see Appendix E for class definitions). 
 
Liver: ≥ 50% decrease in normalization of an initially elevated alkaline 
phosphatase level or reduction in the size of the liver by at least 3 cm (determined 
by clinical exam). 
 
Neuropathy: While neurotoxicity is acceptable for determining organ 
involvement, it will not be adequate for assessing organ response; organ response 
will be indeterminable for subjects in which neurotoxicity is the only site of organ 
involvement. 
 
Gastrointestinal Tract: While GI involvement is acceptable for determining 
organ involvement, it will not be adequate for assessing organ response: organ 


 
 
  
 
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response will be indeterminable for subjects in which GI is the only site of organ 
involvement. 
 
9.2.2 Tolerability 
 
9.2.3 Survival at 1 and 2 years 
 
 
10.0  STATISTICAL CONSIDERATIONS 
 
 Estimated accrual 2-3/month 
 
Accrual in similar clinical trial: X-05292 accrued 35 patients from Jan 2010 to Aug 2013   
 
 Expected Hem CR with HDM/SCT: 34%, Expected Hem CR with Bor-HDM/SCT: 65% 
 Design: Type I error alpha=0.05, power 80% 
 Randomized phase III design 
 
Accrual Goal 
The accrual goal for this trial is 64 subjects, 32 subjects per arm. If unacceptable toxicity or 
treatment related mortality in the first 5 patients exceeds 25%, the study will be terminated 
early. 
 
Optional Sub-Study: As this is an observational study, the sample size is limited to the 
enrollment on the main treatment study. Similar studies investigating psychosocial factors in 
SCT have had sample sizes ranging anywhere between 20 to 320 subjects19. 
 
 
11.0 REFERENCES 
 
1 
Merlini, G. & Bellotti, V. Molecular mechanisms of amyloidosis. The New England journal of medicine 
349, 583-596, doi:10.1056/NEJMra023144 (2003). 
2 
Sanchorawala, V. Role of high-dose melphalan and autologous peripheral blood stem cell transplantation in 
AL amyloidosis. Am J Blood Res 2, 9-17. 
3 
Cibeira, M. T. et al. Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell 
transplantation: long-term results in a series of 421 patients. Blood 118, 4346-4352. 
4 
Seldin, D. C. et al. Improvement in quality of life of patients with AL amyloidosis treated with high-dose 
melphalan and autologous stem cell transplantation. Blood 104, 1888-1893 (2004). 
5 
Sanchorawala, V., Quillen, K., Sloan, J. M., Andrea, N. T. & Seldin, D. C. Bortezomib and high-dose 
melphalan conditioning for stem cell transplantation for AL amyloidosis: a pilot study. Haematologica 96, 
1890-1892. 
6 
Hjermstad, M. et al. The course of anxiety and depression during the first year after allogeneic or 
autologous stem cell transplantation. Bone marrow transplantation 24, 1219-1228 (1999). 
7 
Hjermstad, M. et al. A prospective study of health-related quality of life, fatigue, anxiety and depression 3–
5 years after stem cell transplantation. Bone marrow transplantation 34, 257-266 (2004). 
8 
Prieto, J. M. et al. Role of depression as a predictor of mortality among cancer patients after stem-cell 
transplantation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 
23, 6063-6071, doi:10.1200/jco.2005.05.751 (2005). 
9 
Loberiza, F. R., Jr. et al. Association of depressive syndrome and early deaths among patients after stem-
cell transplantation for malignant diseases. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 20, 2118-2126 (2002). 
10 
Smorti, M., Guarnieri, S., Bergesio, F., Perfetto, F. & Cappelli, F. Anxiety and depression among amyloid 
light-chain cardiac amyloidosis patients: The role of life satisfaction. European journal of cardiovascular 


 
 
  
 
Amendment 3 (7-13-15) 
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nursing : journal of the Working Group on Cardiovascular Nursing of the European Society of Cardiology, 
doi:10.1177/1474515114566737 (2015). 
11 
Smorti, M., Cappelli, F., Bergesio, F. & Perfetto, F. Anxiety and depression among AL amyloidosis 
patients: the role of cardiac symptoms. Amyloid : the international journal of experimental and clinical 
investigation : the official journal of the International Society of Amyloidosis 19, 123-128, 
doi:10.3109/13506129.2012.687420 (2012). 
12 
Smorti, M., Cappelli, F., Guarnieri, S., Bergesio, F. & Perfetto, F. Depression and cardiac symptoms 
among AL amyloidosis patients: the mediating role of coping strategies. Psychology, health & medicine 19, 
263-272, doi:10.1080/13548506.2013.802357 (2014). 
13 
Speilberger, C., Gorsuch, R. & Lushene, R. The state trait anxiety inventory manual. Palo Alto, Cal.: 
Consulting Psychologists (1970). 
14 
Radloff, L. S. The CES-D scale a self-report depression scale for research in the general population. 
Applied psychological measurement 1, 385-401 (1977). 
15 
Frisch, M. B. Quality of life therapy and assessment in health care. Clinical Psychology: Science and 
Practice 5, 19-40 (1998). 
16 
Amirkhan, J. H. A factor analytically derived measure of coping: The Coping Strategy Indicator. Journal of 
personality and social psychology 59, 1066 (1990). 
17 
McHugh, R. K. & Otto, M. W. Refining the measurement of distress intolerance. Behavior therapy 43, 
641-651, doi:10.1016/j.beth.2011.12.001 (2012). 
18 
Ware, J. E., Jr. & Sherbourne, C. D. The MOS 36-item short-form health survey (SF-36). I. Conceptual 
framework and item selection. Med Care 30, 473-483 (1992). 
19 
Mosher, C. E., Redd, W. H., Rini, C. M., Burkhalter, J. E. & DuHamel, K. N. Physical, psychological, and 
social sequelae following hematopoietic stem cell transplantation: a review of the literature. Psycho-
oncology 18, 113-127, doi:10.1002/pon.1399 (2009).