Clinical trial NCT01212952
Conditions: Refractory Multiple Myeloma
Sponsor: Mayo Clinic
Start date: 2011-09-01; Completion date: 2018-03-22
Enrollment: 50 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Pomalidomide and bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bortezomib may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving pomalidomide and bortezomib together with dexamethasone may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of bortezomib when given together with pomalidomide and dexamethasone and to see how well it works in treating patients with relapsed or refractory multiple myeloma.

Detailed description:
PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) of bortezomib in combination with pomalidomide and dexamethasone.

II. To evaluate the hematologic response rate (PR, VGPR, or CR) of pomalidomide, bortezomib and dexamethasone in patients with relapsed or refractory myeloma.

SECONDARY OBJECTIVES:

I. Time to progression.

II. To assess the toxicity of pomalidomide, bortezomib and dexamethasone in this patient population.

OUTLINE : This is a phase I, dose-escalation study of bortezomib followed by a phase II study. Patients receive oral pomalidomide on days 1-21; bortezomib IV on days 1, 8,15, 22; and oral dexamethasone on days 1, 8, 15, 22 . Treatment repeats every 28 days for 8 courses. Patients then receive maintenance therapy comprising oral pomalidomide on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months.

Arms: arm 1: Patients receive oral pomalidomide on days 1-21; bortezomib IV on days 1, 8, 15, 22; and oral dexamethasone on days 1, 8, 15, 22. Treatment repeats every 28 days for 8 courses. Patients then receive maintenance therapy comprising oral pomalidomide on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: pomalidomide intervention 2: bortezomib intervention 3: dexamethasone intervention 4: laboratory biomarker analysis intervention 5: gene expression analysis
Intervention descriptions: intervention 1: Given orally intervention 2: Given IV intervention 3: Given orally intervention 4: Optional correlative studies intervention 5: Optional correlative studies

Protocol documents:
Prot_SAP_ICF_000.pdf: 
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MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
1 
Mayo Clinic Cancer Center 
 
A Phase I/II Trial of Pomalidomide (CC-4047), Bortezomib and Dexamethasone in Patients 
with Relapsed or Refractory Multiple Myeloma 
 
 
Mayo Clinic Study Chair(s): 
 Martha Q. Lacy, M.D. 
 
 
Mayo Clinic Rochester 
 
 
200 First Street, SW 
 
 
Rochester, MN 55905 
 
 
507-284–8430 
 
 
507-266-4962 (FAX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dana Farber Cancer Institute Study Chair: 
 
 
 
 
 
 
University of Chicago Study Chair: 
 
 
 
 
 
 
 
 
Study Co-Chairs: 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
 
Drug Availability 
Commercial Agent: Bortezomib and Dexamethasone 
Drug Company Supplied: Pomalidomide (CC-4047) 
 
√Study contributor(s) not responsible for patient care. 
 
October 25, 2011 
Document History 
Effective Date 
Activation 
March 21, 2012 
MCCC Addendum 1 
May 16, 2012 
MCCC Addendum 2 
October 22, 2012 
MCCC Addendum 3 
March 1, 2013 
MCCC Addendum 4 
March 10, 2014 
MCCC Addendum 5 
MCCC Addendum 6 
December 18, 2015 
December 7, 2017 


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Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
 
Phone: 
 
E-mail: 
 
Drug administration, infusion pumps,  
nursing guidelines 
 
 
  
Forms completion and submission 
 
  
Protocol document, consent form, 
regulatory issues 
 
   
Biospecimens  
 
  
Adverse Events (AdEERS, MedWatch, 
Non-AER, AML/MDS) 
 
  
*No waivers of eligibility per NCI


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Index 
Schema 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Grouping Factor 
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation   
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
Model Consent Form 
Appendix I – ECOG Performance Status 
Appendix II – Mayo Risk Stratification 
Appendix III – NYHA Classification 
Appendix IV – Patient Medication Diary 
Appendix V – Myeloma Tumor Biology Kit  
 
 
 


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Schema 
 
MTD( Bortezomib 1.3 mg/m2) reached in Phase I and permanently closed 11/13/2012  
Phase II opened 01/10/2013 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
     Cycle = 28 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
           ** As of Addendum 6, patients in active treatment and in event monitoring will be 
removed from the study. 
 
Mayo Drug Names/Abbreviations 
Generic name:   Pomalidomide (CC-4047) 
Brand name: 
 
NA  
 
Mayo abbreviation: CC4047 
Availability: Provided by Celgene 
Generic name:   Bortezomib 
Brand name: 
Velcade 
Mayo abbreviation: VELCAD 
Availability:  Commercial 
Generic name:   Dexamethasone  
Brand name: 
 
Decadron 
Mayo abbreviation:  DXM 
Availability: Commercial 
 
 
Registration 
Treatment: 
Pomalidomide (Days 1-21 of each cycle)  
Bortezomib (Days 1, 8, 15, 22 of each cycle) 
Dexamethasone (Days 1, 8, 15, 22 of each cycle) 
X 8 cycles 
Event 
Monitoring** 
PD at any time 
Unacceptable adverse events 
 
 
Event Monitoring 
Patient refusal 
Pomalidomide maintenance 
(Days 1-21 of each cycle)** 
*See section 7.4 


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1.0 
Background 
 
1.1 
Multiple myeloma (MM) is a malignant plasma cell proliferative disorder 
characterized by bone destruction, anemia, hypercalcemia, and renal failure that 
causes about 11,000 deaths in the United States each year1,2. Median survival 
with conventional dose melphalan and prednisone is 3-4 years, which has not 
been significantly improved by the addition of other chemotherapeutic agents3. 
Although improvement in survival occurs with high-dose therapy and stem cell 
transplantation, almost all patients eventually relapse and die of their disease.  
  
1.2 
Autologous stem cell transplantation (SCT) has been shown to be superior to 
conventional dose chemotherapy in the treatment of multiple myeloma in two 
randomized clinical trials4,5. Despite the high response rates it is expected most 
patients will relapse and SCT is not considered curative.  Given the limited 
therapeutic options available for patients with relapsed MM, there is an urgent 
need for novel therapeutic approaches. 
   
1.3 
Thalidomide was first reported as an active agent in relapsed MM in 19996.  Most 
patients had failed stem cell transplantation, and the overall response rate (greater 
than 50% reduction in M protein level) was 32% using doses of 200 to 800 mg 
orally per day. A subsequent study of 16 patients performed at the Mayo Clinic 
used 200 to 800 mg orally per day and found a 25% response to therapy with a > 
50% reduction in the serum or urine m-protein level.  Side effects included 
constipation, sedation, rash, and peripheral neuropathy7.  Several trials including 
ones at Mayo Clinic have since confirmed the significant activity of thalidomide 
in myeloma.  
 
1.4 
Glucocorticoids have significant activity in myeloma.  They are often used in 
relapsed and refractory disease.  In a study of 112 patients with untreated 
myeloma, the response rate with dexamethasone alone was 43%8.  Recent 
randomized trials comparing Thal/Dex to dexamethasone have confirmed this9,10.  
Steroids also have anti-angiogenic properties and this may involve different 
mechanisms than thalidomide.  There is evidence from pre-clinical models that 
anti-angiogenic therapy may be synergistic with conventional chemotherapy.  
Similarly, there may be an additive (or synergistic) anti-angiogenic effect when 
dexamethasone and thalidomide are combined.  While there are no randomized 
trials comparing either thalidomide or lenalidomide alone to those agents with 
dexamethasone, available evidence from multiple phase 2 trials suggests the 
addition of dexamethasone greatly increases response rates from 25-30% to 50-
60% among relapsed patients11-17. However, the combination of either 
thalidomide or lenalidomide with dexamethasone greatly increases risk of 
thromboembolic events 9,10,18-20.  Both aspirin and full dose anticoagulation 
appear to be effective prophylaxis against venous thromboembolism in this 
setting21-23. 
 
1.5 
The utility of thalidomide in the relapsed setting led to its use upfront for newly 
diagnosed MM.  Multiple phase 2 studies show response rates of 60-70% with 
Thal/Dex24.  In a randomized trial conducted by the Eastern Cooperative 
Oncology Group (ECOG)9, the response rate with Thal/Dex was significantly 
higher compared to dexamethasone alone, 58% versus 42%, respectively 


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(p=0.0164).  This was confirmed in an international randomized trial10 which 
showed response rate of 63% for Thal/Dex vs.46% for dexamethasone alone 
(p<0.0005). 
 
1.6 
The astonishing success of thalidomide in this group of heavily treated patients 
led to interest in developing thalidomide analogues (IMiD®s) a proprietary class 
of Celgene compounds. Lenalidomide (CC-5013) belongs to this class of 
thalidomide analogues with immunomodulatory properties. It appears safer and 
more effective than thalidomide in preclinical and clinical studies14,16,25. Data 
from phase II and phase III clinical trials in patients with relapsed myeloma 
suggests lenalidomide is less likely to cause peripheral neuropathy, constipation, 
and sedation than thalidomide, but the incidence of thromboembolism is 
similar15,17,19,26. The combination of lenalidomide and dexamethasone has been 
used in newly diagnosed myeloma with a response rate of 91%21. 
 
1.7 
The myeloma cells are highly dependent on the bone marrow microenvironment, 
including the presence of certain cytokine macromolecules, eg, Interleukin (IL)-
6, in the extracellular matrix, and supportive (stromal) cells for their growth and 
survival. Processes that change the bone marrow microenvironment either retard 
the growth of the tumor or cause the myeloma cells to undergo apoptosis. 
Corticosteroids, for example, which inhibit IL-6 expression, have efficacy in the 
treatment of multiple myeloma. Thalidomide’s activity in multiple myeloma is 
postulated to derive from a number of pharmacologic properties, including 
inhibition of tumor necrosis factor (TNF)-α an angiogenic factor present in the 
tumor microenvironment. Thalidomide also stimulates IL-12 secretion that 
induces interferon gamma (IFN-γ). IFN-γ has numerous effects, including the 
induction of IFN inducible protein 10 (IP-10), which inhibits neovascularity by 
inhibiting vascular endothelial growth factor synthesis (VEGF) and stimulation 
of T cells. IFN-γ also alters the expression of intracellular adhesion molecules 
and other adhesion molecules. The resulting absence of appropriate adhesion 
molecule binding causes multiple myeloma cells to undergo apoptosis. 
Thalidomide also modifies extracellular matrix expression, directly inhibits both 
basic fibroblast growth factor (bFGF) and VEGF expression, and inhibits the 
induction of cyclooxygenase-2 (COX-2), an enzyme whose expression is 
essential for inhibiting neovascular apoptosis. 
 
1.8 
Pomalidomide: Pomalidomide (CC4047), α -(3-aminophthalimido) glutarimide, 
is a novel IMiD under development for potential use in the treatment of various 
conditions. Pomalidomide shares a number of the beneficial pharmacologic 
properties with thalidomide, but has a higher potency. For example, an in vitro 
model of anti-TNF activity has shown that pomalidomide has an IC50 of 
approximately 13 nM (3.6 ng/mL) against TNF produced by lipopolysaccharide 
(LPS)-stimulated human peripheral blood mononuclear cells (PBMCs). 
Thalidomide, by comparison, has an IC50 of ~194 µM (50.1 µg/mL)27. In LPS-
stimulated human whole blood, the 50% inhibitory concentration (IC50) for 
pomalidomide is 25 nM (6.8 ng/mL)28. Pomalidomide’s antitumor activity has 
also been demonstrated in vitro with MM tumor cell lines. Concentrations of 2.73 
to 27.3 ng/mL (0.01 to 0.1 µM) achieved a 50% inhibition of MM.IS and Hs 
Sultan cell proliferation. In contrast, at concentrations of 25.8 µg/mL (100 µM) 
thalidomide was less potent and inhibited the proliferation of MM.1S and Hs 
Sultan cells by 15% and 20%, respectively.  


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1.9 
Preclinical animal studies: A cardiovascular study in dogs was performed using 
an IV formulation in order to maximize systemic exposure. Pomalidomide 
(systolic, diastolic, and mean arterial blood pressure; heart rate; left ventricular 
pressure and its derivative, the maximum force of ventricular contraction 
(dP/dtmax); maximum and mean femoral blood flow and femoral resistance; RR, 
ST, QRS, PR, QT, and QTc-intervals; heights of the R, P, and T-waves of the 
electrocardiogram (ECG) complex; and peak inspiratory and expiratory flow, 
tidal volume, minute volume, and rate of respiration were recorded up to 30 
minutes following completion of the infusion of each dose. Mean plasma 
concentrations 30 minutes postdose were 1010.4 ng/mL following the 2.5 mg/kg 
dose, and 2421.1 ng/mL following the 10 mg/kg dose. The mean plasma 
concentration for the high dose (25 mg/kg) was 6686.0 ng/mL. At doses of 2.5 
and 10 mg/kg there were no significant adverse cardiovascular effects compared 
with the vehicle control group. At 25 mg/kg no significant differences between 
the vehicle group and the test article treated group were observed in 3 of 4 dogs. 
One female animal exhibited an adverse reaction; 7 to 8 minutes into the infusion 
of the 25 mg/kg dose, there was a marked increased in respiration rate and 
decreases in blood pressure, femoral artery blood flow, and dP/dtmax. Peak 
inspiratory flow (PIF) and tidal volume (TV) were more variable in 
pomalidomide treated animals than in control animals. PIF values showed a 
statistically significant increasing dose response in PIF. Administration was 
stopped and the animal was artificially ventilated in order to control the 
respiration. About 18 minutes later, on stopping the respiratory pump, it was 
noticed that although the animal was breathing spontaneously, the respiratory 
rate was still very high (up to 117 brpm). It was decided to artificially ventilate 
the animal. Approximately 40 minutes after the cessation of the high dose, values 
for cardiovascular parameters stabilized and the administration of the high dose 
was repeated. No further changes in any of the vascular parameters were 
observed for at least 30 minutes after the high dose administration. Between 45 
and 120 minutes after the second administration of the high dose, similar 
cardiovascular changes were noted, as previously seen at the beginning of the 
prior infusion at the same dose level. These changes may have been related to the 
assisted ventilation given to the animal for the prolonged period of time. A 
thoracotomy was performed on the animal to determine the possible causes of the 
respiratory problems experienced by this animal. Examination of the lungs 
revealed a large red patch on the posterior lobe indicative of a possible 
pulmonary embolus. Several other smaller patches were also apparent on the 
lungs. Pink fluid was found in the endotracheal tube and in the ventilator tubing. 
Propofol and alfentanil have not been previously associated with any adverse 
effects on pulmonary function. It is expected that these changes may be due to 
prolonged artificial ventilation rather than the effects of the anesthetics or 
pomalidomide. Pomalidomide, therefore, had no significant effects on the 
cardiovascular and respiratory systems following intravenous administration to 
anesthetized beagles at dose levels of up to 25 mg/kg.  
 
1.9a 
A single oral dose bioavailability study was conducted in the rat and monkey. 
Both species received single oral doses of 100 mg/kg. Pomalidomide was 
formulated in a 1% carboxymethylcellulose (CMC) suspension and administered 
in a volume of 5 mL/kg by oral gavage. Peak plasma concentrations (Cmax), time 
of peak concentration (tmax), area under the plasma concentration curve (AUC), 


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and half-life (t½) are summarized in the toxicity of pomalidomide after a single 
dose was studied after intravenous administration to rats (1398/51-1032) and 
mice. In rats, there were no deaths in the study animals dosed with 50 mg/kg and 
no treatment-related macroscopic changes in animals killed on Day 15. In mice 
administered pomalidomide by intravenous injection of 10, 25, and 50 mg/kg, the 
high dose produced piloerection, hunching, and tachypnea. Palpebral closure was 
observed at doses of 25 and 50 mg/kg, and hypernea at 50 mg/kg. The severity 
and persistence of clinical observations increased with increased dose. No 
macroscopic abnormalities in mice were found during necropsy. The acute 
toxicity of pomalidomide after oral administration was also studied in rats and 
mice. In rodents administered 2000 mg/kg pomalidomide, there were no deaths 
and no significant clinical observations. Pomalidomide at oral doses of 100, 500, 
or 1500 mg/kg was well tolerated when administered once daily to male and 
female rats for 90 consecutive days. Therefore the no-observable adverse-effects 
level (NOAEL) under the conditions of this study was considered to be the 
highest dose administered (1500 mg/kg).  
 
1.9b 
Oral administration of pomalidomide to male and female cynomolgus monkeys 
resulted in lesions in the bone marrow, spleen, and thymus in animals dosed at 2 
mg/kg and 10 mg/kg. Treatment was stopped at Week 6 for the 10 mg/kg 
monkeys. Bone marrow lesions included hypercellularity, myeloid series 
immaturity, and decreased megakaryocytes. Spleen lesions included primarily 
lymphoid depletion, but also occasionally lymphoid hyperplasia, and thymic 
lesions were of lymphoid depletion. Thymic lesions were resolved but spleen and 
bone marrow lesions persisted although they were reduced in incidence and/or 
severity in animals dosed with 10 mg/kg for 5 weeks followed by 8 weeks of 
recovery. Based on the results from this study, the NOAEL in this study was 0.2 
mg/kg/day; the Cmax and AUC values at this dosage were approximately 150 
ng/mL and 600 ng•h/mL, respectively.  
 
1.9c 
Pomalidomide was administered by oral gavage at dose levels of 100 or 250 
mg/kg/day to pregnant New Zealand white female rabbits (4/group). 
Administration began on presumed Gestation Day 6 and continued daily through 
presumed Gestation Day 18 (inclusive). Control groups (4/group) received 1% 
w/v CMC (vehicle control) or thalidomide (10, 100, or 250 mg/kg/day). Fetal 
external malformations, characterized by the presence of inward/outward 
hindlimb/hindfoot rotation, shortened limbs, missing or abnormal digits, missing 
or abnormal dew claws, extra digits, or a clubbed foot were seen in fetuses from 
animals that received the positive control (thalidomide, all doses) and in animals 
that had received pomalidomide (100 and 250 mg/kg/day). A relationship was 
noted between increasing pomalidomide dose and the number of fetuses affected, 
as well as the frequency of occurrence of each type of malformation. In 
administered doses of pomalidomide at 100 mg/kg/day, inward/outward rotation 
of hindlimbs/hindfeet, the presence of shortened limbs, and a clubbed foot were 
observed in 31% of viable fetuses. In addition to these malformations, does 
administered pomalidomide 250 mg/day/kg had missing/abnormal dew claws, 
missing/abnormal digits, extra digits on forelegs, and the presence of an 
umbilical hernia; 93% of fetuses from does treated at this higher dose of 
pomalidomide were affected. Based on these data, it was concluded that 
pomalidomide causes significant fetal malformations. The genotoxic potential of 
pomalidomide in a bacterial mutagenesis assay was evaluated at pomalidomide 


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concentrations of up to 5000 µg/plate in 4 strains of Salmonella typhimurium 
(TA98, TA100, TA1535, and TA1537) and 2 strains of Escherichia coli (WP2 
pKM101 and WP2 uvrA pKM101) in the absence and presence of metabolic 
activation. Pomalidomide was found not to be mutagenic. 
 
 
1.9d 
Human studies: In 20 healthy male subjects in study pomalidomide-1398/132, 
nine (56%) of 16 subjects in the 5 mg or higher pomalidomide treatment groups 
reported a total of 13 adverse events and 3 (30%) of 10 subjects in the placebo 
group reported 6 adverse events. All events were mild or moderate in nature. 
While there were no clinically significant changes in any laboratory or other 
parameter tested, there was a dose-related decrease in the CD4+ cell count, 
reaching a maximum at the 50-mg dose. The results of this study showed that 
pomalidomide had an acceptable safety profile and was well tolerated at all doses 
in healthy male subjects. 
 
1.9e 
Phase 1 trial in multiple myeloma:  Schey and colleagues29 conducted a phase 
1 trial using pomalidomide in 24 patients with relapsed or refractory multiple 
myeloma.  Dose levels were 1, 2, 5, and 10 mg/day by mouth.  The maximum 
tolerated dose (MTD) was 2 mg/day. Dose-limiting grade 4 neutropenia occurred 
in a total of six patients at a median of 3 weeks after starting therapy. Two events 
occurred on 10 mg daily at 2 and 3 weeks, two occurred on 5 mg at 3 weeks, and 
two occurred on 2 mg at 3 weeks. Non-hematologic toxicity consisted of DVT in 
4 patients.  Other non-hematologic toxicity was mild and consisted of grade 1or 2 
gastrointestinal toxicity (36%), grade1 skin rash (21%), grade 1 neuropathy 
(16%) and grade 1 or 2 edema (12%). Treatment resulted in a greater than 25% 
reduction in paraprotein in 67% of patients, 13 patients (54%) experienced a 
greater than 50% reduction in paraprotein, and four (17%) of 24 patients entered 
complete remission. 
   
1.9f  
Phase II trial in multiple myeloma:  A Phase II trial in relapsed multiple 
myeloma was conducted at Mayo Clinic30.  Sixty patients were enrolled.  
Treatment consisted of pomalidomide 2 mg by mouth daily with dexamethasone 
40 mg by mouth once a week. (Pom/dex). The overall remission rate was 63% 
with a CR+VGPR rate of 33%.  Importantly responses were seen in 40% of the 
patients who were refractory to lenalidomide, 60% of the patients who were 
refractory to bortezomib, and 37% of patients who were refractory to thalidomide 
suggesting a role for this drug in patients who have relapsed after other novel 
agents.  Toxicity was manageable and consisted primarily of neutropenia (32% 
with at least one episode grade 3 or 4) and fatigue.  One patient died of sepsis 
while neutropenic. Grade 1 or 2 neuropathy was seen in 28%, but neuropathy 
was present at baseline in 60 % of patients. No grade 3/4 neuropathy was seen. 
No patients had thromboembolic complications.  
 
 
Based on these results, another cohort of patients with relapsed myeloma that 
was  refractory to lenalidomide was accrued31.  The same Pom/dex dose regimen 
was used.  The cohort was heavily pre-treated with a median of 4 prior regimens.  
All were lenalidomide-refractory.  Overall remission rate was 50% including 
VGPR+PR rate of 32% and MR 18%.  The major toxicity was myelosuppression 
with grade 3 or 4 neutropenia see in 26%.    
 


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1.9g 
Bortezomib, lenalidomide and dexamethasone in myeloma: The combination 
of bortezomib, lenalidomide and dexamethasone was shown to be safe and 
effective in myeloma patients.  A phase I, dose-escalation study evaluated safety 
and determined the maximum-tolerated dose (MTD) of lenalidomide plus 
bortezomib in patients with relapsed or with relapsed and refractory MM32. 
Patients received lenalidomide 5, 10, or 15 mg/d on days 1 through 14 and 
received bortezomib 1.0 or 1.3 mg/m2 on days 1, 4, 8, and 11 of 21-day cycles. 
Dexamethasone (20 mg or 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) was added 
for progressive disease after two cycles. Primary end points were safety and 
MTD determination. Thirty-eight patients were enrolled across six dose cohorts. 
The MTD was lenalidomide 15 mg/d plus bortezomib 1.0 mg/m2. Dose-limiting 
toxicities (n = 1 for each) were grade 3 hyponatremia and herpes zoster 
reactivation and grade 4 neutropenia. The most common treatment-related, 
grades 3 to 4 toxicities included reversible neutropenia, thrombocytopenia, 
anemia, and leukopenia. Among 36 response-evaluable patients, 61% (90% CI, 
46% to 75%) achieved minimal response or better. Among 18 patients who had 
dexamethasone added, 83% (90% CI, 62% to 95%) achieved stable disease or 
better. Median overall survival was 37 months.  
 
1.9h 
CC-4047-MM-002 Phase 1b Safety and Efficacy Summary 
CC-4047-MM-002 is a phase 1b/2 multi-center, randomized, open-label, dose 
escalation study that is evaluating the safety and efficacy of oral pomalidomide 
alone and in combination with low-dose dexamethasone in patients with relapsed 
and refractory multiple myeloma33.  Eligible patients must have received at least 
2 prior regimens and all patients must have received prior treatment that includes 
lenalidomide and bortezomib.  This study consists of a phase 1 single agent 
pomalidomide (maximum tolerated dose [MTD]) segment and phase 2 
randomized (pomalidomide plus low-dose dexamethasone versus pomalidomide 
alone) segment.  The phase 1 segment is determining the starting dose of 
pomalidomide to be used in both treatment arms in the randomized phase 2 
segment of the study.  The primary endpoint of the phase 1 study is to determine 
the MTD, and subjects were enrolled sequentially to the 2 mg, 3 mg, 4 mg, and 5 
mg dose levels.  A 3 +3 design was used to define the MTD for single agent 
pomalidomide.  Oral pomalidomide was administered according to a cyclic 
schedule (once daily on Days 1-21 of a 28-day cycle); however, patients who 
developed PD at any time or who had not achieved at least a 25% reduction of 
serum M-protein (if measurable) and a 50% reduction of urine M-protein (if 
measurable) compared to baseline after completion of 4 cycles, had the option to 
receive low-dose oral dexamethasone in addition to their current dose of 
pomalidomide.  Patients with PD who choose to not add dexamethasone to 
pomalidomide therapy were discontinued from study treatment.  The phase 2 
study primary objective will be to determine the efficacy of pomalidomide alone 
and in combination with low-dose dexamethasone as treatment for patients with 
relapsed and refractory multiple myeloma.  The primary study endpoint is PFS.  
The secondary endpoints are:  objective response determined by European Group 
for Blood and Marrow Transplantation (EBMT) criteria, time to response, 
duration of response, overall survival, time to progression, safety, response by 
International Myeloma Working Group Uniform Response criteria, and 
exploration of the relationship between response and cytogenetic abnormalities.  
Patients will be randomized (1:1) to receive single agent pomalidomide or 
pomalidomide in combination with low-dose dexamethasone.  Patients in the 


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single agent pomalidomide treatment arm who develop confirmed PD at any time 
will have the option to receive oral dexamethasone in addition to their current 
dose of pomalidomide.  Preliminary data is available from the phase 1b segment 
this study.  To date, 32 patients have been enrolled and 18 patients have 
discontinued.  Fourteen patients are still ongoing for both safety and efficacy 
analyses.  The mean age was 66.5 years (range: 38-83 years), 62% were women, 
66% had Stage III disease, and the median number of prior MM regimens was 
6.8 (range, 2-18).  Prior multiple myeloma therapies were as follows: 
lenalidomide (100%), bortezomib (100%), dexamethasone (100%), thalidomide 
(78%), and stem cell transplant (59%).  The MTD was 4 mg (there were 4 drug-
related DLTs [grade 4 neutropenia] at 5 mg).  Overall, there were a total of 10 
dose reductions (7 -neutropenia, 1-rash, 1-peripheral neuropathy, and 1-fatigue) 
and 9 DLTs (all grade 4 neutropenia) after 133 completed cycles; most of dose 
reduction occurred at 5 mg (see Table 1).  Neutropenia and anemia were the most 
common grade 3/4 toxicities; there was a dose-dependent increase in grade 4 
neutropenia.  There were 22 serious adverse events (SAEs) involving 12 patients; 
the events that were attributed to pomalidomide were deep vein thrombosis, 
syncope, 2nd degree AV block, asthenia, and diarrhea.  In addition, an event of 
lung infection with neutropenia was attributed to dexamethasone and an event of 
sepsis with a pharyngeal abscess was attributed to pomalidomide plus 
dexamethasone.  Common adverse events were fatigue, neutropenia, anemia, 
dyspnea, back pain, nausea, thrombocytopenia, constipation, asthenia, and 
vomiting.  There were 4 deaths which were not attributed to pomalidomide; three 
patients died of disease progression (PD) and one patient died of gastrointestinal 
perforation due to amyloidosis.  There were responses seen at each dose level.  In 
25 evaluable patients, clinical activity (stable disease or better) was reported in 
23 patients (92%).  During the treatment period with pomalidomide alone (25 
evaluable patients), the overall response rate (ORR; 1 complete response [CR], 3 
partial response [PR], 6 minimal response [MR]) was 40% (10 of 25 patients), 
mean duration of response (DOR) was 13.5 weeks (range: 4-36 weeks), and 
mean time to progression (TTP) was 9.5 weeks (range: 2-32 weeks).  Fifteen of 
25 evaluable patients (60%) had dexamethasone added to their regimens at 
different cycles (median cycle: 3, range: 2-9) for PD or lack of response.  During 
the treatment period with pomalidomide plus dexamethasone, the ORR (2 PR, 4 
MR) was 40% (6 of 15 patients), mean DOR of 16.9 weeks (range: 4-36 weeks), 
and mean TTP of 16.6 weeks (range: 8-36 weeks).  In addition, there were 8 
stable disease (SD; 36%) with pomalidomide alone and 7 stable disease (47%) 
with pomalidomide plus dexamethasone.  In 7 of 15 patients (47%), their 
responses improved after dexamethasone was added (2 PR, 3 MR, and 2 SD).  
Median number of completed cycles of pomalidomide was 4 (range: 0-12).   
 
In conclusion, the MTD is 4 mg.  The safety profile was similar across cohorts 
except for grade 4 neutropenia, which increased in the 5 mg cohort.  There were 
responses seen at each dose levels; however, the best response and duration of 
response increased with the dose of pomalidomide and the addition of 
dexamethasone.  Based on the preliminary safety and response data, 4 mg is the 
recommended dose for the phase 2 segment.   


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
12 
 
Table 1 
Dose level 
Completed cycles 
(mean / median / range) 
DLTs 
Dose reductions 
2 mg 
(n=6 / 24Jun08) 
17 
(2.8 / 0.5 / 0-12) 
0 
0 
3 mg 
(n=8 / 25Aug08) 
38 
(4.8 / 4 / 1-11) 
2 
(2-not drug related 
neutropenia) 
1 
(1-neutropenia) 
4 mg 
(n=8 / 03Nov08) 
49 
(6.1 / 7 / 0-11) 
1 
(1-not drug related 
neutropenia) 
0 
5 mg 
(n=10 / 03Apr09) 
29 
(2.9 / 2.5 / 0-5) 
6 
(4-drug related neutropenia; 2-
not drug related neutropenia) 
9 
(6-neutropenia, 1-rash, 1-
peripheral neuropathy, 1- 
fatigue) 
Total 
133 
(4.1 / 4 / 0-12) 
9 
10 
 
2.0 
Goals    
 
 
2.1 
Primary Objective. 
 
2.11 
Phase I:  Determine the maximum tolerated dose (MTD) of bortezomib 
in combination with pomalidomide and dexamethasone 
 
2.12  
Phase II:  To evaluate the confirmed response rate (PR, VGPR, or CR) of 
pomalidomide, bortezomib and dexamethasone in patients with relapsed 
or refractory myeloma 
 
2.2  
Secondary Objectives 
 
2.21 
Overall survival, progression-free survival, and duration of response 
 
2.22 
To assess the toxicity of pomalidomide, bortezomib and dexamethasone 
in this patient population. 
 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
13 
3.0 
Patient Eligibility 
 
3.1 
Inclusion Criteria  
 
3.11 
Age ≥ 18 years. 
 
3.12 
The following laboratory values obtained ≤14days prior to registration. 
• 
Serum Creatinine ≤3 mg/dL 
• 
Absolute neutrophil count ≥1000/μL 
• 
Untransfused platelet count ≥75,000/μL 
 
3.13 
Measurable disease of multiple myeloma as defined by at least ONE of 
the following: 
• 
Serum monoclonal protein ≥1.0 g/dL (see section 11.1 for 
definitions) 
• 
>200 mg of monoclonal protein in the urine on 24 hour 
electrophoresis  
• 
Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal 
serum immunoglobulin kappa to lambda free light chain ratio. 
• 
Monoclonal bone marrow plasmacytosis ≥ 30% (evaluable disease). 
• 
Measurable plasmacytoma that has not been radiated.   
 
3.14 
ECOG Performance status (PS) 0, 1, or 2 (Appendix I). 
 
 
 
3.15 
Previously treated relapsed or refractory multiple myeloma.  
• 
Patients must have received at least one prior therapy but no more 
than 4 therapies.    
o 
One or more of the prior regimens must have included 
lenalidomide and it has been determined the patient is 
refractory, resistant, or relapsed this therapy. 
o 
Prior bortezomib not required but if prior exposure, patients 
should not be refractory.  Refractory means progression on 
therapy or within 60 days from the last dose of bortezomib. 
 
3.17 
Provide informed written consent. 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
14 
 
3.18 
Females of reproductive potential must be willing to adhere to the 
scheduled pregnancy testing as required in the POMALYST REMS™ 
program. 
 
3.19a 
Willing and able to take aspirin or alternate prophylactic anticoagulation. 
 
3.19b All previous cancer therapy, including chemotherapy, high dose 
corticosteroids, immune modulatory drugs or proteosome inhibitors must 
have been discontinued ≥ 2 weeks prior to study registration. 
 
3.19c 
Any prior treatment with investigational agents must be discontinued ≥ 
28 days prior to study registration. 
 
3.19d Willing to abstain from donating blood during study participation and for 
28 days after discontinuation of study drug. 
 
3.19e 
Men must agree to abstain from donating semen or sperm during study 
participation and for 28 days after discontinuation of study drug. 
 
3.19f 
Willingness to return to enrolling institution for follow-up. 
 
3.19g Willing to be registered into the mandatory POMALYST REMS™ 
program, and willing and able to comply with the requirements of the 
POMALYST REMS™ program. 
 
3.2 
Exclusion Criteria 
  
 
3.21  
Concomitant high dose corticosteroids (concurrent use of 
corticosteroids). EXCEPTION: Patients may be on chronic steroids 
(maximum dose 20 mg/day prednisone equivalent) if they are being 
given for disorders other than myeloma, i.e., adrenal insufficiency, 
rheumatoid arthritis, etc. 
 
3.22 
Another malignancy undergoing active treatment with the exception of 
non melanoma skin cancer or in situ cervical or breast cancer.  
 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
15 
3.23 
Any of the following: 
• 
Pregnant women or women of reproductive ability who are 
unwilling to use effective contraception 
• 
Nursing women  
• 
Men who are unwilling to use a condom (even if they have 
undergone a prior vasectomy) while having intercourse with any 
woman, while taking the drug and for 4 weeks after stopping 
treatment. 
 
3.24 
Other co-morbidity which would interfere with patient's ability to 
participate in trial, e.g. uncontrolled infection, uncompensated heart or 
lung disease. 
 
3.25 
Other concurrent chemotherapy, radiotherapy, or any ancillary therapy 
considered investigational.  NOTE: Bisphosphonates are considered to 
be supportive care rather than therapy, and are thus allowed while on 
protocol treatment. 
 
3.26 
Active DVT or PE that has not been therapeutically anticoagulated. 
 
3.27 
Known positive for HIV or active hepatitis infection. 
 
3.28a 
Any condition, including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the 
study or confounds the ability to interpret data from the study. 
 
3.28b Known hypersensitivity to thalidomide or lenalidomide including 
development of erythema nodosum if characterized by a desquamating 
rash. 
 
3.28c 
> grade 2 peripheral neuropathy. 
 
3.29 
Any prior use of pomalidomide. 
 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
16 
4.0 
Test Schedule  As of Addendum 6, discontinue active monitoring and remove patient from study.  
 
 
Active Monitoring 
 
Days Prior to Registration 
Weekly for 
1st cycle 
Prior to each Cycle 
beginning with Cycle 2, 
pre-treatment1, 16 
End of Cycle 3 and 
Q 3 cycles1, 6, 
 
≤30 days 
≤14 days 
Complete medical history 
X 
 
 
 
 
Adverse Event monitoring 
 
X 
 
X 
X 
Physical exam, including height, weight and vital signs 
 
X 
 
X 
X 
Performance status (ECOG scale)  
 
X 
 
X 
X 
CBC with diff. 
 
X 
X 
X 
X 
Chemistry group to include sodium, potassium, glucose, alkaline 
phosphatase; Total bilirubin; SGOT (AST); serum creatinine, 
calcium 
 
X 
X13 
X 
X 
LDH, Beta2-microglobulin 
X 
 
 
 
 
Electrophoresis of serum and urine 
 
X12  
 
X12 
X12 
Affected Immunoglobulin 
 
X8 
 
X8 
X8 
Immunofixation serum and urine 
X 
 
 
X2 
X2 
Immunoglobulin free light chain 
 
X 
 
X 
X 
X-ray skeletal survey 
X 
 
 
X4 
 
ECG 
X 
 
 
 
X  
TSH 
X 
 
 
 
X 
Bone marrow aspirate and biopsy, myeloma FISH, metaphase 
cytogenetics, flow cytometry14  
X 
 
 
 
X5 
Research bone marrow and blood sample as per 521-93 (patients 
enrolled in Rochester only) 
X R 
 
 
 
X5, R 
Research blood sample (see Section 14.0)  
X 15, R 
 
 
X 11, R 
 
Research bone marrow aspirate (see Section 14.0)  
X R 
 
 
 
X R 
Chest x-ray 
X 
 
 
 
 
Serum or urine pregnancy test 
 
X3, 9 
X3, 9 
X3, 9 
 
Pomalidomide Counseling 
 
 
 
X10 
 
Patient Medication Diary (Appendix IV) 
 
 
 
X7 
 
Footnotes on the following page. 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
17 
 
1) 
All scheduled visits will have a window of ± 7 days unless otherwise stated. 
2) 
Immunofixation (IF) needed only in the absence of M-spike. 
3) 
Pregnancy tests for females of childbearing potential.  Patient must follow pregnancy testing requirements as outlined in the POMALYST 
REMS™ program. 
4) 
Once a year while on active treatment. 
5)   
Required after cycle 3, required beyond that only to document CR or if used to assess response. 
6)   
Must return to registering institution every 3 months during pomalidomide maintenance. 
7) 
Must begin the day the patient starts taking and be completed on a daily basis.  Compliance should be documented in the medical record. 
8) 
Affected immunoglobulin refers to the baseline M-protein type, that is, IgG, IgA, or IgD. Not applicable if patient “non-secretory” or 
if patient has no heavy chain, i.e. light chain myeloma. 
9) 
Pregnancy tests must occur 10 – 14 days and again within 24 hours prior to initiation of pomalidomide with a sensitivity of at least 25 
mIU/mL.  FCBP with regular or no menstruation must have a pregnancy test weekly for the first 4 weeks and then every 28 days while on 
therapy (including breaks in therapy); at discontinuation of pomalidomide and at Day 28 post the last dose of pomalidomide.  Females with 
irregular menstruation must have a pregnancy test weekly for the first 4 weeks and then every 14 days while on therapy (including breaks in 
therapy), at discontinuation of pomalidomide and at Day 14 and Day 28 post the last dose of pomalidomide (see Appendix VI: 
Pomalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods).    
10) 
All patients must be counseled according to the POMALYST REMS™ program.   
11) 
Every cycle for the first 4 cycles.  If patient had sample collected at on study, the Cycle 1 Day 1 sample is not needed. 
12) 
Urine electrophoresis only needed at baseline if not measurable. 
13) 
AST only. 
14) 
Non-Mayo sites:  If flow cytometry cannot be ordered clinically, you may send sample to Mayo Clinic Rochester along with the other 
research samples (see Section 14.0 and Appendix VIII). 
15) 
Patient may have the first sample collected at on study or on Cycle 1 Day 1 but both are not needed. 
16) 
After the first 3 months of pomalidomide maintenance, if on a stable dose of CC-4047, CBC, chemistry, and tests necessary for 
disease response can be obtained per test schedule and mailed/faxed to Mayo Clinic and patient can return at least every 3 months for 
follow up to Mayo. All other procedures are per MD discretion.  All unused study drug must be returned to Mayo Clinic and all study 
drug must be accounted for. Only one month supply of study drug may be provided at each cycle. 
R  Research test.  Will be charged to study and not to patient’s account. 
 


MC1082 
18 
MCCC Addendum 5 
Protocol Version: November 23, 2015 
 
5.0 
Grouping Factor: 
 
 
5.1 
Phase: I (permanently closed 11/13/2012) vs. II. 
 
6.0  
Registration/Randomization Procedures 
 
6.1 
Registration Procedures for Phase I portion – Mayo Institutions only 
 
6.11 
Phase I Dose Escalation – Prior to discussing protocol entry with the patient, call the 
Registration Office 
 to insure that a place on the protocol is open to the patient. 
 
6.111 To register a patient, fax 
 a completed eligibility checklist to the 
Registration Office between 8 a.m. and 4:30 p.m. central time Monday through 
Friday. 
 
6.2 
Registration Procedures for Phase II portion  
 
6.21 
Mayo Clinic Cancer Center 
 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter the 
remote registration/randomization application.  The remote registration/randomization 
application is available 24 hours a day, 7 days a week.  Back up and/or system support 
contact information is available on the Web site.  If unable to access the Web site, call the 
MCCC Registration Office at
 between the hours of 8 a.m. and 5:00 p.m. 
Central Time (Monday through Friday). 
 
The instructions for remote registration are available on the MCCC web page 
and detail the process for completing and 
confirming patient registration.  Prior to initiation of protocol treatment, this process must 
be completed in its entirety and a MCCC subject ID number must be available as noted in 
the instructions.  It is the responsibility of the individual registering the patient to confirm 
the process has been successfully completed prior to release of the study agent.  Patient 
registration via the remote system can be confirmed in any of the following ways: 
• 
Contact the MCCC Registration Office
.  If the patient was fully 
registered, the Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
 
6.22     Dana Farber Cancer Institute and the University of Chicago 
 
To register a patient, fax a completed eligibility checklist to the MCCC 
Registration Office at 
 between the hours of 8 a.m. and 4:30 p.m. 
Central Time (Monday through Friday). 
 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
19 
6.3 
Phase I and Phase II 
 
6.31 
Correlative Research 
 
An optional correlative research component is part of this study, there will be an option to 
select if the patient is to be registered onto this component (see Section 14.0). 
 
• 
Patient has/has not given permission to give his/her blood sample for research testing. 
• 
Patient has/has not given permission to give his/her bone marrow sample for research 
testing.   
 
6.32 
Documentation of IRB approval must be on file in the Registration Office before an 
investigator may register any patients. 
 
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
 
  If the necessary documentation is not submitted in advance of 
attempting patient registration, the registration will not be accepted and the patient may 
not be enrolled in the protocol until the situation is resolved. 
 
 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Registration Office is no longer necessary. 
 
6.33 
Prior to accepting the registration, the following will be verified: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information 
 
6.34 
Treatment on this protocol must commence at a Mayo Clinic institution, Dana Farber 
Cancer Institute, or the University of Chicago under the supervision of a medical 
oncologist or hematologist.  
 
6.35 
Treatment cannot begin prior to registration and must begin ≤ 7 days after registration. 
 
6.36 
Pretreatment tests/procedures must be completed within the guidelines specified on the 
test schedule. 
 
6.37 
All required baseline symptoms must be documented and graded. 
 
6.38 
Study drug availability checked. 
   
6.39 
The CRA must notify the Celgene study monitor of each confirmed patient registration. 
 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
20 
7.0 
Protocol Treatment 
 
7.1 
Treatment schedule 
 
Cohort I (Dose Escalation phase) 
 
Agent 
Dose 
Route 
Day 
Cycle length 
 
Pomalidomide* 
 
4 mg/day 
 
PO 
 
Days 1-21 
28 days 
 
Bortezomib 
 
As assigned 
by MCCC 
Registration 
Office 
IV 
 
Days 1, 8, 15, 22 
Dexamethasone 
40 mg/day 
PO  
(with food) 
Days 1, 8, 15, 22 
Aspirin** 
325 mg/day 
PO  
(with food) 
Days 1-28 
 
Cohort II (Phase II studies at MTD) 
 
Agent 
Dose 
Route 
Day 
Cycle length 
 
Pomalidomide* 
 
4 mg/day 
 
PO 
Days 1-21 
28 days 
 
Bortezomib 
 
1.3 mg/m2 
IV or SQ 
Days 1, 8, 15, 22 
Dexamethasone 
40 mg/day 
PO  
(with food) 
Days 1, 8, 15, 22 
Aspirin** 
325 mg/day 
PO  
(with food) 
Days 1-28 
* 
Pomalidomide will be provided free of charge by Celgene. 
 
** 
Full dose anticoagulation with either warfarin or low molecular weight heparin may be 
substituted at MD discretion.  This is advised for patients with personal or strong family 
history of thromboembolism.  If patient cannot tolerate 325 mg/day, they may take 81 
mg/day. 
 
Pomalidomide capsules should be swallowed whole, and should not be broken, chewed or 
opened.  Pomalidomide should be taken without food (at least 2 hours before or 2 hours 
after a meal).      
 
If a dose of pomalidomide is missed, it should be taken as soon as possible on the same 
day.  If it is missed for the entire day, it should not be made up. 
 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
21 
Patients who take more than the prescribed dose of pomalidomide should be instructed to 
seek emergency medical care if needed and contact study staff immediately. 
 
7.2 
Cohort I 
 
7.21 
Dose Escalation: 
*  Starting dose level 
 
7.22 
Three patients will be treated at each dose level and observed for a minimum of 28 days 
(i.e. one cycle) before new patients are treated.  The study will temporarily close during 
this time.   
 
7.23 
For this protocol, dose-limiting toxicity (DLT) will be defined as an adverse event 
attributed (definitely, probably, or possibly) in the first cycle to the study treatment and 
meeting the following criteria: 
 
Toxicity 
DLT Definition* 
Hematologic 
Grade 4 ANC for ≥7 days or Grade 4 PLT for ≥7 
days 
Infection 
Grade 4 
Febrile Neutropenia 
Defined as fever ≥ 38.5oC (38 > 1 hour) with ≥ 
grade 3 Neutropenia 
Other Non-hematologic 
Any other ≥ grade 3 event as per NCI Common 
Terminology Criteria for Adverse Events v4.0**.  
* 
Any toxicities that cause dose delay of > 2 weeks of the intended next dose will also be 
considered dose-limiting. 
** Grade 3 nausea, vomiting, or diarrhea with maximal supportive treatment(s) will be 
considered dose-limiting.  Fatigue and mouth sores that are considered Grade 3 with an 
attribution of definitely, probably, or possibly related to treatment will be reviewed by the 
study team to determine if they were due to other causes (i.e. disease progression or infection) 
or treatment.   If it is determined that the fatigue or mouth sores were due to other causes they 
would not be considered a DLT.  
 
7.24 
MTD Determination: 
 
7.241 MTD is defined as the dose level below the lowest dose that induces dose-
limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 
new patients). 
 
 
 
7.242 Three patients will be treated at a given dose level combination and observed for 
at least 4 weeks to assess toxicity. 
 
Dose Level 
Pomalidomide (mg/day) 
Bortezomib (mg/m2) 
Dexamethasone (mg/day) 
0 
4 (days 1-21) 
0.7 (days 1, 8, 15, 22) 
40 (days 1, 8, 15, 22)  
1* 
4 (days 1-21) 
1.0 (days 1, 8, 15, 22) 
40 (days 1, 8, 15, 22) 
2 
4 (days 1-21) 
1.3 (days 1, 8, 15, 22) 
40 (days 1, 8, 15, 22) 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
22 
7.243 If dose-limiting toxicity (DLT) is not seen in any of the 3 patients, up to 3 new 
patients will be accrued and treated at the next higher dose level. If DLT is seen 
in 2 patients treated at a given dose level, no more patients will be treated at that 
dose level and the next 3 patients will be treated at the next lower dose level.  
 
7.244 If a DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 additional 
patients will be enrolled and treated at the same dose level. If DLT is seen in at 
least one of these additional three patients (≥2 of 6), the MTD will have been 
exceeded, and further accrual will cease to this cohort (see 7.245 for further 
details). If dose-limiting toxicity (DLT) is not seen in any of the three additional 
patients, 3 new patients will be accrued and treated at the next higher dose level. 
 
7.245 If DLT is observed in at least 2 of 6 patients after enrolling 6 patients on a 
specific dose level, then the MTD will have been exceeded and defined as the 
previous dose unless only 3 patients were treated at the lower dose level. In that 
case, 3 additional patients will be treated at this lower dose level such that a total 
of 6 patients are treated at the MTD to more fully assess the toxicities associated 
with the MTD.  
 
7.25 
Dose de-escalation: 
 
If the starting dose exceeds the MTD, then patients will be accrued to level 0.  If level 0 
is tolerated, that will be the dose taken forward to the Phase II.   If level 0 is not 
tolerated, the study team will consider an alternative dosing schedule to study.  
 
7.26 
Dose escalation: 
 
 
All patients will receive their assigned dose for the first cycle.  If no DLT criteria are 
encountered, patients may be dose escalated (per schedule in Section 7.21) in subsequent 
cycles per investigator and patient discretion as long as that dose level has been shown to 
be safe.  Patients on the starting dose level will not be allowed to dose escalate until 
subsequent cohorts of patients have been treated at the higher dose levels. 
 
 
 
7.27 
If a patient fails to complete cycle 1 for reasons other than toxicity, the patient will be 
regarded as inevaluable and an additional patient will be treated at the current dose level; 
however, all toxicity information will be utilized in the analysis.   
 
7.3 
Cohort II 
 
7.31 
The phase II portion of the trial will be based on findings from cohort I.  At that time, an 
amendment will be completed updating the treatment schedule table in section 7.1. 
 
7.4 
Pomalidomide maintenance (Cohort I and Cohort II) 
 
7.41 
After 8 cycles of  treatment patients will discontinue bortezomib and dexamethasone and 
continue pomalidomide 4 mg by mouth daily (or the dose they were on at the end of 8 
cycles if the pomalidomide was  dose reduced) for 21 days of every 28 day cycle until  
progression, adverse event, or refusal of treatment.  Patients returning to study site every 
3 months during maintenance may have drug mailed monthly.  


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
23 
 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
24 
7.5 
Treatment by Local Medical Doctor (LMD)  
 
Cycle 1 and Day 1 of Cycles 2-8 must be administered at the registering site. When it has been 
determined that the patient is tolerating therapy without excessive toxicity at a stable dose level, 
the bortezomib may be administered by the patient’s Local Medical Doctor’s Office (LMD). The 
registering physician retains responsibility for the patient.   
 
In this case, a written statement outlining drug dosage, method of administration, follow-up tests 
required, and telephone number to call to discuss any questions with the responsible investigator 
must be sent with the patient to provide necessary information to the LMD.  The LMD will be 
required to supervise the administration of the study drugs as stipulated in the protocol and 
provide written documentation that the drug was administered.     


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
25 
8.0 
Dosage Modification Based on Adverse Events  
 
Strictly follow the modifications in this table for the first two cycles, until individual treatment tolerance 
can be ascertained.  Thereafter, these modifications should be regarded as guidelines to produce mild-to-
moderate, but not debilitating, side effects.  If multiple adverse events are seen, administer dose based on 
greatest reduction required for any single adverse event observed.  If adverse event could be related to 
more than 1 drug, attribution and dose modifications are at the discretion of the physician. Reductions or 
increases apply to treatment given in the preceding cycle and are based on adverse events observed since 
the prior dose. Treatment modifications are based on adverse events.  All adverse events should be graded 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Dose 
modification recommendations listed below are general guidelines, and appropriate dose adjustments for 
patient safety should be done if needed after approval by the principal investigator or his representative.  
 
ALERT: ADR reporting may be required for some adverse events (See Section 10)  
Subjects will be evaluated for AEs at each visit with the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0 used as a guide for the grading of severity.  
 
8.1 
Pomalidomide  
 
8.11 
Pomalidomide Dose Reduction Levels 
 
Pomalidomide Dose Reduction Steps 
Starting Dose 
4 mg PO daily on days 1 through 21 
every 28 days 
Dose Level -1 
Decrease to 3 mg PO daily on days 1 
through 21 every 28 days 
Dose Level -2 
Decrease to 2 mg PO daily on days 1 
through 21 every 28 days 
Dose Level -3 
Decrease to 1.5 mg PO daily on days 1 
through 21 every 28 days 
Dose Level -4 
Decrease to 1.0 mg PO daily on days 1 
through 21 every 28 days 
Dose Level -5 
Decrease to 0.5 mg PO daily on days 1 
through 21 every 28 days 
Dose Level -6 
Discontinue 
 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
26 
 
8.12 
Pomalidomide Dose Modifications 
 
Pomalidomide is to be dose modified as described in the table below using the following 
dose modifications: 
 
Dose Modification for Pomalidomide (Based on Pomalidomide-Related Adverse Event Observed on 
Days 2-28)  
ADVERSE 
EVENT/SYMPTOMS 
Day 2-14 of Cycle 
≥Day 14 of Cycle  
≥ Grade 3 Febrile neutropenia 
 
or  
 
Grade 4 Neutrophil Count 
Decreased 
 
 
• 
Omit pomalidomide.  
Follow CBC weekly. 
• 
If neutropenia has resolved to ≤ 
grade 2 restart at next lower 
dose level and continue the 
cycle  
 
• 
Omit pomalidomide for 
remainder of cycle.  Begin 
next cycle at next lower dose. 
≥ Grade 4 Platelet Count 
Decreased 
 
 
 
• 
Omit pomalidomide. 
Follow CBC weekly. 
• 
If thrombocytopenia resolves to 
≤ grade 2 restart at next lower 
dose level and continue the 
cycle  
• 
Hold anticoagulation for 
platelet count < 50,000 
• 
Omit pomalidomide for 
remainder of cycle. Begin next 
cycle at next lower dose. 
 
• 
Hold anticoagulation for 
platelet count < 50,000 
Erythroderma 
Grade 3 
 
 
 
 
• 
If Grade 3 Omit pomalidomide. 
Follow weekly. 
• 
If the adverse event resolves to 
≤ grade 2 restart at next lower 
dose level and continue the 
cycle  
• 
Omit pomalidomide for 
remainder of cycle. If the 
adverse event resolves to ≤ 
grade 2 restart next cycle 
at next lower dose. 
 
 
Grade 4 
• 
Discontinue all study drugs and 
go to event monitoring. 
• 
Discontinue all study 
drugs and go to event 
monitoring. 
Grade 1-3 Rash maculo-
papular 
 
 
 
• 
Omit pomalidomide and 
bortezomib for remainder of 
cycle.  If the adverse event 
resolves to ≤ grade 2 restart at 
next lower dose level on next 
cycle. 
• 
Omit pomalidomide and 
bortezomib for remainder of 
cycle.  If the adverse event 
resolves to ≤ grade 2 restart at 
next lower dose level on next 
cycle. 
Grade 3-4 Stevens-Johnson 
syndrome 
• 
Discontinue all study drugs and 
go to event monitoring. 
• 
Discontinue all study drugs 
and go to event monitoring. 
≥ Grade 3 Erythema 
multiforme 
  
• 
Discontinue all study drugs and 
go to event monitoring. 
• 
Discontinue all study drugs 
and go to event monitoring. 


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Dose Modification for Pomalidomide (Based on Pomalidomide-Related Adverse Event Observed on 
Days 2-28)  
ADVERSE 
EVENT/SYMPTOMS 
Day 2-14 of Cycle 
≥Day 14 of Cycle  
Peripheral motor neuropathy 
 Or 
Peripheral sensory neuropathy 
Grade 3 
 
 
• 
If Grade 3 Omit pomalidomide. 
Follow weekly. 
• 
If the adverse event resolves to 
≤ grade 2 restart at next lower 
dose level and continue the 
cycle  
• 
Omit pomalidomide for 
remainder of cycle. Begin next 
cycle at next lower dose. 
 
 
 
Grade 4 
• 
Discontinue all study drugs and 
go to event monitoring. 
• 
Discontinue all study drugs 
and go to event monitoring. 
Sinus bradycardia/other 
cardiac arrhythmia 
Grade 2 
 
 
 
• 
Omit pomalidomide. Follow at 
least weekly. 
• 
If the adverse event resolves to 
≤ grade 1 restart at next lower 
dose level and continue the 
cycle  
• 
Omit pomalidomide for the 
remainder of the cycle. Begin 
next cycle at next lower dose. 
 
 
 
Grade 3 
 
• 
Discontinue all study drugs and 
go to event monitoring. 
• 
Discontinue all study drugs 
and go to event monitoring. 
Allergic reaction  
Grade 2-3 
 
 
 
 
• 
Omit pomalidomide. Follow at 
least weekly. 
• 
If the adverse event resolves to 
≤ grade 1 restart at next lower 
dose level and continue the 
cycle  
• 
Omit pomalidomide for the 
remainder of the cycle. Begin 
next cycle at next lower dose. 
 
 
 
Anaphylaxis  
Grade 4 
• 
Discontinue all study drugs and 
go to event monitoring. 
• 
Discontinue all study drugs 
and go to event monitoring. 
Constipation  
Grade 1-2 
• 
Initiate bowel regimen and 
maintain dose level. 
• 
Initiate bowel regimen and 
maintain dose level. 
≥ Grade 3 
• 
If the adverse event resolves to 
≤ grade 2 restart at next lower 
dose level and continue the 
cycle 
• 
Omit pomalidomide for the 
remainder of the cycle. Begin 
next cycle at next lower dose. 
Thromboembolic event 
≥ Grade 3 
• 
Omit pomalidomide and start 
anticoagulation; restart at 
investigator’s discretion 
(maintain dose level). 
• 
Omit pomalidomide for 
remainder of cycle and start 
anticoagulation. Begin next 
cycle at physician discretion 
(maintain dose level). 


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Dose Modification for Pomalidomide (Based on Pomalidomide-Related Adverse Event Observed on 
Days 2-28)  
ADVERSE 
EVENT/SYMPTOMS 
Day 2-14 of Cycle 
≥Day 14 of Cycle  
Other Non-hematologic 
adverse events 
Assessed as 
POMALIDOMIDE- 
Related ≥ Grade 3 
• 
Omit pomalidomide. Follow at 
least weekly. 
• 
If the adverse event resolves to 
≤ grade 2 restart at next lower 
dose level and continue the 
cycle  
• 
Omit pomalidomide for 
remainder of cycle. Begin next 
cycle at next lower dose. 
≥ Grade 2 Hyperthyroidism or 
Hypothyroidism 
• 
Omit pomalidomide for 
remainder of cycle, evaluate 
etiology, and initiate 
appropriate therapy. Restart 
pomalidomide next cycle 
(decrease dose by one dose 
level). 
• 
Omit pomalidomide for 
remainder of cycle, evaluate 
etiology, and initiate 
appropriate therapy. Restart 
pomalidomide next cycle 
(decrease dose by one dose 
level). 
 
8.2 
Bortezomib  
 
8.21 
Bortezomib Dose Reduction Levels 
 
Bortezomib Dose Reduction Steps 
Starting Dose 
1.3 mg/m2 
1.0 mg/m2 
0.7 mg/m2 
Dose Level -1 
Decrease to 1.0 mg/m2 
IV daily on days 
1,8,15,22 every 28 
days 
Decrease to 0.7 mg/m2 
IV daily on days 
1,8,15,22 every 28 days 
Decrease to 0.3 mg/m2 
IV daily on days 
1,8,15,22 every 28 days 
Dose Level -2 
Decrease to 0.7 mg/m2 
IV daily on days 
1,8,15,22 every 28 
days 
Decrease to 0.3 mg/m2 
IV daily on days 
1,8,15,22 every 28 days  
Discontinue 
Dose Level -3 
Decrease to 0.3 mg/m2 
IV daily on days 
1,8,15,22 every 28 
days 
Discontinue 
 
Dose Level -4 
Discontinue 
 
 
 
 


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29 
 
8.22 
Bortezomib Dose Modifications 
 
Bortezomib is to be dose modified as described in the table below using the following 
dose modifications: 
 
Dose Modification for Bortezomib (Based on Bortezomib-Related Adverse Event Observed on Days 
2-21)  
ADVERSE 
EVENT/SYMPTOMS 
Day 2-14 of Cycle 
≥Day 14 of Cycle  
≥ Grade 3 Febrile neutropenia 
 
or  
Grade 4 Neutrophil Count 
Decreased 
 
• 
Omit bortezomib.  
Follow CBC weekly. 
• 
If neutropenia has resolved to ≤ 
grade 2 restart at next lower 
dose level and continue the 
cycle  
 
• 
Omit bortezomib for 
remainder of cycle.  Begin 
next cycle at next lower dose. 
≥ Grade 4 Platelet Count 
Decreased 
 
• 
Omit bortezomib. 
Follow CBC weekly. 
• 
If thrombocytopenia resolves to 
≤ grade 2 restart at next lower 
dose level and continue the 
cycle until Day 11 
• 
Hold anticoagulation for 
platelet count < 50,000 
• 
Omit bortezomib for 
remainder of cycle. Begin next 
cycle at next lower dose. 
 
• 
Hold anticoagulation for 
platelet count < 50,000 
Erythroderma 
Grade 3 
 
 
 
 
 
• 
If Grade 3 Omit bortezomib. 
Follow weekly. 
• 
If the adverse event resolves to 
≤ grade 2 restart at next lower 
dose level and continue the 
cycle  
• 
Omit bortezomib for 
remainder of cycle. Begin 
next cycle at next lower 
dose. 
 
 
 
 
Grade 4 
• 
Discontinue all study drugs and 
go to event monitoring. 
• 
Discontinue all study 
drugs and go to event 
monitoring. 
Grade 1-3 Rash maculo-
papular 
 
 
 
• 
Omit pomalidomide and 
bortezomib for remainder of 
cycle.  Restart at next lower 
dose level on next cycle. 
• 
Omit pomalidomide and 
bortezomib for remainder of 
cycle.  Restart at next lower 
dose level on next cycle. 
Grade 3-4 Stevens-Johnson 
syndrome 
• 
Discontinue all study drugs and 
go to event monitoring. 
• 
Discontinue all study drugs 
and go to event monitoring. 
≥ Grade 3 Erythema 
multiforme 
 
• 
Discontinue all study drugs and 
go to event monitoring. 
• 
Discontinue all study drugs 
and go to event monitoring. 


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30 
 
Dose Modification for Bortezomib (Based on Bortezomib-Related Adverse Event Observed on Days 
2-11)  
ADVERSE 
EVENT/SYMPTOMS 
Day 2-14 of Cycle 
≥Day 14 of Cycle  
Peripheral motor neuropathy 
 Or 
Peripheral sensory neuropathy 
Grade 3 
 
 
• 
If Grade 3 Omit bortezomib. 
Follow weekly. 
• 
If the adverse event resolves to 
≤ grade 1 or baseline grade and 
restart at next lower dose level 
and continue the cycle  
• 
Omit bortezomib for 
remainder of cycle. Begin next 
cycle at next lower dose. 
 
 
 
 
Grade 4 
• 
Discontinue all study drugs and 
go to event monitoring. 
• 
Discontinue all study drugs 
and go to event monitoring. 
Sinus bradycardia/ other 
cardiac arrhythmia 
Grade 2 
 
 
 
• 
Omit bortezomib. Follow at 
least weekly. 
• 
If the adverse event resolves to 
≤ grade 1 restart at next lower 
dose level and continue the 
cycle  
• 
Omit bortezomib for the 
remainder of the cycle. Begin 
next cycle at next lower dose. 
 
 
 
Grade 3 
 
• 
Discontinue all study drugs and 
go to event monitoring. 
• 
Discontinue all study drugs 
and go to event monitoring. 
Allergic reaction  
Grade 2-3 
 
 
 
 
• 
Omit bortezomib. Follow at 
least weekly. 
• 
If the adverse event resolves to 
≤ grade 1 restart at next lower 
dose level and continue the 
cycle  
• 
Omit bortezomib for the 
remainder of the cycle. Begin 
next cycle at next lower dose. 
 
 
 
Anaphylaxis  
Grade 4 
• 
Discontinue all study drugs and 
go to event monitoring. 
• 
Discontinue all study drugs 
and go to event monitoring. 
Constipation  
Grade 1-2 
• 
Initiate bowel regimen and 
maintain dose level. 
• 
Initiate bowel regimen and 
maintain dose level. 
≥ Grade 3 
• 
If the adverse event resolves to 
≤ grade 2 restart at next lower 
dose level and continue the 
cycle 
• 
Omit bortezomib for the 
remainder of the cycle. Begin 
next cycle at next lower dose. 
Thromboembolic event 
≥ Grade 3 
• 
Omit bortezomib and start 
anticoagulation; restart at 
investigator’s discretion 
(maintain dose level). 
• 
Omit bortezomib for 
remainder of cycle and start 
anticoagulation. Begin next 
cycle at next lower dose. 


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31 
 
Dose Modification for Bortezomib (Based on Bortezomib -Related Adverse Event Observed on Days 
2-28)  
ADVERSE 
EVENT/SYMPTOMS 
Day 2-7 of Cycle 
≥Day 8 of Cycle  
Other Non-hematologic 
adverse events 
Assessed as bortezomib - 
Related ≥ Grade 3 
• 
Omit bortezomib. Follow at 
least weekly. 
• 
If the adverse event resolves to 
≤ grade 2 restart at next lower 
dose level and continue the 
cycle  
• 
Omit bortezomib for 
remainder of cycle. Begin next 
cycle at next lower dose. 
 
8.3 
Dexamethasone 
 
8.31 
Dexamethasone Dose Reduction Levels 
 
Dexamethasone Dose Reduction Steps 
Starting Dose 
40 mg/day PO on days 1, 8, 15, 22.  
Cycles repeat every 28 days 
Dose Level -1 
Decrease to 20 mg/day PO on Days 1, 8, 
15, 22 
Dose Level -2 
Decrease to 12 mg/day PO on Days 1, 8, 
15, 22 
Dose Level -3 
Decrease to 8 mg/day PO on Days 1, 8, 15, 
22 
Dose Level -4 
Decrease to 4 mg/day PO on Days 1, 8, 15, 
22 
Dose Level -5 
Discontinue 
 


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32 
 
8.32 
Dexamethasone Dose Modifications 
 
Dexamethasone is to be dose modified as described in the table below using the 
following dose modifications: 
 
  Use Common Terminology Criteria for Adverse Events (CTCAE) CTEP Active Version unless otherwise 
specified   
SYSTEM ORGAN 
CLASS (SOC) 
ADVERSE 
EVENT/SYMPTOMS 
AGENT 
DOSAGE CHANGE 
BASED ON INTERVAL Adverse Events 
Gastrointestinal 
Disorders 
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
Grade 1-2 (requiring 
medical management) 
 
 
 
 
 
 
 
 
 
 
 
 
DEXAMETHASONE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treat with H2 blockers, sucralfate, or 
omeprazole.   
 
If symptoms persist despite above 
measures, decrease dexamethasone 
dose by 1 dose level. 
 
≥Grade 3 (requiring 
hospitalization or surgery) 
Omit dexamethasone until symptoms 
adequately controlled.  Restart by 
decreasing dose by 1 dose level along 
with concurrent therapy with H2 
blockers, sucralfate, or omeprazole.   
Investigations 
Grade 3 or 4 Serum amylase 
increased 
 
Discontinue dexamethasone and do not 
resume.  Hold pomalidomide and 
bortezomib at physician discretion and 
restart once resolved to ≤grade 2. 
General disorders and 
administration site 
conditions 
 
Edema limbs or Edema trunk 
≥Grade 3 (limiting 
function and unresponsive 
to therapy or anasarca). 
Diuretics as needed, and decrease 
dexamethasone dose by 1 dose level.  
Psychiatric disorders 
 
Confusion or Anxiety or 
Depression  
≥ Grade 2 (interfering with 
function +/- interfering 
with activities of daily 
living). 
Omit dexamethasone until symptoms 
adequately controlled.  Restart by 
decreasing dose by 1 dose level. 
Musculoskeletal and 
connective tissue 
disorders 
 
Muscle weakness  
≥ Grade 2 (symptomatic 
and interfering with 
function +/- interfering 
with activities of daily 
living). 
 
Decrease dexamethasone dose by 1 
dose level. If weakness persists 
decrease dose by 1 dose level as 
needed.  


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33 
  Use Common Terminology Criteria for Adverse Events (CTCAE) CTEP Active Version unless otherwise 
specified   
SYSTEM ORGAN 
CLASS (SOC) 
ADVERSE 
EVENT/SYMPTOMS 
AGENT 
DOSAGE CHANGE 
BASED ON INTERVAL Adverse Events 
Metabolism and 
nutrition disorders 
 
Hyperglycemia 
≥ Grade 3 or higher 
 
 
DEXAMETHASONE 
 
 
 
 
 
Treatment with insulin or oral 
hypoglycemics as needed.  If 
uncontrolled despite above measures, 
decrease dose by 1 dose level. 
Any Other non-
hematologic 
≥ Grade 3 or higher  
Omit dexamethasone until symptoms 
adequately controlled.  Restart by 
decreasing dose by 1 dose level. 
 
8.4 
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
• 
The ANC is ≥ 1,000/μL; 
• 
The platelet count is ≥ 50,000/μL; 
• 
Any pomalidomide-related allergic reaction/hypersensitivity or sinus bradycardia/ other 
cardiac arrhythmia adverse event that may have occurred has resolved to ≤ Grade 1 severity; 
• 
Any other pomalidomide-related adverse event that may have occurred has resolved to ≤ 
Grade 1 severity. 
 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly and a 
new cycle of pomalidomide will not be initiated until the adverse event has resolved as described 
above. When therapy is resumed it will be considered Day 1 of the new cycle.  If pomalidomide 
dosing was halted during the previous cycle and was restarted with a one-level dose reduction 
without requiring an interruption for the remainder of the cycle, then that reduced dose level will 
be initiated on Day 1 of the new cycle.  If pomalidomide dosing was omitted for the remainder 
of the previous cycle or if the new cycle is delayed due to adverse event newly encountered on 
the scheduled Day 1, then the new cycle will be started with a one-level dose reduction.  If the 
study drug cannot be restarted within 35 days of the scheduled Day 1 of a given cycle, the 
principal investigator must be contacted. 
 
NOTE:  If the patient experiences a significant adverse event requiring a dose reduction at 
the start of the next cycle, then the dose will remain lowered for that entire subsequent cycle.  
If that cycle is completed with no further adverse events greater than Grade 2, then the dose 
may be increased, at the investigator’s discretion, one level at a time, in the following cycles.  
 
NOTE:  Adverse events requiring a dose-reduction step for any or all drugs beyond the two 
dose-reduction steps (levels –1 and –2) will be at the discretion of the treating physician, if 
the decision is made for the patient to be kept on study.  These dose reductions must be 
clearly recorded in reported clinical data.  
 


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34 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Patients should receive prophylaxis for varicella zoster with acyclovir or an equivalent antiviral. 
Prophylaxis for other opportunistic infections such as Pneumocystis pneumonia is also 
encouraged. 
 
9.2 
Patients may receive concurrent treatment with a bisphosphonate.   
 
9.3 
Patients may be on chronic steroids (maximum dose 20 mg/day prednisone equivalent) if they are 
being given for disorders other than myeloma, i.e., adrenal insufficiency, rheumatoid arthritis, etc. 
 
9.4 
The following medications are not permitted during the trial: 
• 
Any other investigational treatment  
• 
Any cytotoxic chemotherapy 
• 
Any other systemic anti-neoplastic therapy including, but not limited to, immunotherapy, 
hormonal therapy or monoclonal antibody therapy. 
 
9.5 
Antiemetics may be used at the discretion of the attending physician. 
 
9.6 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations.  The use of growth factors should follow published 
guidelines of the American Society of Clinical Oncology 2006 Update of Recommendations for 
the Use of White Blood Cell Growth Factors:  An Evidence-Based Clinical Practice Guideline.  
Journal of Clinical Oncology 2006;24(19):3187-3205.  
 
9.7 
Patients should receive full supportive care while on this study.  This includes blood product 
support, antibiotic treatment, and treatment of other newly diagnosed or concurrent medical 
conditions.  All blood products and concomitant medications such as antidiarrheals, 
analgesics, and/or antiemetics received from the first day of study treatment administration 
until 30 days after the final dose will be recorded in the medical records. 
 
9.8 
Diarrhea:  This could be managed conservatively with loperamide.  The recommended dose of 
loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free (maximum 
16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed:  hydration, 
octreotide, and antidiarrheals.   
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or severe 
neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed.  Patients with severe 
diarrhea or any diarrhea associated with severe nausea or vomiting should be hospitalized for 
intravenous hydration and correction of electrolyte imbalances. 
 
9.9 
White cell growth factors [G-CSF (Neupogen or Neulasta) or GM-CSF]:  Use of growth factors 
during Phase I to maintain doses is not allowed. The use of white cell growth factors is not 
allowed prophylactically during Cycle 1 but can be used to treat neutropenia during Cycle 1.  In 
Cycles 2 and beyond, the drug can be used prophylactically or to treat neutropenia per physician 
discretion.  Platelet growth factors such as Neumega may be used at physician discretion for 


MC1082 
 
MCCC Addendum 6 
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35 
thrombocytopenia.  Recombinant erythropoietin to maintain adequate hemoglobin levels and 
avoid packed red blood cell transfusions is allowed and should be in concordance with current 
guidelines. Patients can be placed on prophylactic antibiotics as per Infectious Diseases Society 
of America guidelines (Clinical Infectious Diseases 2002; 34:730–751).  During the Phase II 
growth factors may be used in any cycle at physician discretion. 
 
10.0 
Adverse Event (AE) Reporting and Monitoring  
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site:  (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)    
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  First, 
identify and grade the severity of the event using the CTCAE version 4.0.  Next, 
determine whether the event is expected or unexpected (see Section 10.2) and if the 
adverse event is related to the medical treatment or procedure (see Section 10.3).  With 
this information, determine whether the event must be reported as an expedited report 
(see Section 10.4). Expedited reports are to be completed within the timeframes and via 
the mechanisms specified in Sections 10.4. All AEs reported via expedited mechanisms 
must also be reported via the routine data reporting mechanisms defined by the protocol 
(see Sections 10.52 and 18.0). 
 
10.12 
Each CTCAE term in the current version is a unique representation of a specific event used for 
medical documentation and scientific analysis and is a single MedDRA Lowest Level Term 
(LLT).   
 
• 
NOTE:  A severe AE, as defined by the above grading scale, is NOT the same as 
serious AE which is defined in the table in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
• 
The determination of whether an AE is expected is based on agent-specific information 
provided in Section 15.0 of the protocol. 
 
• 
Unexpected AEs are those not listed in the agent-specific information provided in Section 
15.0 of the protocol. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk in the information provided for IRB review nor 
mentioned in the consent form.  
 


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36 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or procedure, the 
following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on the 
SAME Arm 
 
NOTE: The combination of an investigational agent with a commercial agent is considered 
investigational. 
 
Routine Reporting 
 
• Routine AE reporting for Phase 1 and Phase 2 clinical studies using an 
investigational agent /intervention in combination with a commercial agent is stated 
in the protocol.  See Section 10.52. 
 
NOTE:  When a commercial agent(s) is (are) used on the same treatment arm 
as the investigational agent/intervention (also, investigational drug, biologic, 
cellular product, or other investigational therapy under an IND), the entire 
combination (arm) is then considered an investigational intervention for 
reporting. 
 
Expedited Reporting 
 
• An AE that occurs on a combination study must be assessed in accordance with the 
guidelines for CTEP investigational agents/interventions in Section 10.4, and where 
indicated, an expedited report must be submitted. 
 
• An AE that occurs prior to administration of the investigational agent/intervention 
must be assessed as specified in the protocol. In general, only Grade 4 and 5 AEs 
that are unexpected with at least possible attribution to the commercial agent 
require an expedited report.  Refer to Section 10.4 for specific AE reporting 
requirements or exceptions. 
 
• Commercial agent expedited reports must be submitted by the Cooperative Group to the 
FDA via MedWatch. 
 
• An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent.  Therefore, if an expected AE (for the commercial agent) 
occurs with a higher degree of severity, expedited reporting is required.  The clinical 
investigator must determine severity. 
 


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37 
10.32 Special Situations for Expedited Reporting1  
 
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events 
 
An expedited report may not be required for specific Grade 1, 2 and 3 Serious Adverse 
Events where the AE is listed in Section 15.0 of the protocol or the consent form* as 
EXPECTED. Any protocol specific reporting procedures MUST BE SPECIFIED 
BELOW and will supercede the standard Expedited Adverse Event Reporting 
Requirements:  
  
 
System Organ Class 
(SOC) 
 
Adverse event/ 
Symptoms 
 
CTCAE Grade at 
which the event 
will not be 
expeditedly 
reported. 
Expected 
Frequency per 
Section 15.0 
or IB 
Expected 
Frequency per 
PI experience 
Blood and lymphatic 
system disorders 
Anemia 
Grade 3 or 4 
% 
30% 
Investigations 
White blood cell 
decreased 
Grade 3 or 4 
% 
30% 
Lymphocyte count 
decreased  
Grade 3 or 4 
% 
30% 
Neutrophil count 
decreased 
Grade 3 or 4 
% 
30% 
Platelet count 
decreased 
Grade 3 or 4 
% 
30% 
1  This exception only applies if the adverse event does not result in hospitalization ≥ 24 hours.  If this 
adverse event results in hospitalization ≥ 24 hours, then the standard expedited adverse events reporting 
requirements must be followed. 
 
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
 
*The consent form may contain study specific information at the discretion of the Principal 
Investigator; it is possible that this information may NOT be included in the protocol or the 
investigator brochure. 
 
10.331 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions (formerly referred to as disabilities), congenital 
abnormities or birth defects, must be reported immediately if they occur at any time 
following treatment with an agent under an IND/IDE since they are considered to be a 
serious AE and must be reported to the sponsor as specified in 21 CFR 312.64(b). 
 
10.332 Death 
 


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38 
• 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
 
• 
Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 
• 
Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 
 
• 
Death Neonatal:  A disorder characterized by cessation of life 
during the first 28 days of life. 
 
• 
Death NOS:  A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
 
• 
Sudden death NOS:  A sudden (defined as instant or within one 
hour of the onset of symptoms) or an unobserved cessation of life 
that cannot be attributed to a CTCAE term associated with Grade 
5. 
 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benigh, malignant and unspecified (incl cysts and 
polyps) – Other (Progressive Disease)” under the system organ 
class (SOC) of the same name.  Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted. 
 
• 
Any death occurring within 30 days of the last dose, regardless of 
attribution to the investigational agent/intervention requires expedited 
reporting within 24 hours. 
 
• 
Any death occurring greater than 30 days after the last does of the 
investigational agent/intervention requires expedited reporting within 
24 hours only if it is possibly, probably, or definitely related to the 
investigational agent/intervention. 
 
10.333 Secondary Malignancy 
 
• 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 


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39 
• 
All secondary malignancies that occur following treatment with an agent 
under an IND/IDE be reported. Three options are available to describe the 
event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute Myeloctyic 
Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in each 
protocol. 
 
10.334 Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior malignancy 
(and is NOT a metastasis from the initial malignancy).  Second malignancies 
require ONLY routine reporting. 
 
10.335 Pregnancies 
 
Pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject occurring while the subject 
is on IP, or within 28 days of the subject’s last dose of IP, are considered 
immediately reportable events. IP is to be discontinued immediately. The 
pregnancy, suspected pregnancy, or positive pregnancy test must be reported to 
Celgene Drug Safety immediately by facsimile, or other appropriate method, 
using the Pregnancy Initial Report Form (see Forms Packet). 
 
The female subject should be referred to an obstetrician-gynecologist, preferably 
one experienced in reproductive toxicity for further evaluation and counseling. 
 
The Investigator will follow the female subject until completion of the 
pregnancy, and must notify Celgene Drug Safety immediately about the outcome 
of the pregnancy (either normal or abnormal outcome) using the Pregnancy 
Follow-up Report Form (see Forms Packet).  
 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic 
abortion), the Investigator should report the abnormal outcome as an AE. If the 
abnormal outcome meets any of the serious criteria, it must be reported as an 
SAE to Celgene Drug Safety immediately by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the 
Celgene SAE Report Form (see Forms Packet). 
 
All neonatal deaths that occur within 28 days of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 28 days that the 
Investigator suspects is related to the in utero exposure to the IP should also be 


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reported to Celgene Drug Safety immediately by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the 
Celgene SAE Report Form (see Forms Packet). 
 


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41 
Male Subjects 
If a female partner of a male subject taking investigational product becomes 
pregnant, the male subject taking IP should notify the Investigator immediately, 
and the pregnant female partner should be advised to call their healthcare 
provider immediately. 
 
Celgene Drug Safety Contact Information: 
 
Celgene Corporation 
Global Drug Safety and Risk Management 
 
 
 
Fax: 
 
E-mail: 
  
 
10.336 Expedited reporting by investigator to Celgene 
 
Serious adverse events (SAE) are defined above.  The investigator must inform 
Celgene in writing using a Celgene SAE form or MEDWATCH 3500A form (see 
Forms Packet) of any SAE within 24 hours of being aware of the event.  The 
written report must be completed and supplied to Celgene by facsimile within 24 
hours/1 business day.  The initial report must be as complete as possible, 
including an assessment of the causal relationship between the event and the 
investigational product(s), if available.  Information not available at the time of 
the initial report (e.g., an end date for the adverse event or laboratory values 
received after the report) must be documented on a follow-up report.  A final 
report to document resolution of the SAE is required.  The Celgene tracking 
number (PO-MM-PI-0019) and the institutional protocol number should be 
included on SAE reports (or on the fax cover letter) sent to Celgene.  A copy of 
the fax transmission confirmation of the SAE report to Celgene should be 
attached to the SAE and retained with the patient records. 
 
Celgene Drug Safety Contact Information: 
 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
 
 
 
  


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10.4 
Expedited Reporting Requirements for IND/IDE Agents 
 
10.41  Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of 
the Last Administration of the Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the sponsor within 
the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in section 
10.33 of the protocol. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
See additional instructions included on the next page. 
 


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Additional instructions: 
1. Contact Celgene Drug Safety via fax at 
 or via mail at Celgene Corporation, 
Worldwide Drug Safety Surveillance (WWDSS), 
, Summit, NJ 07901.. 
 
2.  Use the Celgene Serious Adverse Event Report Form (see Forms Packet).  Submit to Celgene 
Drug Safety via fax at 
 or via mail at Celgene Corporation, Worldwide Drug 
Safety Surveillance (WWDSS), 
, Summit, NJ 07901.   
 
  Mayo Clinic Cancer Center (MCCC) Institutions:  Provide copies, along with the UPIRTSO 
cover sheet, by fax 
 to the MCCC Regulatory Affairs Unit (RAU) Risk 
Information Specialist who will determine and complete IRB reporting. The RAU will submit to 
the MCCC SAE Coordinator and the MCCC IND Coordinator to determine if FDA submission 
is needed.  
 
  Non-MCCC Institutions:  Provide copies by fax 
to the MCCC SAE Coordinator 
who will forward to the MCCC IND Coordinator to determine if FDA submission is needed.  
 
10.5 
Other Required Reporting 
 
10.51 Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
 
 
SYSTEM ORGAN 
CLASS (SOC) 
 
Adverse event/Symptoms 
 
Baseline 
Each  
evaluation 
Investigations 
Neutrophil count decreased 
X 
X 
 
White blood cell decreased 
X 
X 
 
Platelet count decreased 
X 
X 
Blood and lymphatic 
system disorders 
Anemia 
X 
X 
Vascular disorders 
Thromboembolic event 
X 
X 
General disorders and 
administration site 
conditions 
Fatigue  
X 
X 
Nervous system disorders 
Peripheral sensory neuropathy 
X 
X 
Gastrointestinal disorders 
 
Number of stools 
X 
 
 
Diarrhea 
 
X 
 
Nausea 
X 
X 
 
Vomiting 
X 
X 
Infections and 
infestations 
 
Lung infection 
 
X 
X 
 
Infections and infestations – Other, 
specify (Herpes Zoster) 
X 
X 
 


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10.52 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in Section 10.5: 
 
10.521 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.522 Grade 3 and 4 AEs regardless of attribution to the study treatment or procedure. 
 
10.523  Grade 5 AEs (Deaths) 
 
10.5231  
Any death within 30 days of the patient’s last study treatment or 
procedure regardless of attribution to the study treatment or 
procedure. 
 
10.5232 
Any death more than 30 days after the patient’s last study treatment 
or procedure that is felt to be at least possibly treatment related must 
also be submitted as a Grade 5 AE, with a CTCAE type and 
attribution assigned. 
 
10.53  Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
 
11.0 
Treatment Evaluation – The International Myeloma Working Group (IMWG) uniform response 
criteria37 will be used to assess response to therapy. 
 
11.1  
Terms and definitions 
 
• 
M-protein: synonyms include M-spike, monoclonal protein and myeloma protein, 
paraprotein, M-component. 
 
Serum M-protein level is quantitated using densitometry on SPEP except in cases where the 
SPEP is felt to be unreliable.   
• M-proteins migrating in the β-region (usually IgA M-proteins)  
• Cases in which the M-protein is so large and narrow on agarose (some specimens >4 
g/dL) that they underestimate the actual immunoglobulin level (by greater than 1500 
mg/dL) due to technical staining properties of the agarose gel. 
• Cases in which there are multiple peaks of same M-protein (aggregates or dimers) 
 
If SPEP is not available or felt to be unreliable (above examples) for routine M-protein 
quantitation, then quantitative immunoglobulin levels derived from nephelometry or 
turbidometry can be accepted.  However, this must be explicitly reported at baseline, and only 
nephelometry can be used for that patient to assess response. SPEP derived M-protein values 
and quantitative nephelometric immunoglobulin values cannot be used interchangeably.   
 
Urine M-protein measurement is estimated using 24-h UPEP only.  Random or 24 h urine 
tests measuring kappa and lambda light chain levels are not reliable and are not 
recommended. 


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FLC estimation is currently carried out using the serum FLC assay (Freelite, The Binding 
Site Limited, UK).  Patients with kappa/lambda FLC ratio <0.26 are defined as having 
monoclonal lambda FLC and those with ratios >1.65 as having a monoclonal kappa FLC.  
The monoclonal light chain isotype is considered the involved FLC isotype, and the opposite 
light chain type as the uninvolved FLC type.  
 
• 
Response terms: The following response terms will be used: stringent Complete Response 
(sCR), complete response (CR), very good partial response (VGPR), partial response (PR), 
Minimal Response (MR), stable disease (SD), and progressive disease (PD).  
 
In addition, for each response category, there will be an “unconfirmed” response category, 
which will be for internal use, for the purpose of guiding decision making and test ordering. 
These designations will applied at the time of the first measurement at which the quantitative 
aspect of the response category has been satisfied without the confirmation step having been 
satisfied. The designation “u” will precede the standard abbreviations, and will include usCR, 
uCR, uVGPR, uPR, uMR, uPD.  
 
• 
Measurable disease: Patients who have a measurable serum or urine M-protein.  
 
o Serum M-protein ≥1 g/dl  
o Urine M-protein ≥ 200 mg/24 h 
o Serum FLC assay: Involved FLC level ≥  10 mg/dl provided serum FLC ratio is abnormal 
o Bone marrow plasma cells ≥ 30% 
 
The serum free light chain (FLC) assay is of particular use in monitoring response to therapy in 
patients who have oligo-secretory or non-secretory disease and should be used in assessing 
response only if the baseline serum and/or urine M proteins are not “measurable” as above, 
and the baseline level of the involved FLC is “measurable.”  When using this assay, it is 
important to note that the FLC levels vary considerably with changes in renal function and in 
patients with renal insufficiency, the levels of both the kappa and lambda may remain elevated, 
but the ratio normalizes with achievement of CR.  Thus, both the level of the involved and the 
uninvolved FLC isotype (i.e., the involved/uninvolved ratio or involved-uninvolved difference) 
should be considered in assessing response.  Patients included on the study on the basis of FLC 
alone (i.e., no measurable serum/urine M-protein) should be the only ones who are evaluated 
using FLC response criteria.  The others should follow usual criteria and ignore FLC results 
with the exception of defining stringent complete response. 
 
• 
Evaluable disease: Patients who do not have a “measurable” serum M-protein, serum free 
light chain, or urine M-protein. 
 
• 
Oligosecretory myeloma: Patient with multiple myeloma who has NEVER had 
“measurable” serum M-protein or urine M-protein, but has had a detectable M-protein in 
his/her serum and/or urine and/or measurable serum free light chain.  
 
• 
Non-secretory myeloma: Patient with multiple myeloma who has NEVER had a detectable 
M-protein in his/her serum and/or urine. 
 
 


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47 
 
 
 
 
 
 
 
11.2  
Clarification of test indications 
 
Listed below are the minimal required tests required to assess response based on the 
characteristics of their disease at on study.   
 
Table 11.2 
Tests  Required To Assess Response (Must Be Done At Each Disease Measurement Visit 
except as indicated1,2) 
On Study Baseline Value 
SPEP4  
24 hr 
UPEP2  
Ig 
FLC 
BM Bx 
Serum M-protein ≥1 g/dl, and urine M-protein≥ 
200 mg/24 hrs 
X 
X 
 
 
Serum M-protein ≥ 1 g/dl, but urine M-protein < 
200 mg/24 hrs 
X 
 
 
 
Serum M-protein <1 g/dl, and urine M-protein≥ 
200 mg/24 hrs 
 
X 
 
 
Serum M-protein < 1 g/dl, urine M-protein < 200 
mg/24 hrs, but involved Ig FLC is ≥10 mg/dL 
 
 
X 
 
Serum M-protein < 1 g/dl, urine M-protein< 200 
mg/24 hrs, involved Ig FLC is <10 mg/dL, bone 
marrow ≥30% plasma cells 
 
 
 
X3 
1  SPEP, UPEP, Immunofixation studies of both serum and urine, and Bone marrow biopsy 
are required to document CR regardless of registration values, and in addition FLC 
measurement and bone marrow immunophenotyping is required to document sCR.  SPEP and 
UPEP are required to document VGPR regardless of registration values. 
2  For serum measurable patients, 24 hour urine does not need to be confirmed (i.e. repeated 
after documented response) for any response category 
3  At a minimum, a bone marrow biopsy should be repeated every 3 months until documented 
response.  Bone marrow biopsy results do not need to be repeated after documented response. 
4    If serum M-protein is being followed by quantitative immunoglobulin levels derived from 
nephelometry or turbidometry, quantitative immunoglobulins are required.  SPEP is only 
required to document CR or VGPR.  
 
 
11.3 
Confirmed response  
 
In order to be classified as a hematologic response, confirmation of serum M- protein, serum 
immunoglobulin free light chain (when primary determinant of response) and urine M- protein 
(when primary determinant of response) results must be made by verification on two consecutive 
determinations.   
• 
Bone marrow aspirate and biopsy are only required to document CR or sCR, except for 


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48 
patients with evaluable disease only, where a bone marrow is required to document all 
response categories including progression. However, a second confirmatory bone marrow 
is not required to confirm response in any case. 
• 
Radiographic studies are not required to satisfy these response requirements; however, if 
radiographic studies were performed there should be no evidence of progressive or new 
bone lesions. 
 
Appropriate tests required to document and confirm response are listed in Table 11.2 
 
11.4 
Bone progression  
 
Caution must be exercised to avoid rating progression on the basis of variation of radiologic 
technique alone.  Compression fracture does not exclude continued response and may not indicate 
progression.  When progression is based on skeletal disease alone, it should be discussed with the 
Study Chair before removing the patient from the study.  
 
 11.5 
 Response and Progression 
 
Criteria for response and progression are listed in Table 11.5. Progressive disease for all patients 
as defined in Table 11.5.  
 
Table 11.5 
CATEGORY 
RESPONSE CATEGORY a 
Stringent Complete 
Response (sCR) b 
• CR as defined plus 
• Normal FLC ratio and 
• Absence of clonal PCs by immunohistochemistry or 2- to 4- color 
flow cytometry i 
Complete Response 
(CR) b 
• Negative immunofixation of serum and urine c and 
• Disappearance of any soft tissue plasmacytoma and 
• <5% PCs in Bone Marrow and 
• If the only measurable disease is FLC, a normal FLC ratio d  
Very Good Partial 
Response (VGPR)  
• Serum and urine M-protein detectable by immunofixation but not 
on electrophoresis c or 
• ≥90% reduction in serum M-protein and urine M-protein <100 
mg/24 h c 
• If the only measurable disease is FLC, a >90% reduction in the 
difference between involved and uninvolved FLC levels 
Partial Response (PR) 
• If present at baseline, ≥ 50% reduction of serum M-protein and 
reduction in 24-hour urinary M-protein by ≥90% or to <200 
mg/24hrs c 
• If the only measurable disease is FLC, a ≥50% reduction in the 
difference between involved and uninvolved FLC levels 
• If the only measurable disease is BM, a ≥ 50% reduction in BM 
PCs (provided the baseline PCs was ≥ 30%) 
• If present at baseline, ≥ 50% reduction in the size of soft tissue 
plasmacytomas 
Minor Response (MR)  
• If present at baseline, ≥25% but ≤ 49% reduction of serum M 
protein and reduction in 24-hour urine M-protein by 50-89% 


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49 
which still exceeds 200mg/24 hours c and 
• If present at baseline, 25-49% reduction in the size of soft tissue 
plasmacytoma and 
• No increase in the size or number of lytic bone lesions 
(development of compression fracture does not exclude response) 
Progressive Disease 
(PD) b, h 
 
Increase of 25% from lowest value in any of the following f, g: 
• Serum M-protein (absolute increase must be ≥ 0.5 g/dL) and/or 
• Urine M-protein (absolute increase must be ≥ 200 mg/24 hrs) 
and/or 
• If the only measurable disease is FLC, the difference between 
involved and uninvolved FLC levels (absolute increase must be 
>10 mg/dL)  and/or 
• If the only measurable disease is BM, bone marrow PC percentage 
(absolute increase must be ≥ 10%) e  
 
Or any one or more of the following: 
• Development of new bone lesion or soft tissue plasmacytoma or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytoma 
• Development of hypercalcemia (corrected serum calcium > 
11.5mg/dL) that can be attributed solely to the PC proliferative 
disorder 
Stable Disease (SD) 
Not meeting criteria for sCR, CR, VGPR, PR, MR or PD 
 
a All response categories require two consecutive assessments (sCR, CR, VGPR, PR, MR, PD) made at any time 
before the institution of any new therapy; sCR, CR, VGPR, PR, MR and SD categories also require no known 
evidence of progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not 
required to satisfy these response requirements. Bone marrow assessments need not be confirmed. Each 
category, except for stable disease, will have a working subcategory of “unconfirmed” [prefix ‘u”] to designate first 
time point at which response category MAY have been achieved if confirmed. 
 
b CR patient will need to progress at the same level as VGPR and PR patients to be considered a PD.  A positive 
immunofixation alone is not sufficient. 
 
c If more than one M protein spike meets the criteria for measurable disease at baseline, then both need to be 
followed for response.  Otherwise, only follow the measurable M protein spike for response.   
 
d In patients in whom the only measurable disease is by serum FLC levels: CR in such patients indicates a normal 
FLC ratio of 0.26-1.65 in addition to the CR criteria listed above. 
 
e Bone marrow criteria for PD are only to be used in patients without measurable disease by M protein and by 
FLC;  
 
f A "25% increase" refers to M protein, FLC and bone marrow results and does not refer to bone lesions, soft 
tissue plasmacytoma or hypercalcemia.  The lowest value does not need to be a confirmed value.  If the lowest 
serum M-protein is ≥ 5 g/dL, an increase in serum M-protein of ≥ 1 g/dL is sufficient to define disease progression. 
 
g In the case where a value is felt to be a spurious result per physician discretion (for example, a possible lab 
error), that value will not be considered when determining the lowest value. 
 


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h Progressive disease should be confirmed.  However, treatment may be discontinued for progressive disease 
that is unconfirmed per physician discretion.  In this case, an objective status of PD should be entered on the 
measurement form and progressive disease should be reported on the event monitoring form. 
 
i Presence/absence of clonal cells is based upon the k/l ratio. An abnormal k/l ratio by immunohistochemistry 
requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone 
is k/l of 4:1 or 1:2.  
 
12.0 
Descriptive Factors  
 
12.1 
Prior stem cell transplant:  Yes vs. no 
 
12.2 
High risk cytogenetics or FISH hypodiploidy or karyotypic deletion of chromosome 13), FISH 
(presence of translocations t(4;14) or t(14;16) or deletion 17p: yes vs no 
 
12.3 
Bone Marrow Labeling index: High (>3.0%) vs. low (≤3.0%). 
 
12.4 
Previous Thalidomide: Yes vs. no. 
 
12.5 
Thalidomide refractory: yes vs no 
 
12.6 
Previous Bortezomib: yes vs. no. 
 
12.7 
Bortezomib refractory: yes vs no 
 
12.8 
Parameters of hematologic response (pick all that apply): serum M-spike ≥ 1 g/dL (distinguish 
between SPEP measurement versus quantitative IgA measurement), serum immunoglobulin free 
light chain ≥10 mg/dL, urine M-spike ≥200 mg/24 hours, bone marrow plasma cells >30%, 
measurable plasmacytoma. 
 
12.9 
Dose Level: 0 vs. 1 vs. 2. 
 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient 
 
13.1 
Patients will have disease response measured as per the test schedule in Section 4.0. Stable or 
responding patients will stay on treatment until they have progressive disease, an unacceptable 
toxicity or refuse further treatment at which time they will proceed to Event Monitoring. NOTE: 
As of Addendum 6, patient follow-up is no longer required.   
 
 
13.2 
Patients on Event Monitoring will be followed at progression or initiation of new treatment and 6 
months after progression or initiation of new treatment NOTE: As of Addendum 6, patient 
follow-up is no longer required.  
 


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13.3 
A patient is deemed ineligible if at the time of registration, the patient did not satisfy each and 
every eligibility criteria for study entry. The patient may continue treatment at the discretion of 
the physician as long as there are no safety concerns, and the patient was properly registered.  If 
the patient continues to receive treatment they should be followed according to the protocol. 
 
• 
If the patient received treatment but does not continue with study treatment after deemed 
ineligible, all data up until the point of confirmation of ineligibility must be submitted.  Event 
monitoring will be required per Section 18.0 of the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. Event 
monitoring will be required per Section 18.0 of the protocol. 
 
13.4 
A patient is deemed a major violation, if protocol requirements regarding treatment in cycle 1 of 
the initial therapy are severely violated that evaluability for primary end point is questionable.  
All data up until the point of confirmation of a major violation must be submitted.  The patient 
will go directly to the event-monitoring phase of the study. Event monitoring will be required per 
Section 18.0 of the protocol. The patient may continue treatment at the discretion of the physician 
as long as there are no safety concerns, and the patient was properly registered.  If the patient 
continues to receive treatment they should be followed according to the protocol.  If the patient 
does not continue with study treatment, the patient will go to event monitoring and be followed. 
 
13.5 
A patient is deemed a cancel if he/she is removed from the study for any reason before any study 
treatment is given.  On-study material and the End of Active Treatment/Cancel Notification Form 
must be submitted. No further data submission is necessary.


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52 
MCCC Addendum 5 
Protocol Version: November 23, 2015 
 
 
14.0 
Body Fluid Biospecimens   
 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
 
 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or 
Body 
Fluid 
being 
Collected 
Type of 
Collection 
Tube 
(color of 
tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
On 
Study 
Day 1 of 
first 4 
cycles, 
pre-
treatment2 
End of 
Cycle 3 
& every 
3rd cycle2 
Process 
at site? 
(Yes or 
No) 
Temperature 
 Conditions 
for Storage 
/Shipping  
Parameters of 
immune activation 
(14.42); Circulating 
tumor cells (14.45) 
 
Optional 
Peripheral 
blood 
ACD 
(yellow) 
7 ml (4) 
X3 
X3 
 
No 
 Cold Pack  
Gene expression 
profiles (14.43); 
Cell Proliferation 
and Apoptosis 
(14.44); Tumor cells 
(14.45); 
Quantitative T, B, 
NK Cells (14.42) 
Optional 
Bone 
marrow 
aspirate 
ACD 
(yellow) 
4 ml (2) 
X 
 
X1 
No 
Cold Pack 
PCLI (non-Mayo 
sites only) 
Mandatory 
Bone 
marrow 
aspirate 
Plasma 
Cell 
Labeling 
Index tube 
2-3 ml (1) 
X 
 
X1 
No 
Cold Pack 
1.  Required after Cycle 3, required beyond that only to document CR or if used to assess response. 
2.  +/- 7 days. 
3.  If patient agrees to optional blood sample collection, they may have the first sample collected at on study or on Cycle 1 Day 1 but both are not 
needed. 
NOTE:  The correlative studies samples should not be submitted prior to the patient signing the informed consent.  
NOTE: Baseline samples for research are collected, if possible, at the same time as the diagnostic blood and bone marrow studies that are required 
to establish the diagnosis of myeloma and determine eligibility. 


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53 
MCCC Addendum 5 
Protocol Version: November 23, 2015 
 
 
14.2  Collection and Processing  
 
14.21 See Appendix VIII for Specimen Checklist and Shipping Instructions. 
 
14.3 
Shipping and Handling 
 
14.31 Kits will be used for this study. 
 
Myeloma Tumor Biology Kits are available to order, and will include materials 
necessary for the preparation and shipment of samples. Kits should be ordered at least 
24 hours in advance of each sample time point. To order kits call 
 - 
Mayo Reference Laboratories at 
. 
 
Any questions concerning sample collection and shipments can be directed to 
 
 - Mayo Reference Laboratory, at 
. 
 
14.32 Shipping Specimens 
  
14.321  Mayo Clinic Florida, Mayo Clinic Arizona, University of Chicago, and Dana 
Farber 
 
See Appendix VIII for Specimen Checklist and Shipping Instructions. 
 
14.322 Mayo Clinic Rochester 
 
The Clinical Research Associate will coordinate the sample acquisition with the 
area performing the biopsy and notify the Hematology Research Lab on 
 
 of the sample (For patients accrued at Mayo Clinic Rochester).  Pre-printed, 
protocol specific cards accompany the patient to the biopsy suite and follow the 
sample to the lab. 
 
14.4 
Background and Methodology 
 
14.41 Specific Aims: 
 
1.  Examine the effect of treatment on parameters of immune function and correlate 
changes in parameters of immune response and measures of disease response. 
 
2.  Examine the gene expression profiling before and after treatment to understand 
changes in tumor cells and potential markers of response. 
 
3.  Examine the effect of pomalidomide alone on tumor cell survival and proliferation. 
 
14.42 Parameters of immune activation:   
One of the expected immunomodulatory changes resulting from therapy will be a 
change in the relative ratio of Th1 to Th2 cells in peripheral blood. This will be 
performed by flow cytometric methods. 
 


M C 1 0 8 2 
 
M C C C A d de n d u m 6 
Pr ot oc ol Versi o n: Oct o ber 7, 2 0 1 7  
 
5 4  
T he “ gl o bal” i m pact of t hera p y o n i m m u ne cell s u bsets will be ascertai ne d b y 
i m m u n o p he n ot y pic a nal ysis of P B M Cs f or s u bsets of T, B, N K cells, m o n oc ytes a n d 
de n dritic cells ( D C) a n d t heir acti vati o n stat us usi n g c o m merciall y a vaila ble 
m o n ocl o nal a nti b o dies directe d at t he f oll o wi n g a nti ge ns: C D 3, C D 4, C D 8, C D 1 1c, 
C D 1 4, C 1 6, C D 1 9, C D 2 0, C D 2 5, C D 4 5 R A/ R O, C D 5 6, C D 6 9, C D 6 3 L, C D 8 0, C D 8 3, 
C D 8 6, C D 1 2 3, D R.  T he fl o w c yt o metric a nal ysis will als o be perf or me d o n t he b o ne 
marr o w sa m ples.  
 
Acti v ati o n of D C a n d s u bse q ue nt m o d ulati o n of t he i m m u ne res p o nse ca use d b y 
treat me nt wit h le nali d o mi de ma y directl y or i n directl y alter t he c yt o ki nes prese nt i n 
plas ma. T he Bi o Ra d h u ma n 2 7- ple x c yt o ki ne pa nel will be use d f or t he meas ure me nts 
of plas ma c o nce ntrati o ns of I L- 1 β, I L- 1r α, I L- 2, I L -4, I L -5, I L -6, I L -7, I L -8, I L -9, I L -
1 0, I L- 1 2( p 7 0), I L- 1 3, I L - 1 5, I L- 1 7, basic F G F, e ota xi n, G-C S F, G M -C S F, I F N -γ, I P-
1 0, M C P- 1, MI P- 1 α, MI P- 1 β, 
P D G F, R A N T E S, T N F- α, a n d V E G F. 
 
1 4. 4 3 
Ge ne e x pressi o n pr ofiles of myel o m a cells bef ore a n d after tre at me nt.  
  
  
 
  
C D 1 3 8-s orte d M M t u m ors cells, o btai ne d fr o m cli nical b o ne marr o w sa m pli n g, will be 
ba n ke d bef ore a n d after 3 c ycles of t hera p y; hi g h- res ol uti o n arra y-base d ge ne 
e x pressi o n st u dies of paire d ( bef ore/after) sa m ples fr o m m atc he d res p o n di n g a n d n o n-
res p o n di n g patie nts will be u n derta ke n t o l o o ke d m ore br oa dl y f or a d diti o nal 
tra nscri pti o nal mar kers of res p o nse, i ncl u di n g t h ose e xisti n g pri or t o t hera p y (f or 
e xa m ple, t o i de ntif y mar kers t hat are u pre g ulate d or s u p presse d i n a s u b gr o u p of t u m ors 
t hat res p o n d or fail t o res p o n d). T he d y na mic c ha n ge i n t he tra nscri pti o nal pr ofile of 
res p o n di n g vers us n o n-res p o n di n g sa m ples, fr o m bef ore t o after treat me nt, will als o be 
e xa mi ne d t o assess if s u p pressi o n of s pecific tra nscri pts c orre lates wit h res p o nse. 
Sa m ples will be a nal yze d usi n g hi g h- de nsit y oli g o n ucle oti de micr oarra ys c o ntai n i n g 
pr o bes f or 5 0, 0 0 0 tra nscri pts a n d varia nts i ncl u di n g 1 4, 5 0 0 k n o w n ge nes ( U 1 3 3 Pl us 
2. 0 arra y; Aff y metri x, Sa nta Clara, C A) usi n g sta n dar d met h o ds. 
 
  
Sa m ple Pre parati o n, Fra g me ntati o n, Arra y H y bri dizati o n, a n d Sca n ni n g: T he p uri ﬁe d 
c D N A is use d as t he te m plate f or i n vitr o tra nscri pti o n reacti o n f or s y nt hesizi n g 
bi oti n ylate d c o m ple me ntar y R N A (c R N A) usi n g a n R N A tra nscri pt la beli n g rea ge nt 
( Aff y metri x). T he q ualit y of t he fra gme nte d bi oti n – la bele d c R N A i n eac h e x peri me nt is 
e val uate d bef ore h y bri dizi n g b y b ot h gel electr o p h oresis a n d h y bri dizi n g (fracti o n of 
t he sa m ple) o nt o test- 3 micr oarra y a n d a nal yzi n g as a meas ure of q ualit y c o ntr ol. 
A p pr o priate a m o u nts of la bele d c R N A a n d c o ntr ol oli g o n ucle oti de B 2 are a d de d al o n g 
wit h c o ntr ol c R N A ( Bi o B, Bi o C, Bi o D), herri n g s per m D N A, a n d b o vi ne ser u m 
al b u mi n t o t he h y bri dizati o n b uffer. T he h y bri dizati o n mi xt ure is heate d at 9 9° C f or 5 
mi n utes f oll o we d b y i nc u b ati o n at 4 5° C f or 5 mi n utes bef ore a p pl yi n g t he sa m ple o nt o 
t he Ge ne C hi p. H y bri dizati o n is perf or me d at 4 5° C f or 1 6 h o urs wit h mi xi n g, f oll o wi n g 
w hic h t he s ol uti o ns are re m o ve d, a n d arra ys was he d a n d stai ne d wit h stre pta vi di n-
p h yc oer yt hri n ( M olec ular Pr o bes, P ortla n d, O R). After was hes, pr o be arra ys are 
sca n ne d usi n g t he ge ne c hi p s yste m c o nf ocal sca n ner. All sa m ples will r u n i n di vi d uall y 
wit h n o p o oli n g. 
 
 
Data A nal ysis a n d I nter pretati o n: T he arra ys will be sca n ne d usi n g a Ge nec hi p 3 0 0 
sca n ner a n d Ge ne C hip 5. 0 s oft ware ( Aff y metri x) will use d t o q ua ntitati vel y a nal yze t he 
sca n ne d i ma ge. Al g orit h ms i n t he s oft ware use pr o be cell ﬂu oresce nce i nte nsities t o 


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55 
calculate an average intensity for each set of probe pairs representing a gene, which 
directly correlates with the amount of mRNA. The plasma cell gene expression from 
different patient groups as described before will be compared using Genespring. The 
selection criteria for all genes reported as differentially expressed will be as follows: (1) 
in absolute analysis, a detection call of present; (2) a change either increased or 
decreased; (3) signal of greater than 1,000; and (4) greater than 2-fold differences in 
expression in all pair wise comparisons. Only genes with transcript levels that satisﬁed 
all 4 criteria will be considered as signiﬁcantly differentially expressed. Average 
differences in mean expression (as measured by ﬂuorescence intensity) of transcripts 
that met all of these criteria are compared across groups using the 2-sided Student’s t 
test. P values for differences between means of P less than .05 are considered 
statistically signiﬁcant.   
 
14.44 Cell Proliferation and Apoptosis:  These studies will be performed on marrow 
aspirates. The multiple myeloma cells are separated by positive selection using CD138 
coated magnetic beads in a Robosep system. The tumor cells are suspended in RPMI-
1640 media containing 20% fetal bovine serum, 2 mmol/L L-glutamine, 100 U/mL 
penicillin, and 100 µg/mL streptomycin, placed in 24 well plates and drug added at 
different concentrations. Patient cells are cultured for 48 hours, harvested and washed 
twice with PBS, and stained with FITC conjugated CD45 monoclonal antibody and PE 
conjugated Apo 2.7 antibody or 7-AAD for identification of apoptotic cells. The cells 
are then analyzed using software on an FACS CANTOS FC. 
 
14.45 Circulating tumor cells: Plasma cells are identified by their characteristic CD45/CD38 
staining pattern.  Using BD Biosciences TruCount bead technology, an absolute count 
is calculated in the lysed but not washed sample. 100 microliter of whole blood or BM 
is added to a TruCount tube containing CD45 FITC, CD31 PE and CD38 APC.  The 
tube is incubated for 15 minutes at room temperature, in the dark.  One ml of ACK 
(ammonium chloride potassium) lyse is added to each tube, mixed, and incubated for 15 
minutes at room temperature, in the dark. Using FL2 (CD31 PE) as the threshold, up to 
2 million events are collected for each tube on the Cantos flow cytometer (BD 
Biosciences, San Jose, CA).  The number of events in the plasma cell (PC) gate and the 
number of events in the bead gate are used to calculate the absolute number of PC per 
milliliter. 
 
 
 


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MCCC Addendum 5 
Protocol Version: November 23, 2015 
 
 
15.0 
Drug Information 
 
15.1 
15.1 
Pomalidomide (CC-4047) 
 
15.11 Background: Pomalidomide (CC-4047) is a novel drug in the class of 
immunomodulatory agents known as IMiD compounds.  Pomalidomide binds to 
its molecular target cereblon (CRBN), a protein that is part of an E3 ubiquitin 
ligase complex, which is responsible for the polyubiquitination of substrate 
proteins, targeting them for subcellular redistribution and destruction by the 
proteasome. The pharmacologic properties of pomalidomide are of potential 
therapeutic benefit in the treatment of various hematologic neoplasms (such as 
multiple myeloma and myeloproliferative neoplasm-associated myelofibrosis), 
non-neoplastic hematologic disorders (such as β-thalassemia and sickle cell 
disease) and non-hematologic disorders such as systemic sclerosis, as well as 
solid tumor neoplasms. 
 
15.12 Formulation:  Pomalidomide  capsules can be 0.5-mg gelatin capsules (size 4 
reddish brown), 1-mg hard gelatin capsules (size 4 reddish brown), 2-mg (size 2 
reddish-brown), 3-mg and 4-mg hard gelatin capsules (size 2 reddish-brown), and 
5-mg gelatin capsules (size 1 reddish-brown), containing pomalidomide, 
mannitol, pregelatinized starch, and sodium stearyl fumarate.  
 
Placebo capsules for pomalidomide  are available to use in blinded studies. The 
placebo capsules contain microcrystalline cellulose.  
 
Pomalidomide capsules and pomalidomide placebo capsules are supplied in high 
density polyethylene (HDPE) containers fitted with induction seals and child-
resistant plastic closures or PVC/PCTFE blister with push-through foil. 
 
15.13 Preparation and storage:  Store drug at controlled room temperature, 
between 68-77 ºF (20-25ºC) or as indicated on the manufacturer’s label.  
The expiration date is indicated on the label. 
 
 
Only enough study drug for one cycle of therapy may be dispensed with 
each cycle of therapy. 
 
15.14 Administration:  Pomalidomide is administered by mouth at approximately the 
same time each day. Pomalidomide should be taken without food (at least 2 hours 
before or 2 hours after a meal).  Capsules should be swallowed whole, and should 
not be broken, chewed or opened. If a dose of pomalidomide is missed, it should 
be taken as soon as possible on the same day. If it is missed for the entire day, it 
should not be made up.  Patients should be instructed never to give this medicinal 
product to another person and to return any unused capsules to the study doctor at 
the end of treatment.  Patients who take more than the prescribed dose of 
pomalidomide should be instructed to seek emergency medical care if needed 
and contact study staff immediately.   


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57 
 
15.15 Pharmacokinetic information:  
a)  Absorption – oral absorption has been moderately rapid with first dose Cmax 
occurring in 1.5 to 4 hrs. More than 70% of the pomalidomide dose is absorbed 
in humans.  A high fat meal decreased the rate of absorption but had minimal 
effect on overall extent of absorption; therefore drug may be administered 
without regard to food intake. 
 
b)  Distribution – Apparent volume of distribution in healthy subjects 
ranged from 74-138 L across a dose range of 1 to 10 mg daily.  
Pomalidomide protein binding in human plasma is low to moderate 
(15.8% for R-enantiomer, 42.2% for S-enantiomer) and the binding is 
concentration independent in the concentration range of 30 and 1000 
ng/mL.  Drug distributes into semen. 
 
c)  Metabolism – Eight metabolites were detected in plasma, each at 
exposures <10% of the plasma pomalidomide.   CYP-dependent 
metabolites accounted for approximately 43% of the excreted 
radioactivity, while non-CYP dependent hydrolytic metabolites accounted 
for 25%, and excretion of unchanged pomalidomide accounted for 10%. 
d)  Excretion – In healthy patients, 72.8% of the dose was recovered in 
urine and 15.5% was recovered in feces. Less than 3% of the dose is 
excreted as unchanged pomalidomide in the urine.  The geometric mean 
terminal elimination half-life (t1/2) of pomalidomide was approximately 7.5 
hours. 
 
 
15.16 Potential Drug Interactions:  No formal drug interaction studies have been 
conducted with pomalidomide. Pomalidomide is primarily metabolized by 
CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-
gp).  
 
1) Drugs That May Increase Pomalidomide Plasma Concentrations  
CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of pomalidomide with 
drugs that are strong inhibitors of CYP1A2, CYP3A, or P-gp could increase 
exposure and should be avoided.  
 
Strong inhibitors of CYP1A2 include ciprofloxacin, enoxacin, and fluvoxamine.  
Strong inhibitors of CYP3A include boceprevir, clarithromycin, conivaptan, 
grapefruit juice, indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir,mibefradil, nefazodone,nelfinavir,posaconazole, ritonavir, 
saquinavir, telaprevir, telithromycin, and voriconazole. 
 
Inhibitors of P-gp include amiodarone, azithromycin, captopril, carvedilol, 
clarithromycin, conivaptan, cyclosporine, diltiazem, dronedarone, erythromycin, 
felodipine,  itraconazole, ketoconazole, lopinavir and ritonavir, quercetin, 
quinidine, ranolazine, and verapamil. 
 
2) Drugs That May Decrease Pomalidomide Plasma Concentrations  
CYP3A, CYP1A2 or P-gp inducers: Co-administration of pomalidomide with 
drugs that are strong inducers of CYP1A2, CYP3A (or P-gp could decrease 
exposure and should be avoided.  


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CYP3A inducers include rifampin and carbamazepine.  
 
P-gp inducers include Avasimibe, carbamazepine, phenytoin, rifampin, St John’s 
wort, tipranavir/ritonavir 
 
Smoking: Cigarette smoking may reduce pomalidomide exposure due to 
CYP1A2 induction. Patients should be advised that smoking may reduce the 
efficacy of pomalidomide.  
 
Dexamethasone: Co-administration of multiple doses of 4 mg pomalidomide 
with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients 
with multiple myeloma had no effect on the pharmacokinetics of pomalidomide 
compared with pomalidomide administered alone.  
 
15.17 Known potential toxicities:   
Common known potential toxicities, > 10%:   
Cardiovascular: Peripheral edema (23%) 
Central nervous system: Fatigue (55%), dizziness (18% to 20%), fever (19%), 
neuropathy (18%), headache (13%), confusion (10% to 12%), anxiety (11%) 
Dermatologic: Skin rash (22%), pruritus (15%) 
Endocrine & metabolic: Hypercalcemia (21%), hyperglycemia (12%) 
Gastrointestinal: Constipation (36%), nausea (36%), diarrhea (34%), decreased 
appetite (22%), vomiting (14%), weight loss (14%) 
Hematologic & oncologic: Neutropenia (50% to 52%; Grades 3/4: 43% to 47%), 
anemia (38%; grades 3/4: 22%), thrombocytopenia (25%; grades 3/4: 22%), 
leukopenia (11%; grades 3/4: 6%) 
Neuromuscular & skeletal: Back pain (32%), musculoskeletal chest pain (22%), 
muscle spasm (19%), arthralgia (16%), ostealgia (12%), myasthenia (12%), and 
musculoskeletal pain (11%) 
Renal: Increased serum creatinine (15%), renal failure (15%) 
Respiratory: Dyspnea (34%), upper respiratory tract infection (32%), pneumonia 
(23%), epistaxis (15%), cough (14%) 
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular: Thrombosis (venous thrombosis, pulmonary embolism, 3%), 
atrial fibrillation (2%) 
Central nervous system: Peripheral neuropathy (10%), chills (9%), insomnia 
(7%), pain (6%) 
Dermatologic: Xeroderma (9%), hyperhidrosis (6%) 
Endocrine & metabolic: Hypokalemia (10%), hyponatremia (10%), 
hypocalcemia (6%), and dehydration (5%) 
Gastrointestinal: Weight gain (1%) 
Genitourinary: Urinary tract infection (8%) 
Hematologic & oncologic: Lymphocytopenia (4%; grades 3/4: 2%), febrile 
neutropenia (3% to 5%) 
Infection: Sepsis (6%) 
Neuromuscular & skeletal: Tremor (9%), limb pain (5%) 
Miscellaneous: Night sweats (5%) 


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59 
 
Frequency not defined: Acute myelocytic leukemia, hyperbilirubinemia, 
hyperkalemia, increased serum ALT, hepatotoxicity,  interstitial pulmonary 
disease (including pneumonitis), neutropenic sepsis, pelvic pain, Pneumocystis 
jiroveci pneumonia, respiratory syncytial virus infection, urinary retention, 
vertigo, pancytopenia, tumor lysis syndrome, angioedema, severe dermatologic 
reactions (including urticaria) 
 
All study participants must be registered into the mandatory 
POMALYST REMS™ program, and be willing and able to comply 
with the requirements of the POMALYST REMS™ program.  
Females of reproductive potential must adhere to the scheduled 
pregnancy testing.  Females of childbearing potential should not 
handle or administer pomalidomide unless they are wearing gloves. 
 
15.18 Drug procurement:   
Pomalidomide will be provided to research subjects for the duration of 
their participation in this trial at no charge to them or their insurance 
providers.  Pomalidomide will be provided in accordance with Celgene 
Corporation’s POMALYST REMS™ program.  Per the standard   
POMALYST REMS™ program requirements, all physicians who 
prescribe pomalidomide for research subjects enrolled into this trial, and 
all research subjects enrolled into this trial, must be registered in and must 
comply with all requirements of the POMALYST REMS™ program.   
 
Drug will be shipped on a per patient basis by the contract pharmacy to the 
clinic site for IND studies.  Only enough pomalidomide for one cycle of 
therapy will be supplied to the patient each cycle. 
 
15.19 Nursing Guidelines: 
 
15.191 Agent is known to be teratogenic in rabbits.  Therefore all women who 
are pregnant or who could become pregnant, should not handle the agent 
outside of the original packaging. Chemotherapy gloves should be worn 
if contact is necessary. 
 
15.192 Because of the similarity of this agent to thalidomide certain precautions 
MUST be employed by all subjects on protocol and for 4 weeks after 
discontinuation of agent. Instruct patients the following must be adhered 
to: No donation of tissue/blood/semen/sperm; sexually active males/ 
females must use protocol-specific contraception (regardless of fertility 
status-i.e. history of vasectomy). 
 
15.193 Cytopenias are common (neutropenia most common). Monitor CBC 
closely and instruct patient to report any signs/symptoms of infection or 
unusual bruising or bleeding to the study team. 
 


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60 
15.194 Thrombotic events have been reported. Anticoagulation prophylaxis may 
be recommended. Instruct patients to report any problems with bleeding, 
extremity pain or swelling, or shortness of breath to the study team 
immediately.  
 
15.195 Patients may experience cough, URI, pneumonia, or sinusitis. Instruct 
patients to report respiratory symptoms to the study team. 
 
15.196 Gastrointestinal side effects consisting of diarrhea, constipation, 
stomatitis, nausea, decreased appetite, and abdominal pain have been 
seen. Treat symptomatically and monitor for effectiveness. 
 
15.197 Drug should be taken without food (at least 2 hours before or 2 
hours after a meal). Do not open or crush capsules. 
 
15.198 Patients may experience myalgias and muscle spasms. Treat 
symptomatically and monitor for effectiveness. 
 
15.199aFatigue is common. Instruct patient in energy conserving lifestyle. 
 
15.199b Warn patients about the possibility of peripheral neuropathy, 
headache, confusion, and dizziness. 
 
15.2 
Bortezomib (Velcade®, PS341) 
 
15.21 Background: Bortezomib inhibits proteasomes, enzyme complexes which 
regulate protein homeostasis within the cell. Specifically, it reversibly inhibits 
chymotrypsin-like activity at the 26S proteasome, leading to activation of 
signaling cascades, cell-cycle arrest, and apoptosis. 
 
15.22 Formulation: Bortezomib for Injection is supplied as individual cartons with 10 
mL vials containing 3.5 mg of bortezomib as a white to off-white cake or 
powder.  
 
15.23 Preparation, storage, and stability: Unopened vials may be stored at 
controlled room temperature 25°C (77°F); excursions permitted from 15°C 
to 30°C (59°F-86°F). Retain in original package to protect from light. 
 
IV administration: Dilute each 3.5 mg vial with 3.5 mL 0.9% Sodium 
Chloride, resulting in a final concentration of 1 mg/mL bortezomib. 
 
Subcutaneous administration: To minimize volume of injected solution, 
dilute each 3.5 mg vial with 1.4 mL 0.9% Sodium Chloride, resulting in a 
final concentration of 2.5 mg/mL bortezomib.  Attach a subcutaneous 
needle to syringe. 
 
Bortezomib contains no antimicrobial preservative.  Reconstituted product 
should be administered within 8 hours of preparation.  When reconstituted 


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61 
as directed, bortezomib may be stored at 25ºC (77 ºF), in the original vial 
and/or syringe.  Protect from light.  See investigator brochure or package 
insert for more complete information. . 
 
15.24 Administration:  Bortezomib is administered intravenously as a 3 to 5 second 
bolus IV injection at a concentration of 1 mg/mL; or subcutaneously at a 
concentration of 2.5 mg/mL.  Rotate injection sites for subcutaneous 
administration between the abdomen (right or left) and thighs (right or left). 
 
 
Bortezomib is contraindicated for intrathecal administration. 
 
 
15.25 Pharmacokinetic information: 
Distribution: 498-1884 L/m2. The rapid distribution period has a half-life 
(t1/2) of less than 10 minutes. Data from studies conducted in nonhuman 
primates have shown that the tissue distribution for bortezomib is 
extensive with the exception of penetration into the central nervous system 
and various regions of the eye and testes, where bortezomib levels were 
below the limit of quantification of the assays. 
Pharmacokinetic parameters from SC administration were comparable 
with those from the established IV route, with no differences in overall 
systemic availability between SC and IV administration on Days 1 and 11 
in Cycle 1.  Following SC administration, mean Cmax values were 
significantly lower and Tmax was longer as was expected since drugs 
administered SC require more time to be absorbed. Mean volume of 
distribution (Vd) was similar and high for both routes, confirming 
extensive distribution of bortezomib into peripheral tissues. 
 
Protein binding, plasma: ~83% 
Metabolism: Hepatic primarily via CYP2C19 and 3A4 and to a lesser extent 
CYP1A2; forms metabolites (inactive) via deboronization followed by 
hydroxylation. Total exposure to bortezomib is increased in patients with 
moderate to severe hepatic impairment; consider reduction of starting dose in 
these patients (0.7 mg/m2 per injection during the first 
cycle, with a subsequent dose escalation to 1.0 mg/m2 or further dose 
reduction to 0.5 mg/m2 considered based on patient tolerance). 
Half-life elimination: Single dose: 9-15 hours; multiple dosing, twice 
weekly schedule: 1 mg/m2: 40-193 hours; 1.3 mg/m2: 76-108 hours 
 
 
15.26 Potential Drug Interactions:   
Co-administration of ketoconazole, a potent CYP3A4 inhibitor, increased 
the exposure to bortezomib. Therefore, subjects should be closely 
monitored when given bortezomib in combination with potent CYP3A4 
inhibitors such as ketoconazole or ritonavir.  Co-administration of 
omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure 
of bortezomib. Co-administration of rifampicin, a strong CYP3A4 inducer, 
decreased the systemic exposure of bortezomib by 45%. Efficacy may be 
reduced when bortezomib is used in combination with strong CYP3A4 
inducers; therefore, concomitant use of strong CYP3A4 inducers is not 
recommended in patients receiving bortezomib.  Co-administration of 


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62 
dexamethasone, a relatively weak CYP3A4 inducer, had no effect on 
systemic exposure of bortezomib. 
 
15.27 Known potential adverse events: Consult the package insert for the most 
current and complete information. 
 
Common known potential toxicities, ≥ 10%:   
Blood and Lymphatic System Disorders: Thrombocytopenia, anemia, 
neutropenia 
Gastrointestinal Disorders:  Constipation, diarrhea, nausea, vomiting, 
abdominal pain (excluding oral and throat) 
General Disorders and Administration Site Conditions:  Fatigue, pyrexia, 
chills, edema peripheral, asthenia 
Infections and Infestations:  Upper respiratory tract infection, 
nasopharyngitis, pneumonia, Herpes zoster 
Metabolism and Nutritional Disorders:  Decreased appetite, anorexia, 
dehydration 
Musculoskeletal and Connective Tissue Disorders:  Bone pain, myalgia, 
arthralgia, back pain 
Nervous System Disorders:  Peripheral neuropathy, paresthesia, dizziness 
excluding vertigo, headache 
Psychiatric Disorders: Anxiety, insomnia 
Respiratory, Thoracic, and Mediastinal Disorders: Cough, dyspnea 
Skin and Subcutaneous Tissue Disorders: Rash 
Less common known potential toxicities, 1% to < 10%:  
Blood and Lymphatic System Disorders: Lymphopenia, pancytopenia, 
leukopenia, febrile neutropenia 
Cardiac Disorders: Tachycardia, atrial fibrillation, palpitations, cardiac 
failure congestive  
Eye Disorders: Blurred vision, conjunctivitis, conjunctival hemorrhage 
Gastrointestinal Disorders: Dyspepsia, pharyngolaryngeal pain, 
gastroesophageal reflux, abdominal distension, gastritis, stomatitis, mouth 
ulceration, dysphagia, gastrointestinal hemorrhage, lower gastrointestinal 
hemorrhage, rectal hemorrhage 
General Disorders and Administration Site Conditions:  Neuralgia, 
lethargy, malaise, chest pain, mucosal inflammation 
Infections and Infestations: Lower respiratory tract infection, sinusitis, 
pharyngitis, oral candidiasis, urinary tract infection, sepsis, bacteremia, 
cellulitis, Herpes simplex, bronchitis, gastroenteritis, infection  
Injury, Poisoning, and Procedural Complications:  Fall 
Investigations: Weight decreased, alanine aminotransferase (ALT) 
increased, aspartate aminotransferase (AST) increased, blood alkaline 
phosphatase increased, liver function test abnormal, blood creatinine 
increased 
Metabolism and Nutritional Disorders: Hyperglycemia, hypoglycemia, 
hyponatremia, hypokalemia, hypercalcemia 
Musculoskeletal and Connective Tissue Disorders: Muscular weakness 
Nervous System Disorders:  Polyneuropathy, syncope, dysesthesia, 
dysgeusia, postherpetic neuralgia 


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63 
Psychiatric Disorders:  Confusional state 
Renal and Urinary Disorders: Renal impairment, renal failure, hematuria 
Respiratory, Thoracic, and Mediastinal Disorders:  Epistaxis, dyspnea 
exertional, pleural effusion, rhinorrhea, hypoxia, pulmonary edema 
Skin and Subcutaneous Tissue Disorders:  Rash pruritic, rash 
erythematous, urticaria, petechiae 
Vascular Disorders:  Hypotension, orthostatic hypotension 
Uncommon (<1%):  
Cardiac Disorders:  Cardiogenic shock, atrial flutter, cardiac tamponade, 
bradycardia, atrioventricular block complete, arrhythmia, cardiac arrest, 
cardiac failure, arrhythmia, pericardial effusion, pericarditis, pericardial 
disease, cardiopulmonary failure 
Ear and Labyrinth Disorders:  Deafness, hearing impaired 
Gastrointestinal Disorders: Eructation, gastrointestinal pain, tongue 
ulceration, retching, upper gastrointestinal hemorrhage, 
hematemesis, oral mucosal petechiae, ileus paralytic, ileus, odynophagia, 
enteritis, colitis, esophagitis, enterocolitis, diarrhea hemorrhagic, acute 
pancreatitis, intestinal obstruction  
General Disorders and Administration Site Conditions:  Injection site pain, 
injection site irritation, injection site phlebitis, general physical health 
deterioration, catheter-related complication 
Hepatobiliary Disorders:  Hyperbilirubinaemia, hepatitis 
Immune System Disorders:  Drug hypersensitivity, angioedema 
Infections and Infestations:  Septic shock, catheter-related infection, skin 
infection, Herpes zoster disseminated, lung infection, infusion site 
cellulitis, catheter site cellulitis, infusion site infection, urosepsis, 
Aspergillosis, tinea infection, 
Herpes zoster ophthalmic, Herpes simplex ophthalmic, 
meningoencephalitis herpetic, varicella, empyema, fungal esophagitis 
Injury, Poisoning, and Procedural Complications:  Subdural hematoma 
Investigations:  Gamma-glutamyltransferase (GGT) increased, oxygen 
saturation decreased, blood albumin decreased, ejection fraction 
decreased 
Musculoskeletal and Connective Tissue Disorders: Limb discomfort 
Neoplasms, Benign, Malignant, and Unspecified (including cysts and 
polyps): Tumor lysis syndrome 
Nervous System Disorders: Convulsion, loss of consciousness, ageusia, 
encephalopathy, paralysis, autonomic neuropathy, posterior reversible 
encephalopathy syndrome  
Psychiatric Disorders: Delirium 
Renal and Urinary Disorders:  Micturition disorder 
Respiratory, Thoracic, and Mediastinal Disorders:  Hemoptysis, acute 
respiratory distress syndrome, respiratory failure, pneumonitis, lung 
infiltration, pulmonary alveolar hemorrhage, interstitial lung disease, 
pulmonary hypertension, pleurisy, pleuritic pain 
Skin and Subcutaneous Tissue Disorders:  Cutaneous vasculitis, 
leukocytoclastic vasculitis 
Vascular Disorders:  Cerebral hemorrhage 
 


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64 
15.28 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
 
15.29 Nursing Guidelines:  
 
15.191 Monitor CBC.  Instruct patient to report any signs or symptoms of 
infection, unusual bruising, or bleeding to the health care team. 
 
15.192 Gastrointestinal side effects were common (i.e diarrhea, etc).   Instruct 
patient to report symptoms and treat symptomatically.  Evaluate for 
effetiveness 
 
15.193 Instruct patient to report any cardiac palpitations, increased pulse, 
lightheadedness, visual changes, feelings of weakness or dizziness.  
Periodically assess vital signs. 
 
15.194 Peripheral neuropathy can be seen. Instruct patient to report any   
numbness, tingling, or pain in the hands and/or feet to the health care 
team. 
 
15.195 Instruct patient to report any rash. 
 
15.196 Thrombus and embolisms are a rare but serious and potentially life 
threatening side effect of bortezomib.  Instruct patient to report any signs 
or symptoms of DVT or PE (calf pain, extremity swelling, SOB, chest 
pain) immediately or seek immediate medical attention. 
 
15.197 Review all of patient’s medications. There are drug-to drug interactions 
with other drugs that are metabolized through the CYP3A4 pathway. 
Instruct patient to contact the study team prior to starting any new 
medications. 
 
15.198 Progressive Multifocal Leukoencephalopathy (PML) is a rare, but 
serious condition. Instruct patients to report any mental status changes, or 
other neurological symptoms to the study team immediately. 
 
15.3 
Dexamethasone for Oral Administration (DXM) 
 
15.31 Background: Dexamethasone is an adrenal corticosteroid compound. 
Dexamethasone decreases inflammation by suppression of neutrophil migration, 
decreased production of inflammatory mediators, and reversal of increased 
capillary permeability; suppresses normal immune response. Dexamethasone’s 
mechanism of antiemetic activity is unknown. 
 
15.32 Formulation: Commercially available for oral administration as:  
 
Tablets [scored]: 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg, and 6 mg 
 
Solution, oral: 0.5 mg/mL (500 mL) 
Solution, oral concentrate: Dexamethasone Intensol: 1 mg/mL (30 mL) 
 


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65 
15.33 Preparation, storage, and stability: Refer to package insert for complete 
preparation and dispensing instructions. Store oral tablets at room 
temperature between 20ºC to 25ºC (60ºF to 77ºF). Protect from moisture. 
Dispense in a well-closed, light-resistant container as defined in the 
USP/NF. Store oral liquid at room temperature, do not freeze. Do not use 
if solution contains a precipitate. Refer to commercial package for drug 
expiration date. 
 
15.34 Administration:  Refer to the treatment section for specific administration 
instructions. May be taken with meals to decrease GI upset.  
 
 
15.35 Pharmacokinetic information: 
Onset of action: Prompt 
Duration of metabolic effect: 72 hours 
Metabolism: Hepatic 
Half-life elimination: Normal renal function: 1.8-3.5 hours; Biological 
half-life: 36-54 hours 
Time to peak, serum: Oral: 1-2 hours 
Excretion: Urine and feces 
 
15.36 Potential Drug Interactions: 
Cytochrome P450 Effect: Substrate of CYP3A4 (major); Induces 
CYP2A6 (weak), 2B6 (weak), 2C8 (weak), 2C9 (weak), 3A4 (strong) 
Increased Effect/Toxicity: Aprepitant, azole antifungals, calcium channel 
blockers, cyclosporine, estrogens, and macrolides may increase the serum 
levels of corticosteroids. Corticosteroids may increase the hypokalemic 
effects of amphotericin B or potassium-wasting diuretics (loop or 
thiazide); monitor. Refer to the package insert for a listing of other drugs. 
Decreased Effect: Antacids and bile acid sequestrants may reduce the 
absorption of corticosteroids; may reduce the absorption of corticosteroids; 
separate administration by 2 hours. Aminoglutethimide, barbiturates, and 
CYP3A4 inducers may reduce the serum levels/effects of dexamethasone 
and dexamethasone may decrease the levels/effects of other CYP3A4 
substrates. Serum concentrations of isoniazid may be decreased by 
corticosteroids. Corticosteroids may lead to a reduction in warfarin effect. 
Corticosteroids may suppress the response to vaccinations. 
Ethanol/Nutrition/Herb Interactions:  
Ethanol: Avoid ethanol (may enhance gastric mucosal irritation). 
Food: Dexamethasone interferes with calcium absorption. Limit caffeine. 
Herb/Nutraceutical: Avoid cat’s claw, Echinacea (have immunostimulant 
properties) 
 
15.37 Known potential adverse events: Consult the package insert for the most 
current and complete information.  
 
Common known potential toxicities, frequency not defined:   
Fluid and electrolyte disturbances, congestive heart failure in susceptible 
persons, hypertension, euphoria, personality changes, insomnia, 
exacerbation of infection, exacerbation or symptoms of diabetes, 


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66 
psychosis, muscle weakness, osteoporosis, vertebral compression 
fractures, pancreatitis, esophagitis, peptic ulcer, dermatologic disturbances, 
convulsions, vertigo and headache, endocrine abnormalities, ophthalmic 
changes, and metabolic changes. Some patients have experienced itching 
and other allergic, anaphylactic or hypersensitivity reactions. Withdrawal 
from prolonged therapy may result in symptoms including fever, myalgia 
and arthralgia. 
 
15.38 Drug procurement:  Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
 
 
15.39 Nursing Guidelines:  
 
15.391 Monitor regularly for hypertension, CHF and other evidence of fluid 
retention. 
 
15.392 Advise patient of possible mood or behavioral changes, i.e., depression, 
euphoria, insomnia, even psychosis.  Instruct patient to report any 
suspected changes to healthcare team. 
 
15.393 Assess for symptoms of gastric ulcer, heartburn, or gastritis.  Suggest 
antacids.  Instruct patient to report symptoms to healthcare team if unable 
to control. 
 
15.394 Evaluate signs of infection, particularly local candidal infections and 
treat appropriately. 
 
15.395 Monitor blood glucose frequently. 
 
15.396 Instruct patient to report frequent, unrelenting headaches or visual 
changes to healthcare team. 
 
15.397 Advise patient that easy bruising is a side effect. 
 
16.0 
Statistical Considerations and Methodology  
 
16.1 
Overview:  This is a phase I/II study in multiple myeloma treated with a combination of 
pomalidomide, bortezomib, and dexamethasone.  The phase I portion of the study is 
designed to determine the MTD of this treatment combination.  The phase II portion will 
accrue patients at the MTD.  The goal of the phase II portion is to assess the efficacy of 
the treatment regimen.  A two-stage design will be utilized to assess this endpoint.  
Included will be a threshold at which we can report findings early based on extremely 
successful response rates. 
 
16.11 
Primary Endpoint:   The primary endpoint of the phase I portion is toxicity, and 
more specifically, MTD determination.  For the phase II portion of the trial, the 
primary endpoint is confirmed response rate. 
 
16.12 
Sample Size:  The phase I portion of the trial will require at least 9 patients and 
as many as 12 patients to determine the MTD.  The 6 phase I patients treated at 


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MCCC Addendum 6 
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67 
the MTD will also be included in the phase II portion.  The phase II portion will 
require an additional 10 or 36 evaluable patients for a minimum of 16 evaluable 
patients and a maximum of 42 evaluable patients.  We will plan to accrue an 
additional 6 patients (2 Phase I, 4 Phase II) to account for ineligibles, major 
protocol violations, etc.  Considering all possibilities, this phase I/II will require a 
minimum of 9 patients (if a MTD is not found) and a maximum of 54 patients 
(12 in phase I plus 36 evaluable in phase II plus 6 to account for replaced 
patients). 
 
16.13 
Accrual Rate and Study Duration: Based on accrual on a recent pomalidomide 
trial, we can expect to accrue approximately 7-8 patients per month.  At this rate, 
it will likely take about 2 months to enroll, treat, and evaluate each set of 3 
patients in the phase I portion of this study.  The phase I portion is expected to 
take between 6 and 12 months.  Once the phase II portion of the trial begins, we 
can expect to accrue the required patients in about 10 months, assuming a month 
4 month suspension to evaluate the first stage.  Allowing for data maturity, we 
can expect to begin final analysis approximately 16 months after beginning the 
phase II portion, i.e. as soon as the last patient accrued has been observed for at 
least 6 months.  The overall study duration is expected to be a maximum of 2.5 
years. 
 
 
Phase I Portion (Cohort I): 
This portion of the study is designed to determine the MTD and toxicity of this 3-drug 
combination in patients with multiple myeloma. 
 
16.2 
Study Design:  This portion of the study will consist of a standard 3+3 phase I design to 
determine the MTD of the 3-drug combination.  
 
16.21   MTD Determination:  MTD is defined as the dose level below the lowest dose 
that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a 
maximum of 6 new patients). See section 7.24 for the MTD determination 
algorithm and section 7.23 for DLT definitions. 
 
16.22 
Primary Outcome Analyses: 
 
16.221 Adverse Events Profile:  The number and severity of all adverse events 
will be tabulated and summarized in this patient population. The grade 
3+ adverse events will also be described and summarized in a similar 
fashion. This will provide an indication of the level of tolerance for this 
treatment combination in this patient group.  
 
16.222 Toxicity Profile:  The term toxicity is defined as adverse events that are 
classified as either possibly, probably, or definitely related to study 
treatment.  Non-hematologic toxicities will be evaluated via the ordinal 
CTC standard toxicity grading. Hematologic toxicity measures of 
thrombocytopenia, neutropenia, and leukopenia will be assessed using 
continuous variables as the outcome measures (primarily nadir) as well 
as categorization via CTC standard toxicity grading.  Overall toxicity 
incidence as well as toxicity profiles by dose level and patient will be 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
68 
explored and summarized. Frequency distributions, graphical techniques 
and other descriptive measures will form the basis of these analyses.  
 
Phase II Portion (Cohort II) 
 
16.3  
Statistical Design: 
 
16.31 Decision Rule:  In a previous study of Pomalidomide and Dexamethasone 
(MC0789), 52 patients had at least 2 prior regimens (one of which was 
lenalidomide).  Of these 52 patients, 35% achieved a confirmed response.  The 
addition of Bortezomib to this combination is expected to increase the confirmed 
response rate.  A confirmed response rate of 45% for the combination of 
Pomalidomide, Bortezomib, and Dexamethasone in this patient population is of 
interest. 
 
The largest success proportion where the proposed treatment regimen would be 
considered ineffective in this population is 25%, and the smallest success 
proportion that would warrant subsequent studies with the proposed regimen in 
this patient population is 45%.  The following two-stage Fleming design requires 
a minimum of 16 evaluable patients or a maximum of 42 evaluable patients to 
test the null hypothesis that the true success proportion in a given patient 
population is at most 25%.34  A patient is considered a success if they have an 
objective status of PR, VGPR, or CR on two consecutive evaluations. 
 
16.311 Stage 1: Enter 16 patients into the study. If 3 or fewer successes are 
observed in the first 16 evaluable patients, we will consider this regimen 
ineffective in this patient population and terminate this study. If at least 4 
successes are observed, we will continue accrual.   
 
16.312 Early Reporting: If there are at least 9 successes, out of the first 16 
evaluable patients, we will consider this enough evidence that the 3-drug 
combination is promising and will allow early reporting of efficacy 
results.  This cutoff is based on the positive Stage 1 stopping rule from a 
two-stage Fleming design. 
 
16.313 Stage 2:  Enter an additional 26 patients into the study.  If 14 or fewer 
successes are observed in the first 42 evaluable patients, we will consider 
this regimen ineffective in this patient population.  If 15 or more 
successes are observed in the first 42 evaluable patients, we may 
recommend further testing of this regimen in subsequent studies in this 
patient population. 
 
16.314 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making process. 
 
16.32 Power and Significance Level:  Assuming that the number of successes is 
binomially distributed, the significance level is .10 (i.e. there is a 10% chance of 
finding the drug to be effective when it truly is not).  The probability of declaring 
that this regimen warrants further study (i.e. statistical power) under various 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
69 
success proportions and the probability of stopping after the first stage can be 
tabulated as a function of the true success proportion as shown in the following 
table. 
 
If the true success proportion is... 
0.25 
0.30 
0.35 
0.40 
0.45 
Then the probability of declaring that the 
regimen warrants further study is… 
0.08 
0.25 
0.51 
0.75 
0.90 
And the probability of stopping after the 
first stage is… 
0.41 
0.25 
0.13 
0.07 
0.03 
And the probability of early reporting of 
the first stage results is… 
<0.01 
0.03 
0.07 
0.14 
0.26 


MC1082 
 
MCCC Addendum 6 
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70 
16.33 Other considerations:  Adverse events, quality/duration of response, and patterns 
of treatment failure observed in this study, as well as scientific discoveries or 
changes in standard care will be taken into account in any decision to terminate 
the study 
 
16.4   Analysis Plan 
 
16.41 Primary Outcome Analyses: 
 
16.411 Definition:  The primary endpoint for the phase II portion of this trial is 
confirmed response rate.  As stated above, a success is defined as a 
patient that has achieved a response (PR, VGPR, or CR) on two 
consecutive evaluations. 
 
16.412 Estimation:  The proportion of successes will be estimated by the 
number of successes divided by the total number of evaluable patients. 
Confidence intervals for the true success proportion will be calculated 
according to the approach of Duffy and Santner.35 
 
16.42 
Secondary Outcome Analyses 
 
16.421  Overall survival:  Survival time is defined as the time from registration to 
death due to any cause. The distribution of survival time will be 
estimated using the method of Kaplan-Meier.36 
 
16.422 Progression-free survival: The progression-free survival (PFS) time is 
defined as the time from registration to progression or death due to any 
cause.  The distribution of progression-free survival will be estimated 
using the method of Kaplan-Meier.36 
 
16.423  Duration of response is defined for all evaluable patients who have 
achieved a confirmed response as the date at which the patient’s 
objective status is first noted to be either a CR, VGPR, or PR to the 
earliest date progression is documented. The distribution of duration of 
response will be estimated using the method of Kaplan-Meier.36                                          
 
16.43   Adverse Events:  All eligible patients that have intitiated treatment will be 
considered evaluable for assessing adverse event rates.  The maximum grade for 
each type of adverse event will be recorded for each patient, and frequency tables 
will be reviewed to determine patterns.  Additionally, the relationship of the 
adverse events to the study treatment will be taken into consideration. 
 
16.44   Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any 
decision making processes; however, they will be included in final point 
estimates and confidence intervals. 
 


MC1082 
 
MCCC Addendum 6 
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71 
16.45    Data & Safety Monitoring: 
 
16.451   The principal investigator(s) and the study statistician will review the 
study at least twice a year to identify accrual, adverse event, and any 
endpoint problems that might be developing. The Mayo Clinic Cancer 
Center (MCCC) Data Safety Monitoring Board (DSMB) is responsible 
for reviewing accrual and safety data for this trial at least twice a year, 
based on reports provided by the MCCC Statistical Office. 
 
16.452   Adverse Event Stopping Rules (These rules apply to all patients in this 
study treated at the MTD):   The stopping rules specified below are based 
on the knowledge available at study development. We note that the 
Adverse Event Stopping Rule may be adjusted in the event of either (1) 
the study re-opening to accrual or (2) at any time during the conduct of 
the trial and in consideration of newly acquired information regarding the 
adverse event profile of the treatment(s) under investigation. The study 
team may choose to suspend accrual because of unexpected adverse 
event profiles that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended to this study if at any time we 
observe events considered at least possibly related to study treatment (i.e. 
an adverse event with attribute specified as “possible”, “probable”, or 
“definite”) that satisfy either of the following: 
• 
if 2 or more patients in the first 10 treated patients experience a grade 4 
cardiac, lung, liver or neurological toxicity that is felt to be drug related  
• 
if after the first 10 patients have been treated, 20% of all patients 
experience a grade 4 cardiac, lung, liver or neurological toxicity that is 
felt to be drug related 
 
We note that we will review grade 4 and 5 adverse events deemed 
“unrelated” or “unlikely to be related”, to verify their attribution and to 
monitor the emergence of a previously unrecognized treatment-related 
adverse event. 
 
The probability of meeting the stopping rule criteria under various 
scenarios is estimated to be the following (based on simulations with 
10,000 iterations): 
 
If the true proportion of patients that 
meet the stopping rule criteria is … 
.10 
.15 
.20 
.25 
.30 
Then the probability of meeting the 
stopping rule criteria in the 1st 10 
patients is…. 
.26 
.44 
.61 
.75 
.84 
And the probability of meeting the 
stopping rule criteria after the 1st 10 
patients is… 
.07 
.15 
.20 
.19 
.14 
And the probability of meeting the 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
72 
stopping rule criteria at any time is… 
.33 
.60 
.82 
.94 
.98 
 
16.5 
Results Reporting on ClinicalTrials.gov: At study activation, this study will have been 
registered within the “ClincialTrails.gov” website. The Primary and Secondary Endpoints 
(ie, “Outcome Measures”) along with other required information for this study will be 
reported on ClinicalTrials.gov. For purposes of timing of the Results Reporting, the 
initial estimated completion date for the Primary Endpoint of this study is 2 years after 
the study opens to accrual. The definition of “Primary Endpoint Completion Date” 
(PECD) for this study is the time the last patient registered has been followed for at least 
6 months. 
 
16.6 
Inclusion of Women and Minorities 
 
16.61 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.62 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analysis will, as 
always, look for differences in treatment effect based on racial and gender 
groupings, the sample size is not increased in order to provide additional power 
for subset analyses. 
 
16.63 The geographical region served by Mayo, has a population which includes 
approximately 3% minorities. Based on prior Mayo studies involving similar 
disease sites, we expect about 3-5% of patients will be classified as minorities by 
race and about 33% of patients will be women.  Expected sizes of racial by 
gender subsets are shown in the following table: 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
73 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
1 
0 
1 
Not Hispanic or Latino 
18 
35 
0 
53 
Unknown 
0 
0 
0 
0 
Ethnic Category: Total of all subjects 
18 
36 
0 
54 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
1 
1 
0 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
17 
35 
0 
52 
More than one race 
0 
0 
0 
0 
Unknown 
0 
0 
0 
0 
Racial Category: Total of all subjects 
18 
36 
0 
54 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central American, or 
other Spanish culture or origin, regardless of race. The term “Spanish origin” can also be used 
in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original peoples 
of North, Central, or South America, and who maintains tribal affiliations or community 
attachment. 
Asian – a person having origins in any of the original peoples of the Far East, Southeast Asia, 
or the Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, 
Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam. (Note: Individuals from the 
Philippine Islands have been recorded as Pacific Islanders in previous data collection 
strategies.)  
Black or African American – a person having origins in any of the black racial groups of 
Africa. Terms such as “Haitian” or “Negro” can be used in addition to “Black or African 
American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the original 
peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle East, or 
North Africa. 
  
 
 


MC1082 
74 
MCCC Addendum 5 
Protocol Version: November 23, 2015 
 
17.0 
Pathology Considerations: 
 
 
17.1 
Bone marrow reports will be obtained from the laboratory reports.  No special review 
will be required prior to patient entry on the study. 
 
18.0 
Records and Data Collection Procedures (As of Addendum 6, patients in active 
monitoring and in event monitoring will be removed from study. No further follow-
up is required)  
18.1 Submission Timetable 
 
Initial Material(s)  
 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
On-Study Form 
 
 
 
 
≤2 weeks after registration 
Baseline Adverse Event Form 
Pretreatment Measurement Form 
Baseline Research Blood Submission Form 
Research Bone Marrow Aspirate Submission Form 
Bone marrow biopsy report 
SPEP, UPEP, FLC, Immunofixation, FISH, 
Cytogentics, PCLI reports 
Skeletal Survey 
End of Active Treatment/Cancel Notification Form 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
 


MC1082 
 
MCCC Addendum 6 
Protocol Version: October 7, 2017 
 
75 
Test Schedule Material(s)  
 
 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of treatment 
Evaluation/Treatment Form 
X1 
X 
Nadir/Adverse Event Form 
X 
X 
Measurement Form 
X 
X 
Research Blood Submission Form 
X2 
 
Research Bone Marrow Aspirate Submission 
Form 
X2 
 
End of Active Treatment/Cancel Notification 
Form 
 
X 
Notification Form – Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization Form (see 
Section 10.2) 
At each occurrence 
 
ADR/AER (see Section 10.0) 
At each occurrence 
 
Bone marrow biopsy report 
X2 
X 
SPEP, UPEP, FLC, Immunofixation reports 
X3 
X3 
Skeletal Survey 
X2 
X 
1. Complete at each evaluation during Active Treatment (see Section 4.0). 
2. Only when required by the Test Schedule (see Section 4.0). 
3. Submission of these reports is only required for documentation of CR (including sCR) or 
progression.  For documentation of CR, submit all of these reports at the first confirmation of CR.  
For documentation at first signs of progression, submit reports to the 
. 
 
Follow-up Material(s) 
 
CRF 
Event Monitoring Phase 
 
 
 
 
At PD or 
initiation of 
new 
treatment 1 
6 months 
After PD 
or 
initiation 
of new 
treatment 
 
 
 
Death 
 
 
 
New Primary 
Event Monitoring Form 
X 
X 
X 
At each occurrence 
 
1. Submit documentation of progression to the MCCC Operations Office, Attention: 
 
. 
 


MC1082 
 
MCCC Addendum 6 
Protocol Version: November 23, 2015 
 
76 
 
18.2 
Dana Farber Cancer Institute and the University of Chicago 
 
18.21 Submit forms for computer entry to:  
 
Data CRA for MC1082 
Mayo Clinic Cancer Center 
 
  
Rochester, MN 55905 
Fax: 
 
 
18.22 Patient identification labels will be produced for each patient entry.  The 
labels are produced for use on the data forms and will be mailed to the 
co-sponsors twice weekly.  Additional labels may be obtained by directly 
calling the Mayo Clinic Cancer Center (MCCC) Registration Office 
. 
 
18.23 Each co-sponsor will be responsible for insuring that all materials 
contain the patient’s initials, MCCC registration number, and MCCC 
protocol number.  Patient’s name must be removed. 
 
18.24 Any materials deemed incomplete by the MCCC Operations Office will 
be considered “not received” and will not be edited or otherwise 
processed until the missing information is received.  A list of the missing 
documents will be made available to the appropriate co-sponsor. 
 
18.25 Overdue lists:  A list of overdue materials and forms for study patients 
will be generated monthly.  The listings will be sorted by location and 
will include the patient study registration number.  The appropriate co-
sponsor will be responsible to obtain the overdue material. 
 
18.26 Corrections forms:  If a correction is necessary the QAS will query the 
co-sponsor.  The query will be sent to the appropriate co-sponsor who 
will make the correction and return the query and documentation of 
correction back to the QAS.  
 
19.0 
Budget Considerations 
 
19.1 
Costs charged to patient: routine office visits and pharmacy charges.  Patients and their 
insurance carriers will also be billed for non-research lab tests deemed necessary to safely 
administer the drugs.  Since bortezomib and dexamethasone are standard therapy of 
myeloma, commercial supplies will be used and it is reasonable to charge for its 
distribution.  Pomalidomide will be supplied free by Celgene. 
 
19.2 
Other budget concerns: Protocol administration, data management, research testing on 
samples and statistical analysis efforts will be by funded by Celgene, according to the 
terms of the contract. 


MC1082 
 
MCCC Addendum 6 
Protocol Version: November 23, 2015 
 
77 
 
20.0 
References 
 
1. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. Ca: a 
Cancer Journal for Clinicians. 2003;53:5-26. 
2. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed 
multiple myeloma. Mayo Clin Proc. 2003;78:21-33. 
3. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple 
myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists' 
Collaborative Group. J Clin Oncol. 1998;16:3832-3842. 
4. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous 
bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais 
du Myelome. New England Journal of Medicine. 1996;335:91-97. 
5. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-
cell rescue for multiple myeloma. New England Journal of Medicine. 2003;348:1875-1883. 
6. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple 
myeloma [see comments]. New England Journal of Medicine. 1999;341:1565-1571. 
7. Rajkumar SV, Fonseca R, Dispenzieri A, et al. A phase II trial of thalidomide in the treatment 
of relapsed multiple myeloma (MM) with laboratory correlative studies. Blood. 2000;96:168a 
(A723). 
8. Alexanian R, Dimopoulos MA, Delasalle K, Barlogie B. Primary dexamethasone treatment of 
multiple myeloma. Blood. 1992;80:887-890. 
9. Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR. Phase III clinical trial of 
thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed 
multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J 
Clin Oncol. 2006;24:431-436. 
10. Rajkumar SV, Hussein M, Catalano J, et al. A Randomized, Double-Blind, Placebo-
Controlled Trial of Thalidomide Plus Dexamethasone Versus Dexamethasone Alone as 
Primary Therapy for Newly Diagnosed Multiple Myeloma. ASH Annual Meeting Abstracts. 
2006;108:795-. 
11. Weber DM, Gavino M, Delasalle K, Rankin K, Giralt S, Alexanian R. Thalidomide alone or 
with dexamethasone for multiple myeloma. Blood. 1999;94 (Suppl 1):604a (A 2686). 
12. Weber DM, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide with 
dexamethasone for resistant multiple myeloma. Blood. 2000;96:167a (A719). 
13. Wang M, Weber DM, Delasalle K, Alexanian R. Thalidomide-dexamethasone as primary 
therapy for advanced multiple myeloma. Am J Hematol. 2005;79:194-197. 
14. Richardson PG, Schlossman RL, Weller E, et al. Immunomodulatory drug CC-5013 
overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. 
Blood. 2002;100:3063-3067. 
15. Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide 
therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 
2006;108:3458-3464. 
16. Richardson PG, Schlossman RL, Hideshima T, et al. A Phase 1 Study of Oral CC5013, an 
Immunomodulatory Thalidomide (Thal) Derivative, in Patients with Relapsed and Refractory 
Multiple Myeloma (MM). Blood. 2001;98:775a (A3225). 
17. Wang M, Knight R, Dimopoulos M, et al. Lenalidomide in Combination with 
Dexamethasone Was More Effective Than Dexamethasone in Patients Who Have Received 
Prior Thalidomide for Relapsed or Refractory Multiple Myeloma. ASH Annual Meeting 
Abstracts. 2006;108:3553-. 
18. Rajkumar SV, Jacobus S, Callander N, Fonseca R, Vesole D, Greipp P. A Randomized Phase 
III Trial of Lenalidomide Plus High-Dose Dexamethasone Versus Lenalidomide Plus Low-


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Dose Dexamethasone in Newly Diagnosed Multiple Myeloma (E4A03): A Trial Coordinated 
by the Eastern Cooperative Oncology Group. ASH Annual Meeting Abstracts. 2006;108:799. 
19. Rajkumar SV, Blood E. Lenalidomide and venous thrombosis in multiple myeloma. N Engl J 
Med. 2006;354:2079-2080. 
20. Rajkumar SV. Thalidomide therapy and deep venous thrombosis in multiple myeloma. Mayo 
Clin Proc. 2005;80:1549-1551. 
21. Rajkumar SV, Hayman SR, Lacy MQ, et al. Combination therapy with lenalidomide plus 
dexamethasone (Rev/Dex) for newly diagnosed myeloma 
10. 1182/blood-2005-07-2817. Blood. 2005;106:4050-4053. 
22. Bennett CL, Angelotta C, Yarnold PR, et al. Thalidomide- and lenalidomide-associated 
thromboembolism among patients with cancer. Jama. 2006;296:2558-2560. 
23. Zonder JA, Barlogie B, Durie BGM, et al. Thrombotic complications in patients with newly 
diagnosed multiple myeloma treated with lenalidomide and dexamethasone: benefit of aspirin 
prophylaxis 10.1182/blood-2006-01-0154. Blood. 2006;108:403-404. 
24. Rajkumar SV, Hayman S, Gertz MA, et al. Combination therapy with thalidomide plus 
dexamethasone for newly diagnosed myeloma. J Clin Oncol. 2002;20:4319-4323. 
25. Zangari M, Tricot G, Zeldis J, Eddlemon P, Saghafifar F, Barlogie B. Results of Phase I 
Study of CC-5013 for the Treatment of Multiple Myeloma (MM) Patients Who Relapse after 
High Dose Chemotherapy (HDCT). Blood. 2001:775a (A3226). 
26. Richardson PG, Barlogie B, Berenson J, et al. Extended follow-up of a phase II trial in 
relapsed, refractory multiple myeloma: final time-to-event results from the SUMMIT trial. 
Cancer. 2006;106:1316-1319. 
27. Corral LG, Haslett PA, Muller GW, et al. Differential cytokine modulation and T cell 
activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-
alpha. Journal of Immunology. 1999;163:380-386. 
28. Muller GW, Chen R, Huang SY, et al. Amino-substituted thalidomide analogs: potent 
inhibitors of TNF-alpha production. Bioorganic & Medicinal Chemistry Letters. 
1999;9:1625-1630. 
29. Schey SA, Fields P, Bartlett JB, et al. Phase I Study of an Immunomodulatory Thalidomide 
Analog, CC-4047, in Relapsed or Refractory Multiple Myeloma 10.1200/JCO.2004.10.052. J 
Clin Oncol. 2004;22:3269-3276. 
30. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose 
dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27:5008-5014. 
31. Lacy MQ, Gertz MA, Hayman SR, et al. Pomalidomide (CC4047) Plus Low Dose 
Dexamethasone (Pom/dex) Is Active and Well Tolerated in Lenalidomide Refractory 
Multiple Myeloma (MM). ASH Annual Meeting Abstracts. 2009;114:429-. 
32. Richardson PG, Weller E, Jagannath S, et al. Multicenter, phase I, dose-escalation trial of 
lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin 
Oncol. 2009;27:5713-5719. 
33. Richardson P, Siegel D, Baz R, et al. A Phase 1/2 Multi-Center, Randomized, Open Label 
Dose Escalation Study to Determine the Maximum Tolerated Dose, Safety, and Efficacy of 
Pomalidomide Alone or in Combination with Low-Dose Dexamethasone in Patients with 
Relapsed and Refractory Multiple Myeloma Who Have Received Prior Treatment That 
Includes Lenalidomide and Bortezomib. ASH Annual Meeting Abstracts. 2009;114:301. 
34. Fleming TR: One sample multiple testing procedures for phase II clinical trials. Biometrics 
38:143-151, 1982. 
35. Duffy D, Santner T: Confidence intervals for a binomial parameter based on multistage tests. 
Biometrics 43:81- 93, 1987. 
36. Kaplan E, Meier P: Nonparametric estimation for incomplete observations. J Am Stat Assoc 
53:457-481, 1958. 


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37. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, Blade  J, 
Richardson P, Orlowski R, Siegel D, Jagannath S, Facon T, Avet-Loiseau H, Lonial S, 
Palumbo A, Zonder J, Ludwig H, Vesole D, Sezer O, Munshi NC, San Miguel J; 
International Myeloma Workshop Consensus Panel 1. Consensus recommendations for the 
uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus 
Panel 1. Blood. 2011 May 5;117(18):4691-5. 
 
 


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Model Consent Form 
 
*NOTES FOR LOCAL INVESTIGATORS: The goal of the informed consent process is to provide 
people with sufficient information for making informed choices.   The informed consent form 
provides a summary of the clinical study and the individual's rights as a research participant.  It 
serves as a starting point for the necessary exchange of information between the investigator and 
potential research participant.  This template for the informed consent form is only one part of the 
larger process of informed consent. For more information about informed consent, review the 
"Recommendations for the Development of Informed Consent Documents for Cancer Clinical 
Trials" prepared by the Comprehensive Working Group on Informed Consent in Cancer Clinical 
Trials for the National Cancer Institute.  The Web site address for this document is 
http://cancer.gov/clinicaltrials/understanding/simplification-of-informed-consent-docs/ 
• 
A blank line, __________, indicates that the local investigator should provide the appropriate 
information before the document is reviewed with the prospective research participant.  
• 
Suggestion for Local Investigators:  An NCI pamphlet explaining clinical trials is available for 
your patients.  The pamphlet is entitled: "If You Have Cancer…What You Should Know about 
Clinical Trials".  This pamphlet may be ordered on the NCI Web site at 
https://cissecure.nci.nih.gov/ncipubs/ or call 1-800-4-CANCER (1-800-422-6237) to request a 
free copy.  
• 
Optional feature for Local Investigators: Reference and attach drug sheets, pharmaceutical 
information for the public, or other material on risks.  Check with your local IRB regarding 
review of additional materials. 
 
*These notes for {authors and} investigators are instructional and should not be included in the informed 
consent form given to the prospective research participant. 


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1. General Information About This Research 
Study  
Study Title:  MC1082, “A Phase I/II Trial of Pomalidomide (CC-4047), Bortezomib, and 
Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma” 
 
 
Name of Principal Investigator on this Study: [investigator’s name(s)] and Colleagues 
 
A.  Study Eligibility and Purpose 
 
You are being asked to take part in this research study because you have multiple myeloma that has 
recurred or not responded to treatment. 
 
This study is divided into 2 phases. The Phase I part will find the best dose of bortezomib that can be used 
in combination with pomalidomide and dexamethasone in patients with multiple myeloma. The Phase II 
part will further study the dose that is determined to be the best in Phase I and will study how effective 
the treatment is against multiple myeloma.  
 
As you read this form describing the study, ask any questions you have.  Take your time to decide.  Feel 
free to discuss the study with your family, friends, and healthcare provider before you decide.  If you 
decide to participate, you may stop participating at any time during the study.  You may decide not to 
participate.  If so, none of your current benefits or normal health care will be affected in any way.  When 
you feel comfortable that all your questions have been answered, and you wish to take part in this study, 
sign this form in order to begin your participation.  If you are agreeing for someone else, you need to sign 
this form. Your signature means you have been told about the study and what the risks are. Your signature 
on this form also means that you want yourself to take part in this study.  
 
B.  Number of Participants 
 
The plan is to have 54 people take part in this study at Mayo Clinic, Dana Farber, and the University of 
Chicago.  
 
C.  Additional Information You Should Know 
 
Celgene is funding the study.  Celgene will pay your study doctor or the institution to cover costs related 
to running the study.  
 
2. What Will Happen To You While You Are In 
This Research Study? 
 
If you agree to be in the study, you will be asked to participate in the following:  
 


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On your first visit you will have tests done to evaluate your myeloma.  These include routine blood and 
urine tests, routine bone marrow aspirate and biopsy (a large needle will be inserted into your hip to 
remove some bone marrow and small sample of bone tissue), a complete set of bone x-rays, and a chest x-
ray.  Your doctor will ask you questions about your medical history and examine you.  If you are a 
woman who can have children, you will be required to have a negative pregnancy test 10 – 14 days prior 
to and again 24 hours before starting therapy.  The pregnancy tests must be negative for you to start 
treatment. 
 
If you are eligible and agree to participate, you will begin treatment.   Twenty-eight days will be 
considered one cycle of treatment. During each cycle you will take pomalidomide in capsules at about the 
same time on days 1-21.  You will also take dexamethasone, a steroid pill, once a week on days 1, 8, 15 
and 22 of each cycle.  You will also get bortezomib by intravenous infusion (through a vein in your arm) 
on days 1, 8, 15 and 22. You will also take aspirin daily, unless you can not tolerate aspirin, and then an 
alternative medication may be given. You will be asked to keep a diary to record when you take your oral 
medication.   
 
Swallow pomalidomide capsules whole. Do not break, chew or open the capsules.  Pomalidomide should 
be taken without food, at least 2 hours before or 2 hours after a meal.  If you miss a dose of 
pomalidomide, it should be taken as soon as possible on the same day.  If you miss taking your dose of 
pomalidomide for the entire day, it should not be made up.  If you take more than your prescribed dose of 
pomalidomide, you should seek emergency medical care if needed and contact study staff immediately. 
 
For the first cycle of treatment, you will need to receive all doses of bortezomib at [Insert local institution 
name].  You will need to return to [Insert local institution name] every month for a re-evaluation 
before receiving your next cycle of treatment.  If your doctor feels you are tolerating treatment well you 
may be able to receive days 8, 15, and 22 of bortezomib from your local physician.  You will be asked to 
return your diary, empty pill bottle or any remaining capsules at the end of each cycle.   
 
In order to obtain pomalidomide free of charge from Celgene, your name, address, phone, date of birth 
and the fact that you are participating in this trial will be Celgene and its agents or vendors that supply 
pomalidomide and administer the POMALYST REMS™ program. By signing this consent form you 
agree to this disclosure. 
 
 


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Below is a table that shows the procedures and study visits: 
Before study enrollment 
 
• 
Routine blood and urine tests and exams 
• 
Bone marrow biopsy and aspirate (removal of 
bone marrow with a needle and syringe). 
OPTIONAL: A portion of the bone marrow 
aspirate will be collected for research tests if 
you agree. 
• 
Bone x-rays 
• 
Chest x-ray 
• 
Pregnancy test 10 – 14 days and again 24 
hours before starting treatment (only for 
females who may still become pregnant) 
• 
OPTIONAL: Research blood collection 
(about 2 tablespoons) 
• 
ECG (Electrocardiogram-a measurement of 
your heart’s electrical activity) 
Weekly for the first two months (may be 
done at home and sent to your doctor at 
Mayo) 
 
• 
Pregnancy test (only for females who may 
still become pregnant) will be done weekly 
for the first month and then monthly for 
women with regular menstruation and every 
two weeks for women with irregular 
menstruation 
• 
Routine blood work including complete 
blood count 
Every month during study  
 
• 
Routine blood and urine tests and exams 
• 
Pregnancy test (only for females who may 
still become pregnant) 
• 
Check for side effects 
• 
OPTIONAL: Research blood collection 
(about 2 tablespoons) for the first 4 cycles.  If 
you had a sample collected at the time you 
enrolled you will not have to have the Cycle 1 
sample collected.  
Every 3 months 
 
• 
Disease assessment (includes blood tests, 
may include 24 hour urine collection) 
• 
Physical Exam 
• 
ECG 
• 
Bone x-ray (every 12 months while on 
treatment) 
• 
Bone marrow biopsy and aspirate after 3 
cycles.  This may be repeated  if your doctor 
determines this is needed to see if your 
disease has responded to treatment or gotten 
worse. OPTIONAL: A portion of the bone 
marrow aspirate will be collected for research 
tests if you agree. 
 


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One month after discontinuing study 
• 
Pregnancy test (only for females who may 
still become pregnant) – women with 
irregular menstruation will have a pregnancy 
tests 14 day and 28 days after discontinuing 
study 
I agree to have a portion of my bone marrow aspirate sample used for research testing at the timepoints 
described in the table above: 
 
  Yes 
  No  
Please initial here:________ 
Date: _________ 
 
I agree to the have my blood collected and used for research testing at the timepoints described in the table 
above: 
 
  Yes 
  No  
Please initial here:________ 
Date: _________ 
 
The drug used in this study is considered investigational, which means it has either not been approved by 
the Food and Drug Administration (FDA) for routine clinical use or for the use described in this study.  
However the FDA has allowed the use of this drug/device in this research study. 
 
3. How Long Will You Be in This Research 
Study? 
 
You will receive up to 8 cycles of treatment with pomalidomide, bortezomib and dexamethasone.  After 8 
cycles of treatment you will continue to take pomalidomide maintenance treatment until your disease gets 
worse, you experience a bad side effect, or you decide not to continue treatment.  After you have 
completed treatment will followed every 6 months until your disease progresses or you begin another 
treatment. 
 
4. Why You Might Want To Take Part In This 
Research Study 
 
This study may not make your health better.    However, this is the newest in a class of medicines that 
have been used successfully for myeloma.  There is a chance this medicine combination may improve or 
stabilize your myeloma and information learned from this study may help other patients with myeloma in 
the future. 
 
5. What Are the Risks Of This Research Study? 
 
Pomalidomide 
 
Likely risks of pomalidomide (events occurring greater than 20% of the time) 
• 
A low number of white blood cells, which are the infection fighting cells, which could put you 
are risk for infection (Neutropenia or Leukopenia) 


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• 
A low number of a particular white blood cell, which is important to the immune system 
(Lymphopenia) 
• 
Feeling tired (Fatigue) 
• 
Difficulty passing stool (Constipation) 
• Feeling sick to your stomach (Nausea) 
• Decreased number of blood cells (platelets) that help to clot the blood (which could put 
you at increased risk of bleeding (Thrombocytopenia) 
• Decrease in red blood cells, which are the oxygen carrying cells, which could make you 
feel tired (Anemia) 
• Back pain 
• Shortness of breath 
• Loose stools (Diarrhea) 
 
Less likely risks of pomalidomide (events occurring less than or equal to 20% of the time) 
• 
When CC-4047 or related drugs (i.e. thalidomide and lenalidomide) have been used along with 
cortico steroids and certain other chemotherapy drugs, there has been an increased risk of 
individuals developing blood clots.  Your doctor may request or require that you take aspirin or 
another blood thinner in this situation. 
• 
Abdominal pain 
• 
Sore mouth or throat 
• 
Numbness, tingling, or inflammation of the nerves (usually in the hands and feet), which may be 
painful.(peripheral neuropathy) 
• 
Drop in blood pressure or dizziness 
• 
Headache 
• 
Chest pain 
• 
Swelling of the hands and feet 
• 
Tremors 
• 
Fever (Pyrexia) 
• 
Infections including potentially life threatening infections 
• 
Muscle aches or cramps 
• 
Muscle weakness 
• 
Joint swelling or achiness 
• 
Dry or itchy skin 
• 
Blushing or redness to face (Flushing) 
• 
Decreased function of the thyroid gland, which can result in feeling tired and weight gain, that 
may first show up as an increased levels of thyroid stimulating hormone (hypothyroidism) If your 
thyroid function becomes abnormal, your doctor may have you take a thyroid replacement pill 
daily. 
• 
Dizziness (Vertigo) 
• 
Difficulty emptying the bladder (Urinary retention) 
• 
Pelvic pain 
• Rash 
• Cough 
• Vomiting 
• Reduced appetite   
• Decreased sodium levels in the blood (Hyponatremia) 
• Abnormally high calcium in the blood stream, that can result in fatigue, confusion, 
feeling sick to your stomach, throwing up, difficulty passing stool, abnormal heartbeat, 
coma, and death (Hypercalcemia) 
• Abnormally low calcium in the blood stream, that can result in muscle cramps, 


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abdominal cramps, spasms (Hypocalcemia) 
• Abnormal levels of potassium in the blood (Hyper or Hypokalemia) 
•  Weakness or lack of energy (Asthenia) 
• Death 
• Kidney failure (Renal failure) 
• Excessive sweating (Hyperhidrosis) 
• High blood sugar (Hyperglycemia) 
 
Rare but serious risks of pomalidomide (events occurring less than 2-3% of the time) 
• 
Chest wall pain 
• 
Blood clot in a vein (deep venous thrombosis) 
• 
Blood clots in the lungs which could be life threatening or cause death (pulmonary embolism) 
• 
Inability of the heart to properly pump blood to the lungs (Right ventricular failure) 
• 
Bleeding from the stomach large intestine and/or small intestine (Gastrointestinal bleeding) 
• 
Narrowing of the stomach or intestines (Gastrointestinal stenosis) 
• 
Chest pain that occurs when your heart doesn't get enough oxygen. It can be a warning sign of a 
heart attack (Angina unstable) 
• 
An irregular heartbeat that results from the top/upper chambers of the heart “quivering” instead of 
beating normally. (Atrial Fibrillation) 
• 
Fast heart rate (Tachycardia) or slow heart rate (Bradycardia) 
• 
Decrease in the ability of the heart to pump blood, because of weakening of the heart muscle 
(congestive heart failure) 
• 
Lack of oxygen to the heart muscle which can cause damage to the heart (Heart attack) ) 
• 
Feeling like your heart is “fluttering or skipping” (Heart palpitations) 
• 
Bleeding in the brain (Cerebral Hemorrhage) 
• 
Lack of oxygen to the brain caused by either bleeding in the brain or blood clot. Also called a 
stroke.(Cerebral vascular accident) 
• 
Memory impairment 
• 
Blood creatinine increased 
• 
Excessive or abnormal loss of body fluids (Dehydration) 
• 
Failure to thrive 
• 
Anxiety 
• 
Confusion 
• 
Feeling sad or blue (Depression)  
• 
Difficulty falling or staying asleep (Insomnia) 
• 
Changes in mood 
• 
Kidney stones (Nephrolithiasis) 
• 
Collection of fluid in the space around the lung (Pleural Effusion) 
• 
Inability of the lungs to function properly (Respiratory failure) 
• 
High blood pressure (Hypertension) or low blood pressure (Hypotension) 
• 
Acute inflammation of the liver including hepatitis and possible jaundice 
• 
Inflammation of the lungs (Interstitial lung disease) 
• 
Possible second cancer with prolonged use 
• 
Blurred vision 
• 
Decreased level of phosphorus in the blood (Hypophosphatemia) 
• 
Decreased albumin in the blood (Hypoalbuminemia) 
• 
Low levels of magnesium in the blood (Hypomagnesemia) 
• 
Night sweats 
• 
Changes in the voice or hoarseness (Dysphonia) 


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• 
Nose bleed (Epistaxis) 
• 
Very Sleepy, difficulty arousing (Lethargy) 
• 
Fainting (Syncope) 
• 
Excessive sleepiness (Somnolence/Depressed level of consciousness) 
• 
Change in taste sensation (Dysgeusia) 
• 
Dry mouth 
• 
Chills 
• Recurrent areas of skin or mucosal swelling of sudden onset, usually disappearing within 
24 hours; an allergic reaction to the medication (Angioedema) an exaggerated or 
inappropriate immune response (hypersensitivity) to Pomalidomide. 
 
ANIMAL STUDIES 
In an animal study, one monkey developed acute myelogenous leukemia (AML) after receiving high 
doses of pomalidomide for several months.  The cause of the leukemia is still being investigated and the 
risk of this animal finding to human subjects is unknown.   
 
Bortezomib 
 
Likely risks of Bortezomib (events occurring greater than 20% of the time) 
•  Decreased number of blood cells (platelets) that help to clot the blood (which could put you at 
increased risk of bleeding)(Thrombocytopenia) 
• Decrease in red blood cells, which are the oxygen carrying cells, which could make you feel tired 
(Anemia) 
• Fever (Pyrexia) 
• Severe shaking chills (Rigors) 
• Difficulty passing stool (Constipation) 
• Loose stools (Diarrhea) 
• Feeling sick to your stomach (Nausea) 
• Throwing up (Vomiting) 
• Loss of appetite not feeling hungry (Anorexia) 
• Excessive or abnormal loss of body fluids (Dehydration) 
• Weight loss 
• Generalized weakness and loss of strength  (Asthenia)  
• Headache 
• Difficulty falling or staying asleep (Insomnia)  
• Cough 
• Shortness of breath or difficulty breathing (Dyspnea) 
• Numbness, tingling, or inflammation of the nerves, which may be painful or increase your tendency to 
trip or fall. (Neuropathy), which may not get better after discontinuation of this drug. Uncommonly the 
nerves that control things like your heart rate, gut movement, and urinary bladder may be affected. 
• Back pain 
• Swelling in the arms and legs (Edema) 
• Infections, including bladder and/or kidney (urinary tract infection), lungs (for example, bronchitis or 
pneumonia), and blood stream (bacteremia), etc. 
• Rash with itching and redness. 
 
Less likely risks of Bortezomib (occurring greater than 3% and less than 20% of the time): 
• Decreased white blood cells, which are the infection fighting cells, which could put you at risk for 
infection (Leukopenia) 


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• Muscle pain (Myalgia) 
• Joint pain (Arthralgia)  
• Low blood pressure (Hypotension)  
• A painful blistery red rash that is confined to one side of the body, similar to chicken pox (herpes 
zoster) or blisters in the nose, mouth, genitals or elsewhere on the skin, caused by the herpes virus 
(herpes simplex virus) 
• Decrease in kidney function  
• Decrease in the ability of the heart to pump blood, because of weakening of the heart muscle 
(Congestive heart failure) 
• A cluster of signs and symptoms (including but not limited to) chest pain, shortness of breath, 
sweating, feeling sick to your stomach, and/or throwing up, seen when there is a reduced amount of 
blood being supplied to the heart muscle (Acute coronary syndrome) 
• Fever, aching joints (Flu-like-syndrome) 
• Sore throat (Pharyngitis) 
• Cold symptoms, such as runny or stuffy nose (Rhinitis) 
• Abnormal Liver function tests which may indicate that your liver is not functioning properly 
• Certain kind of infection of the liver which causes inflammation and can cause liver damage 
(Hepatitis) 
• Changes in blood sugar have been reported in a few diabetic patients receiving oral anti-diabetic 
medication.  If you are taking oral antidiabetic agents you may require close monitoring of your blood 
sugar levels 
• Decreased sodium levels in the blood (Hyponatremia)  
• Low potassium levels in the blood (Hypokalemia)  
• Abnormally high calcium in the blood stream, that can result in fatigue, confusion, feeling sick to your 
stomach, throwing up, difficulty passing stool, abnormal heartbeat, coma, and death (Hypercalcemia) 
• Infection around the eye, also called pink eye  (Conjunctivitis) 
• Inflammation and/or sores in the mouth that may make swallowing difficult and are painful  
(Mucositis) 
• Heartburn (Dyspepsia) 
• Abdominal pain 
• Nose bleeds (Epistaxis) 
• Infection that has spread to the bloodstream and can cause low blood pressure, fever, and/or death 
(Sepsis) 
• Confusion and feeling anxious 
• Blurred vision 
• An uncommon risk, severe rash which causes blistering and peeling of the skin (Steven Johnson 
Syndrome) 
• Inflammation/infection of the lungs (Pneumonitis/Pneumonia) 
• Yeast (fungal) infection of the mouth and throat (Thrush/oral candidiasis)  
• Fungal infection of the skin (Tinea corporis) 
• Fungal infection of the nails (Onychomycosis)  
• Change in taste sensation (Dysgeusia) 
• Blood in the urine (Hematuria) 
• Painful swallowing (Odynophagia) 
• Decreased protein in blood 
• Muscle weakness 
• Increased blood pressure (hypertension) 
 
Rare but serious events of Bortezomib (occurring less then 3% of the time): 


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• Severe bleeding, including bleeding from the stomach, large intestine and/or small intestine 
(gastrointestinal bleeding).  Your doctor may recommend preventative platelet transfusions to reduce 
the risk of bleeding 
• Inability of the intestines to pass food and drink normally (Ileus)  
• Blockage in the intestines (Bowel obstruction) 
• Inflammation of the intestines (Colitis) 
• Inflammation of the pancreas (Pancreatitis) 
• Inflammation of the stomach (Gastritis) 
• Irritation and infection at site of injection 
• Bleeding in the brain (Intracranial hemorrhage) 
• Bleeding in the brain between the skull and the brain (Subarachnoid hemorrhage) 
• Fluid buildup in the lungs (Pulmonary edema) 
• A medical condition related to leakiness of the blood vessels in the brain (RPLS can cause confusion, 
blindness, or vision changes, seizures and other symptoms, as well as changes in brain scans). RPLS 
may go away after bortezomib is stopped. In rare cases, it may be potentially life-threatening and may 
have long-term effects on brain function. (Reversible posterior leukoencephalopathy or RPLS) 
• A complication that may occur if the cancer cells die too quickly that includes inappropriate increase 
or decrease of various natural chemicals in the blood stream, called uric acid, phosphorus, potassium, 
creatinine, and calcium). Severe tumor lysis can result in kidney failure and may harm muscle or nerve 
function. (Tumor lysis syndrome) 
• Loss of hearing 
• Severe, life-threatening, or deadly lung diseases of unknown cause which may include inflammation of 
and accumulation of fluid in the lungs which can cause breathing problems and decrease in oxygen 
content of the blood. This problem has been seen most commonly in Japan. Other risk factors for this 
complication include co-administration of a drug called cytarabine and a drug called daunorubicin.  
• Coughing up of blood or blood tinged sputum (Hemoptysis) 
• Infections of the throat, stomach and intestines (gut), skin and at the area of skin where your catheter is 
placed 
• Serious allergic reaction to the medication which can cause hives, itching, shortness of breath, swelling 
of the lips or throat, difficulty breathing , and could be life threatening  (Anaphylactic reaction) 
• Loss of control or weakness in the muscles under voluntary control- such as the arms, legs, or mouth 
(i.e talking), which can make movement of these areas difficult or not possible (Motor neuropathy). 
• Inflammation and/or infection of the lining surrounding the lung which can be painful 
(Pleurisy/pleuritis) 
• Collection of pus around the lungs (Empyema) 
• Changes to the brain that may cause convulsions and confusion or loss of consciousness 
• Abnormal heartbeat (Arrhythmia). These could be life threatening  
• A collection of fluid or blood in the space around the heart  (Pericardial effusion) 
• Rash associated with fever (Acute febrile neutrophilic dermatosis) 
• Herpes infection of the eye, damage to optic nerve and blindness 
• Deterioration in brain function (Progressive multifocal leukoencephalopathy) 
 
Dexamethasone  
 
Likely risks of dexamethasone: 
• 
Stomach and throat ulcers or worsening of any ulcers you had before treatment 
• 
Swelling and pain of the pancreas 
• 
Weight gain around the stomach 
• 
Puffiness (especially in the face) 
• 
Buildup of fluids and a rise in blood pressure 
• 
Possible rise in your blood sugar 
• 
Changes in the blood levels of potassium.   
• 
Infection 


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Less Likely risks of dexamethasone: 
• 
Muscle weakness 
• 
Brittle bones 
• 
Menstrual changes 
• 
Itching, and other allergic reactions, some severe.   
 
Rare but serious risks of dexamethasone: 
• 
Mood swings 
• 
Depression 
• 
Trouble sleeping 
• 
Changes in personality 
• 
Seizures 
• 
Dizziness 
• 
Patients who are more likely to get heart disease may have heart failure 
 
As with any medication, allergic reactions are a possibility.   
 
The risks of drawing blood include pain, bruising, or rarely, infection at the site of the needle stick. 
 
Pregnancy and Birth Control:  
 
1)  Will women of child-bearing-potential (able to become pregnant) be allowed to participate in this 
study? 
 
Yes:  Women of child-bearing-potential will be able to participate in this study if they have a negative 
pregnancy test and agree to use TWO reliable methods of birth control (see #5) or practice complete 
abstinence from heterosexual intercourse 28 days before starting pomalidomide, during treatment 
with pomalidomide, and for at least 28 days after you stop taking pomalidomide, since the risks to an 
unborn child are either unknown or potentially serious. 
 
You will be considered a woman of child bearing potential unless you have had natural absence of 
menstrual periods for the past 24 consecutive months or have had a hysterectomy (the surgical 
removal of the uterus) or have had both ovaries surgically removed.  If there is ANY chance that you 
can become pregnant, you will be considered a woman of child bearing potential. 
 
You agree to inform the investigator immediately if: 1) you have any reason to suspect you are 
pregnant; 2) you find that circumstances have changed and that there is a risk of becoming pregnant; 
or 3) you have stopped using the approved forms of TWO reliable birth control methods. 
 
2)  Will pregnant, and/or nursing women be allowed to participate in this study?  
 
No:  There is not enough medical information to know what the risks might be to a breast-fed 
infant or to an unborn child carried by a woman who takes part in this study.  Breast-feeding 
mothers must stop breast-feeding to take part in this study. 
 
3)  Do you need to have a pregnancy test done to be part of the study?   
 
Yes: As part of this study a pregnancy test is required for all women who are able to become 
pregnant. 
 


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A blood/urine pregnancy test will be done within 10-14 days of starting CC-4047 and again within 24 
hours of starting pomalidomide. For the blood pregnancy test, blood will be taken from your arm. 
 
You will be told the results of the pregnancy test.  If the pregnancy test is positive, you will 
not be able to take part in the study. 
 
You will have pregnancy tests before and during treatment, even if you agree not to have 
reproductive heterosexual intercourse. You will have a pregnancy test done by the doctor 
every week during the first 28 days of this study.  You will then have a pregnancy test every 
28 days during your participation in this study if your menstrual cycles are regular or every 
14 days if your cycles are irregular.  You will also have a pregnancy test if you miss your 
period or have unusual menstrual bleeding.  In addition, you will have pregnancy tests when 
you are discontinued from the study and at day 28 after discontinuation from the study if your 
menstrual cycles are regular.  If your menstrual cycles are irregular, you will have pregnancy 
tests when you are discontinued from the study and at days 14 and 28 after discontinuation 
from the study. 
 
If you have any reason to suspect you are pregnant, you must IMMEDIATELY stop taking 
pomalidomide and tell your doctor.  If you have a positive pregnancy test while participating in this 
study, you must IMMEDIATELY stop taking pomalidomide and tell your doctor.  If you have a 
positive pregnancy test within 28 days after you have stopped participating in the study, you must 
IMMEDIATELY tell your doctor. 
 
Study subjects who become pregnant will be monitored throughout the pregnancy and will continue 
to be monitored for 30 days after delivery (premature delivery, aborted fetus, full-term pregnancy, or 
no longer pregnant). 
 
You must NEVER share pomalidomide (or other study drugs) with someone else. You must NEVER 
donate blood while you are participating in this study and for at least 28 days after you have been 
discontinued from the study. You will be counseled at least every 28 days and at discontinuation from 
the trial about not sharing pomalidomide (and other study drugs), the potential risks of fetal exposure, 
and abstaining from blood and donations. 
 
4)  Will men who are able to father a child be allowed to participate in this study? 
 
Yes: Men who are able to father a child are allowed to take part in this study and must agree 
to use a latex condom every time you have sex with a female of child bearing potential during 
treatment with pomalidomide and for at least 28 days after you stop taking pomalidomide 
even if you have had a vasectomy. 
 
You must NEVER share pomalidomide (or other study drugs) with someone else. You must 
NEVER donate blood, sperm, or semen while you are participating in this study and for at 
least 28 days after you have been discontinued from the study. You will be counseled at least 
every 28 days regarding abstaining from donating blood, sperm, or semen; birth control 
requirements; not sharing pomalidomide (and other study drugs); and the potential risks of 
fetal exposure. 


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5)  What types of birth control are acceptable?  
 
Highly Effective Methods 
 
Intrauterine device (IUD) 
 
Hormonal (birth control pills, injections, implants) 
 
 
Tubal ligation 
 
Partner’s vasectomy 
 
 
Additional Effective Methods 
 
Latex condom 
 
Diaphragm 
 
Cervical cap 
 
Certain drugs interfere with hormonal contraception and may reduce the effectiveness of the 
contraception for up to 30 days after stopping these medications.  These medications include HIV 
protease inhibitors, penicillins, modafinil (Provigil ®), griseofulvin (Fulvicin ®), phenytoin (Dilantin ®), 
carbamazepine (Carbatrol ®, Tegretol ®), rifampin (Rifamycin ®, Rifamate ®, Rifater ®), rifbutin 
(Mycobutin ®), or certain herbal supplements such as St. John’s Wort.  If you are taking any of these 
medications, please notify your doctor.  If you are a female of childbearing potential taking these 
medications you must use two other effective or highly effective methods of contraception. 
 
PREGNANCY  
Pomalidomide was found to cause birth defects in an experimental study in animals.  
Pomalidomide is related to thalidomide.  Thalidomide is known to cause severe life-threatening 
human birth defects. Pomalidomide is therefore considered to have the potential to cause birth 
defects in humans.  If pomalidomide is taken during pregnancy, it may cause birth defects or 
death to an unborn baby.  Females must not become pregnant while taking pomalidomide.  
 
In order to participate in this study you must register into and follow the requirements of 
the POMALYST REMS™ program of Celgene Corporation.  This program provides 
education and counseling on the risks of fetal exposure, blood clots and reduced blood 
counts.  You will be required to receive counseling, follow the pregnancy testing and birth 
control requirements of the program that are appropriate for you and take surveys 
regarding your compliance with the POMALYST REMS™ program.   
 
By signing this consent form you understand and agree to receive counseling and to comply with 
the pregnancy precaution requirements of the POMALYST REMS™ program. 
  
 
Risk summary  
 
Many side effects go away shortly after the pomalidomide, dexamethasone, and bortezomib are stopped, 
but in some cases side effects can be serious, long lasting, or may never go away.  There may be a risk of 
death. 
 
Some side effects may not be known.  Side effects may range from mild to life-threatening. Other drugs 
may be given to make side effects less serious and less uncomfortable.  Talk to the researcher and/or your 
healthcare provider about side effects and ask any other questions. 


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6. What Other Choices Do You Have If You 
Don’t Take Part In This Research Study? 
 
You do not have to be in this study to receive treatment for your condition.  Your other choices may 
include chemotherapy, thalidomide, lenalidomide, corticosteroids, other research studies or supportive 
care.  You should talk to the researcher and your regular physician about each of your choices before you 
decide if you will take part in this study. 
 
7. Are There Reasons You Might Leave This 
Research Study Early? 
 
Taking part in this research study is voluntary.  You may decide to stop at any time.  You should tell the 
researcher if you decide to stop and you will be advised whether any additional tests may need to be done 
for your safety.  
 
In addition, the researchers, Celgene, or Mayo may stop you from taking part in this study at any time: 
o 
if it is in your best clinical interest,  
o 
if you do not follow the study procedures,  
o 
if the study is stopped.  
 
8. Will You Need To Pay For Any Of The Tests 
And Procedures? 
 
You will not need to pay for tests and procedures which are done just for this research study.  These tests 
and procedures are: 
o Study drug (pomalidomide) 
o Research tests done on your blood and bone marrow aspirate sample 
 
However, you and/or your health plan will need to pay for all other tests and procedures that you would 
normally have as part of your regular medical care.  These tests and procedures are: 
o Bortezomib and dexamethasone as well as preparation charges and other drugs or 
treatment given to help control side effects  
o Routine physical exams and blood and urine tests 
o Bone marrow aspirate and biopsy 
o X-ray skeletal survey 
o Chest x-ray 
o Pregnancy tests for women of childbearing potential 
 
If you have study related questions regarding billing, insurance or reimbursement, stop by or call:  
Rochester: Admission and Business Services office, or call Patient Account Services at (507) 287-1819 
 


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Florida: The receptionist at the Registration Desk at the first floor, main lobby of the Davis Building or 
call (904) 953-7058 
 
Arizona:  The concourse level Patient Financial Services office or call this office at 800-603-0558 
 
9. Will You Be Paid For Participating In This 
Research Study? 
 
You will not be paid for taking part in this study. 
 
10. What Happens If You Are Injured Or Ill 
Because You Were In This Research Study? 
 
If you have side effects from the study treatment, you need to report them to the researcher and your 
regular physician, and you will be treated as needed.  Mayo will bill you or your insurer for these services 
at the usual charge.  Mayo will not offer free medical care or payment for any bad side effects from taking 
part in this study. 
 
11. What Are Your Rights If You Are In This 
Research Study? 
 
Taking part in this research study will not change your rights and benefits.  Taking part in this research 
study does not give you any special privileges.  If you decide to not participate in this study, or stop in the 
middle of the study, no benefits are taken away from you.  Specifically, you do not have to be in this 
research study to receive or continue to receive medical care from Mayo Clinic. 
 
You will be told of important new findings or any changes in the study or procedures that may affect you 
or your willingness to continue in the study. 
 
12. What About Your Privacy? 
Your privacy is important to us, and we want to protect it as much as possible.  By signing this form, you 
authorize (name of institution) and the investigators to use and disclose any information created or 
collected in the course of your participation in this research protocol. This information might be in 
different places, including your original medical record, but we will only disclose information that is 
related to this research protocol for the purposes listed below. 
 
This information will be given out for the proper monitoring of the study, checking the accuracy of study 
data, analyzing the study data, and other purposes necessary for the proper conduct and reporting of this 
study. If some of the information is reported in published medical journals or scientific discussions, it will 
be done in a way that does not directly identify you. 
 


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Information Disclosed to Study Supporter 
 
The study data sent by the study doctor to the study supporter does not include your name, address, social 
security number, or other information that directly identifies you.  Instead, the study doctor assigns a code 
number to the study data and may use your initials.  Some study data sent to the sponsor may contain 
information that could be used (perhaps in combination with other information) to identify you (eg, date 
of birth). If you have questions about the specific health information that will be sent to the sponsor, you 
should ask the study doctor. 
 
This information may be given to other researchers in this study, including those at other institutions, 
representatives of the company supplying drug and funding for the study, including representatives in the 
USA or other countries, or private, state or federal government parties or regulatory authorities in the 
USA and other countries responsible for overseeing this research.  These may include the Food and Drug 
Administration, the Office for Human Research Protections, or other offices within the Department of 
Health and Human Services. 
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed by the 
local institution.  The regulations may or may not be included in the informed consent form depending on 
local institutional policy.] 
 
13. What Will Happen to Your Samples? 
 
Your sample of blood and bone marrow will be kept at Mayo for use in this study.  Researchers at Mayo 
who are not involved with this study may ask to use your sample for more research.  You have a say in 
how your stored sample is used in future research.  You can still take part in the treatment study without 
giving your sample for future use.   
 
 
Identification information:  
If you agree to allow your sample to be used for further research, the sample may be stored forever.  The 
sample will be stored at Mayo and would be given a code (instead of your name) while it is stored and 
when it is used in research.  This code allows your sample to be used without anyone knowing that it is 
your sample just by looking at the label. 
 
There is a very small chance that some commercial value may result from the use of your donated sample.  
If that happens, you will not be offered a share in any profits. 
 
Risks: 
Some future studies may be for testing the genes you inherited from your parents (also known as genetic 
testing).  If a researcher finds that future test results may be useful for your health care, you will be 
contacted and given the choice to learn the test results.  At that time, you will be given general 
information on the potential risks, benefits, and costs of choosing to learn the test results.  The risks of 
learning genetic test results may include emotional upset, insurance or job discrimination, and/or family 
conflicts from learning unknown information about your parents or blood relatives.  Test results will only 
be put into your medical record if you chose to learn the results.  Sometimes results should be released 
only through a genetic counselor, who can help explain the possible risks and benefits of learning the 
results. 
 


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Exceptions when your samples may be used without your permission:  
1)  When government rules allow your sample to be used without identifying you, even with a code. 
2)  When use of the sample is not considered human subject research.   
 
At all other times:   
-You can let Mayo use your sample.  
-You can say NO to have your sample used by Mayo. 
 
Please read the following statements and mark your choice: 
 
1.  I permit my sample to be stored and used in future research of multiple myeloma at Mayo: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
2.  I permit my sample to be stored and used in future research at Mayo to learn about, prevent, or 
treat any other health problems: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
Who will use your sample? 
If you agree to give your sample, it will be the property of Mayo and may be used for research by Dr. 
Lacy and other staff at Mayo Clinic.  Researchers at other institutions may also ask for a part of your 
sample for future studies.   
 
How do researchers from other institutions get the sample? 
Researchers from universities, hospitals, and other health organizations conduct research using tissue.  
They may contact Mayo and request samples for their studies.  If you approve release of your sample by 
checking ‘yes’ below, Mayo may send the tissue sample(s) and some information about you to 
researchers who request them, but Mayo will not send your name, address, phone number, social security 
number, or any other identifying information with the sample.  If you allow your sample to be given to 
researchers at other institutions, it will be given to them with a code number rather than your name.  If 
these researchers use the sample for future research and decide that a test result may be useful for your 
health care, they may contact the [Insert local institution name] and [Insert local institution name] would 
then contact you to offer you the choice to learn the test results.  [Insert local institution name] has the 
right to end storage of the sample without telling you. 
 
I permit Mayo to give my sample to researchers at other institutions: 
Please mark one box: 
 
  Yes 
  No  
Please initial here: ________Date: ________ 
 
 
If you want your sample destroyed at any time, write to: 
Secretary of the ______________Institutional Review Board ______________________. 


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14. Who Can Answer Your Questions? 
 
You can call … 
At … 
 If you have questions or 
concerns about … 
Insert site Principal 
Investigator(s) if 
applicable 
Insert study 
coordinator’s name 
(optional) 
Phone:  
 
insert SC’s 
phone # 
Questions about the study tests 
and procedures 
Research-related injuries or 
emergencies 
Any research-related concerns 
or complaints 
 
15. Summary and Enrollment Signatures 
 
You have been asked to take part in a research study, at Mayo Clinic.  The information about this study 
has been provided to you to inform you about this study. 
 
• 
I have read the whole consent form, and all of my questions have been answered to my 
satisfaction. 
 
• 
I am satisfied that I have been given enough information about the purpose, methods, risks, and 
possible benefits of the study to decide if I want to join. 
 
• 
I know that joining the study is voluntary and I agree to join the study. 
 
 
• 
I know that I can call the investigator and research staff at any time with any questions or to tell 
them about side effects. 
 
• 
I know that I may withdraw from the study at any time. 
 
A copy of this form will be put in my medical records and I will be given a copy of this completed 
form. 
 


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Please sign and date to show that you have read all of the above guidelines.  Please do not sign unless you 
have read this entire consent form.  If you do not want to sign, you don’t have to, but if you don’t you 
cannot participate in this research study.  
 
 
______________   
__________________________________________    ________________ 
(Date / Time) 
(Printed Name of Participant) 
(Clinic Number) 
 
 
_____________________________________________ 
(Signature of Participant) 
 
 
______________ 
_______________________________________________ 
(Date / Time) 
(Printed Name of Individual Obtaining Consent) 
 
 
 _______________________________________________ 
(Signature of Individual Obtaining Consent) 
 
 
This model informed consent form has been reviewed by the Mayo Clinic Cancer Center and is the 
official consent document for this study.  Local IRB changes to this document are allowed.  Sections 
“What are the risks of the research study” or “What other choices do I have if I don’t take part in 
this research study?” should always be used in their entirety if possible.  Editorial changes to these 
sections may be made as long as they do not change information or intent.  If the institutional IRB 
insists on making deletions or more substantive modifications to these sections, they must be 
justified in writing by the investigator and approved by the IRB.  Under these circumstances, the 
revised language and justification must be forwarded to the Mayo Clinic Cancer Research Protocol 
Specialist for approval before a patient may be registered to this study. 
 
Consent forms will have to be modified for each institution as it relates to where information may 
be obtained on the conduct of the study or research subject.  This information should be specific for 
each institution. 


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Appendix I:  
ECOG Performance Status Scale 
 
SCORE  
DESCRIPTION  
0  
Fully active, able to carry on all pre-disease performance without 
restriction.  
1  
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, office 
work.  
2  
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.  
3  
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours.  
4  
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair.  
5  
Dead.  
 


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Appendix II 
Mayo Risk Stratification 
 
High Risk 
FISH deletion 17p 
FISH t(4:14) 
FISH t(14:16) 
Metaphase cytogenetic del 13 
Hypodiploidy 
PCLI >3% 
 


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Appendix III  
NYHA Classification 
 
Class I:  
NO Symptoms with ordinary activity  
Class II:  
Symptoms with ordinary activity  
Class III:  Symptoms with minimal activity 
Class IV:  Symptoms at rest 
 
 


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Patient Initials ______________________ 
 
 
 
Study No. MC1082 
Patient ID number ______________ 
Appendix IV:  
MEDICATION DIARY 
 
Please complete this diary on a daily basis. Write in the amount of the dose of pomalidomide, bortezomib, and 
dexamethasone that you took in the appropriate “Day” box.   
 
On the days that you do not take any study drug, please write in “0”. Swallow pomalidomide capsules whole. Do not 
break, chew or open the capsules.  Pomalidomide should be taken without food, at least 2 hours before or 2 hours 
after a meal.  If you miss a dose of pomalidomide, it should be taken as soon as possible on the same day.  If you 
miss taking your dose of pomalidomide for the entire day, it should not be made up, please write in “0”, and 
remember to take your prescribed dose at the next regularly scheduled time. 
 
If you experience any health/medical complaints or take any medication other than pomalidomide, bortezomib, or 
dexamethasone, please record this information. 
 
Week of: _________________________ 
Study Drug 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Dexamethasone 
 
 
 
 
 
 
 
Bortezomib 
 
 
 
 
 
 
 
Pomalidomide 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Dexamethasone 
 
 
 
 
 
 
 
Bortezomib 
 
 
 
 
 
 
 
Pomalidomide 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 15 
Day 16 
Day 17 
Day 18 
Day 19 
Day 20 
Day 21 
Dexamethasone 
 
 
 
 
 
 
 
Bortezomib 
 
 
 
 
 
 
 
Pomalidomide 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
 
Week of: _________________________ 
Study Drug 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Day 27 
Day 28 
Dexamethasone 
 
 
 
 
 
 
 
Bortezomib 
 
 
 
 
 
 
 
Pomalidomide 
 
 
 
 
 
 
 
Aspirin* 
 
 
 
 
 
 
 
*Warfarin or low molecular weight heparin can be substituted in place of Aspirin at MD discretion. Discuss with 
your doctor. 
 
My next scheduled visit is: _______________________________ 
If you have any questions, please call:  ______________________ 
Patient Signature:  _________________________________ Date:  _______________________ 


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Appendix V: Myeloma Tumor Biology Kit 
Specimen Checklist and Shipping Instructions 
 
** PLEASE AVOID DRAWING OR SENDING SPECIMENS ON FRIDAYS AND 
HOLIDAYS** 
 
Kit Contents: 
• 
5 lb Styrofoam box and cardboard mailing sleeve 
• 
Patient Information Form 
• 
7ml ACD (yellow top) collection tubes 
• 
Plasma Cell Labeling Index (PCLI) Kit 
• 
(2) zip lock specimen bags labeled for bone marrow and peripheral blood  
• 
(1) ice pack.  Place the ice pack in the freezer for at least 24 hours prior to specimen shipment.  
Allow the frozen ice pack to thaw at room temperature for 2-3 hours before preparing the 
specimen for shipment. 
 
Packing and Shipping Instructions: 
1. Collect the following specimens: 
 
Peripheral blood - Draw 28 mL of peripheral blood in four ACD tubes  
 
Bone marrow aspirate - Draw 8 mL of a 'redirect' bone marrow aspirate in two ACD tubes 
 
Bone marrow aspirate – Draw 2-3 mL of a ‘redirect’ bone marrow aspirate and place in the 
Plasma Cell Labeling Index tube; process according to kit instructions   
2. Label specimens with the protocol number MC1082, the patient’s initials (last name, first name), date 
of collection, and type of sample (PB, BM). 
 
3. Place the slightly thawed Kool-PAK in bottom of Styrofoam container. 
 
4. Place absorbent toweling on top of Kool-PAK. 
 
5. Place specimens in their individual plastic bags provided, wrap in paper toweling and place them in 
the Styrofoam container and close the lid.  Do not place the specimen(s) directly on the ice pack. 
 
6. Place the Styrofoam container and the completed Patient Information Form within the cardboard 
mailing sleeve. 
 
7. Prepare the package for shipping, applying packing tape as needed.  Ship specimens Fed Ex priority 
overnight delivery the same day collected. 
 
8. Notify Federal Express for pick-up and/or leave package at the designated FedEx drop-off location. 
Please call 
 or e-mail 
 to notify the 
Mayo Clinic Myeloma Reference Laboratory when specimen(s) are being shipped.  The samples in 
prepared kits should be shipped to the following: 
 
 
Mayo Clinic Myeloma Reference Laboratory 
 
200 First Street Southwest 
Rochester, MN  55905 


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Patient Information Form 
 
Specimen Date:      /        /           
Institution/Affiliate:                 
Physician:                             
Patient Initials (last name, first name):                 
Hospital ID or Social Security #:  
Study Number #: MC1082                                                                                             
 
 
Contact Person:                                                                                                            
Institution:                                                                                                            
Address:  
 City                                           State                  Zip 
Phone #:                                                                                                            
FAX #:  
 
 
Please circle the time-point being shipped at this time: 
Peripheral Blood  
1. On-Study 
2. Start of cycle 1/ 2/ 3/ 4 (sample at start of cycle 1 not needed if sample at on study was already 
collected). 
 
Bone Marrow 
1. On-Study 
2. After 3 cycles 
3. Marrow to assess disease response or document CR 
4. Other 
 
Any questions concerning these samples or to obtain a Myeloma Tumor Biology Kit, please contact: 
 
Affiliates who anticipate participating in this study should please call in advance for kits