Tandem High-Dose Therapy With Melphalan and Total Marrow Irradiation (TMI) With Peripheral Blood Progenitor Cell Support and Lenalidomide Maintenance in Multiple Myeloma: A Phase I/II Trial
Phase: PHASE1
Conditions: Refractory Multiple Myeloma, Smoldering Multiple Myeloma, Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma
Sponsor: City of Hope Medical Center

 
IRB # 04064 
 
11/10/2017 
Version: 17 
CITY OF HOPE  
1500 E. DUARTE ROAD, DUARTE, CA 91010 
 
DIVISION of HEMATOLOGY & HCT and RADIATION ONCOLOGY 
 
TITLE:  
Tandem High-Dose Therapy with Melphalan and Total Marrow Irradiation (TMI) with 
Peripheral Blood Progenitor Cell Support and Lenalidomide Maintenance in Multiple 
Myeloma: A Phase I/II Trial  
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 04064  
 
 
VERSION: 17 
 
DATE(S)/ OF AMENDMENT(S)/REVISION(S): 
 
Initial Review 
Protocol dated 5/7/04 
Version 00 
Initial Approval 
Protocol dated 10/4/04 
Version  00 
COH Amendment 1 
Protocol dated 2/7/05 
Version 01  
COH Amendment 2 
Protocol dated 7/18/05 
Version 02 
COH Amendment 3 
Protocol dated 10/21/05 
Version 03  
COH Amendment 4 
Protocol dated 2/14/06 
Version 04 
COH Amendment 5 
Protocol dated 8/8/07 
Version 05 
COH Amendment 6 
Protocol dated 8/8/07 
Version 06 
COH Amendment 7 
Protocol dated 3/19/08 
Version 07 
COH Amendment 8 
Protocol dated 7/17/08 
Version 08 
COH Amendment 9 
Protocol dated 4/01/09 
Version 09  
COH Amendment 10 
Protocol dated 12/11/09 
Version 10 
COH Amendment 11 
Protocol dated 06/08/10 
Version 11 
COH Amendment 12 
Protocol dated 10/06/11 
Version 12 
COH Amendment 13 
Personnel Change only 8/15/12 
Version 13 
COH Amendment 14 
Personnel Change only 12/19/12 
Version 14 
COH Amendment 15 
Personnel Change only 02/18/13 
Version 15 
COH Amendment 16 
Personnel Change only 01/28/14 
Version 16 
COH Amendment 17 at Continuation 
Personnel Change only 11/10/17 
 
       Version 17 
DISEASE SITE: 
Bone Marrow 
HISTOLOGY: 
Myeloma 
 
 
 
 
 
 
 
STAGE (If applicable): 
I-III 
 
 
MODALITY(IES): 
Chemotherapy and radiation therapy/Stem cell transplant 
TYPE (e.g., Pilot, Phase I): 
Phase I/II 
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR: 
George Somlo, M.D. 
 
 
 
 
COLLABORATING INVESTIGATOR(S): 
Jeffrey Wong MD, Stephen Forman MD, Amrita Krishnan MD, Chatchada 
 
Karanes MD, Leslie Popplewell MD, Firoozeh Sahebi MD, Pablo Parker MD, 
Paul Frankel MD 
 
 
 
 
PARTICIPATING CLINICIANS: 
Hematology:  Warren Chow MD, Neil Kogut MD,  
Auayporn 
Nademanee MD, Ryotaro Nakamura MD,  
 
 
Margaret O’Donnell MD,  
 
Ricardo Spielberger MD, Anthony Stein MD, Ji-Lian Cai MD, Len Farol MD, 
Robert Chen MD, Tanya Siddiqi MD, Samer Khaled MD. Nitya Nathwani, 
MD, Ahmed Aribi, MD, Michael Rosenzweig, MD. 
 
 
Radiation Oncology:  Yi-Jen Chen MD, An Liu PhD, Nayana Vora MD, 
Eric Radany MD 
 

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TABLE OF CONTENTS 
 
 
 
SCHEMA 
 
1.0  
OBJECTIVES 
 
2.0  
BACKGROUND AND RATIONALE 
 
3.0  
THERAPEUTIC AGENTS 
 
4.0 
STAGING CRITERIA  
 
 
 
 
 
 
 
 
5.0 
PATIENT ELIGIBILITY 
 
6.0 
TREATMENT PLAN 
 
7.0 
EVALUATION AND TOXICITIES 
 
8.0 
STUDY PARAMETERS 
 
9.0  
EVALUATION AND RESPONSE 
 
10.0 
REPORTING DATA 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
12.0 
MINORITIES AND WOMEN STATEMENT 
 
13.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
14.0 
DATA AND SAFETY MONITORING  
 
15.0 
BIBLIOGRAPHY 
 
 

 
SCHEMA
 
 
PRIMING and APHERESIS  
 
CYCLOPHOSPHAMIDE 1.5-g/m2 and FILGRASTIM 10 µg/kg/day 
 
CYCLE 1                                       
 
DAY –2 
Hydration 6 hours; MELPHALAN 100 mg/m2 IV 
 
 
2/14/06 
DAY –1 
MELPHALAN 100 mg/m2 IV 
 
DAY  0 
REINFUSION OF PERIPHERAL BLOOD PROGENITOR CELLS (PBPC) 
 
 
    
DAY  5 
START FILGRASTIM 5 µg/kg/day, IV 
 
CYCLE 2 
START TOTAL MARROW IRRADIATION (TMI) AT LEAST 6 WEEKS 
FROM DAY 1 and NOT BEYOND 18 WEEKS           
 
DAY  - 6 
200 cGy /D    to 200 cGy  BID 
DAY  - 5 
200 cGy /D    to  200 cGy BID
03/19/08
DAY  - 4 
200 cGy /D    to  200 cGy BID   
- 3 
200 cGy /D    to  200 cGy BID 
- 2 
200 cGy /D    to  200 cGy BID 
- 1 
200 cGy /D    to  200 cGy BID 
 
DAY 0 
Reinfusion of PBPC 
 
2/14/06
DAY 0 
START FILGRASTIM 5 µg/kg/day, IV 
 
STARTING WITHIN 6-8 WEEKS OF DAY ZERO OF CYCLE 2, (except for the patients with 
slow recovery after cycle 2, who need more time)LENALIDOMIDE 10 MG/D WILL BE 
ADMINISTERED ORALLY  
2/14/06
 
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1.0 
OBJECTIVES 
 
1.1 
PRIMARY OBJECTIVES 
 
 
 
1.1.1  To assess the feasibility and toxicities of tandem cycle ablative therapy 
consisting first of high-dose melphalan and then escalating doses of 
fractionated total marrow irradiation (TMI) using helical tomotherapy in 
patients with advanced multiple myeloma.  To establish the maximum 
tolerated dose of TMI using helical tomotherapy. 
 
1.1.2 To assess response rate, progression free and over-all survival following 
treatment with tandem cycle ablative therapy consisting first of high-dose 
melphalan and then escalating doses of TMI using helical tomotherapy 
with Dexamethasone/Thalidomide maintenance therapy in patients with 
advanced multiple myeloma. 
 
1.1.3 To assess the feasibility of adding decadron and thalidomide as 
maintenance following the second cycle of high-dose therapy. 
 
1.2 
SECONDARY OBJECTIVES 
 
1.2.1 To perform cytogenetic, gene rearrangement, and fluorescence in situ 
hybridization (FISH) studies on baseline and post-treatment bone marrow 
and blood specimens and correlate the presence/persistence of these 
features with treatment outcome. 
 
1.2.2 To bank/develop cell lines developed for future investigations of tumor 
biology, and for potential assessment of efficacy of novel therapeutic 
agents. 
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1 
The incidence of multiple myeloma (MM) has been on the rise with an estimated 
15,000 new cases being predicted in 2004, accounting for approximately 13% of 
all hematological malignancies (1).  The entire spectrum of plasma cell dyscrasias 
affects an even greater percentage of the population.  These diseases include 
benign gammopathy, macroglobulinemia, solitary plasmacytoma and, within the 
category of MM, smoldering and indolent forms as well as immunoblastic 
lymphoma and plasma cell leukemia (2).  Adverse prognostic factors such as high 
plasma cell labeling index, elevated beta-2 microglobulin, low albumin at 
diagnosis, the presence of specific chromosomal abnormalities, plasmablastic 
morphology and abnormal renal function, poor performance status at diagnosis 
and elevated serum levels of interleukin-6 are of grave clinical significance (3-6). 
Chemotherapy with melphalan and prednisone, a combination of alkylating 
agents, or vincristine, doxorubicin and dexamethasone is effective in 50-70% of 
patients with newly diagnosed MM; however, less than 10% of patients will 
achieve complete remission (7,8).  Unfortunately, the effects of chemotherapy are 

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usually short lasting. This lack of long-term effectiveness is due to either primary, 
or acquired resistance.  Attempts to improve overall response and response 
duration have been focusing on overcoming drug resistance due to over 
expression of the MDR-1 gene product (9), or utilizing myeloablative therapy 
followed by allogeneic, or autologous bone marrow, or peripheral blood 
progenitor cell rescue (PBPC) (10).  There has been a statistically significant but 
moderate trend with improved 5-year relative survival rates ranging from 24 
months to 31 months, when comparing patients treated from 1974-76, 1983-85, 
and 1992 through 1999 (1). While recent incorporation of both older, 
rediscovered agents (thalidomide), and newly developed classes of drugs 
(bortezomib) have contributed to our ability to better control the myelomatous 
process both as initial and salvage therapy, the long-term impact of these and 
other agents under development is still unknown (11,12). 
 
 
2.2 
High-dose chemo-/radiotherapy in the treatment of MM. 
 
 
 
Single agent high-dose melphalan therapy results in response rates of > 80% with 
complete response rates of >30% as described in earlier studies, but pancytopenia-
related toxicities without the use of stem cell support are substantial.   In an 
update, 1/3 of the patients from an early cohort treated with high-dose melphalan 
were reported to be alive at 9 years (13).  Thousands of patients with multiple 
myeloma have received dose-intense bone marrow ablative therapy followed by 
autologous bone marrow, or peripheral stem cell rescue. Following such 
interventions, increased complete remission rates have been reported in selected 
cohorts of patients with good performance status and already limited tumor 
burden at the time of initiating high-dose therapy (10).  Induction regimens 
consisting of total body radiation with cyclophosphamide or melphalan, 
melphalan alone, or combination chemotherapy, have resulted in similar outcome 
(14-17). A prospective randomized study comparing high-dose consolidation 
therapy and stem cell rescue following induction therapy vs. conventional 
chemotherapy alone, yielded higher complete response rates (22% versus 5%) and 
improved progression-free and overall survival following high-dose therapy; 
projected 5 year event-free and overall survivals were 28% and 52% versus 10% 
and 12%, thereby establishing the role of high-dose chemotherapy as standard, for 
patients with multiple myeloma (18). A second trial yielded similar results, with a 
median survival of 54 months versus 42 months favoring outcome for patients 
treated with high-dose chemotherapy (19).  Comparison of early vs. late (at the 
time of progression) autologous transplant favors early high-dose therapy, 
resulting in prolonged progression-free survival and better quality of life (20). 
Tandem cycle high-dose chemo/radiotherapy in the setting of “total therapy” in 
the largest series by a single institution suggested additional benefit associated 
with the second transplant in a series of 231 patients, independent of the presence 
of unfavorable cytogenetics and elevated beta 2 microglobulin; with a median 
follow-up of 4.2 years among surviving patients actuarial 5-year event-free and 
overall survivals were 58% and 42%, respectively (4).  More recently, a 
prospective randomized trial of tandem cycle high-dose therapy consisting of 
melphalan 140 mg/m2 first, followed by melphalan 140 mg/m2 and total body 

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irradiation with 8 Gy versus single cycle high-dose melphalan 140 mg/m2 and 
total body irradiation with 8 Gy resulted in a 20% probability of 7-year event-free 
survival versus 10% (21).    
 
 
 
Allogeneic bone marrow transplantation has resulted in a disappointing median 
overall survival of 13 months as described in a registry review by the European 
Group for Blood and Bone Marrow Transplantation, with approximately 40% 
early, treatment-related mortality (22).   More recent data suggest diminished early 
mortality rates possible due to incorporation of PBPC reinfusions, in addition to 
the increased non-myeloablative transplants (23-24). 
 
 
 
Early utilization of myeloablative therapy is recommended both with autologous 
and allogeneic bone marrow transplantation in order to consolidate complete or 
partial response to conventional treatment.   
 
2.3 
High-dose Chemotherapy Regimens in Multiple Myeloma 
 
The most frequently used single high-dose regimens in an autologous stem cell 
transplant setting include melphalan alone, or in combination with busulfan, 
cyclophosphamide, or with fractionated total body irradiation. (16, 17) There are 
no definitive comparative studies evaluating these regimens, except for melphalan 
200 mg/m2 versus melphalan 140 mg/m2 and FTBI 8 Gy. (14).  In a comparative, 
randomized, prospective study patients treated with melphalan alone experienced 
better projected 45-month overall survival rates of ~66% versus ~ 46%, but event-
free survivals were equivalent. Toxicities, especially cytopenias were 
substantially worse in the melphalan/FTBI-treated cohort. 
 
2.4 
Rationale for total marrow irradiation (TMI) in multiple myeloma 
 
Rapid advances in computer and medical imaging technologies have resulted in 
the ability to deliver radiotherapy with greater precision and conformality. 
External beam radiotherapy has traditionally relied on radiologic imaging to direct 
therapy to appropriate anatomic regions. The integration of CT imaging into 
radiation treatment planning, allows for a three dimensional view of each patient’s 
tumor relative to dose-limiting adjacent normal organs, allowing for customized 
beam shaping, beam orientation and dose conformality. The use of 3D conformal 
radiotherapy allows for further escalation of dose, which has resulted in higher 
tumor control, while maintaining risks and side effects at acceptable levels.  
 
Intensity modulated radiation therapy (IMRT) has opened a new era in radiation 
oncology. By delivering therapy from multiple directions using multiple 
segmented or modulated beamlets, one can now sculpt radiation doses to fit the 
unique shape of each patient’s tumor, optimizing radiation delivery to complex 
volumes and regions of the body. Some compare IMRT to “painting” radiation 
with a finer brush, where more precise, conformal and sophisticated dose patterns 
are now possible. This has also resulted in a greater degree of conformal dose 
avoidance of adjacent normal organs. Dose  escalation is now possible with 

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IMRT, which was not possible with technology just a decade ago. For example, 
radiation doses for prostate cancer, which have been limited to approximately 
7000 cGy with conventional technologies, are now >8000 cGy using IMRT. As a 
result, a significant improvement in tumor control and a reduction in bladder and 
rectal toxicities have been reported (25). 
 
Helical tomotherapy (HT) represents the next major breakthrough in beam 
delivery systems. HT is a ground breaking, FDA approved radiation therapy 
delivery device, which is a marriage of spiral CT and IMRT technology. 
Specifically, a 6 MV linear accelerator is mounted on a CT ring gantry and rotates 
around the patient as the patient translates through the ring. The treatment fan 
beam is segmented using a 64-leaf collimator. Each leaf casts a 0.6 mm width 
shadow at 85 cm isocenter distance with the fan beam, which varies in width from 
0.5 to 5 cm. The minimum voxel or beamlet size is therefore 5 x 6 mm. By rapid 
opening and closing of leaves as a function of gantry angle while the patient slides 
trough the ring, helical tomotherapy provides unprecedented ability to sculpt 
radiation doses to complex shaped tumor regions while simultaneously avoiding 
dose to normal organs (26, 27).  Grigorov et al. (28) evaluating HT treatment 
plans for prostate cancer, demonstrated rapid drop-off of dose around the target 
(prostate gland) in all directions resulting in excellent sparing of rectum, bladder 
and femoral heads superior to prior IMRT techniques. Scrimger et al. (29) 
predicted that for select patients with lung cancer, tumor doses as high as 16,000 
cGy will be achievable while maintaining normal lung doses (and therefore risks) 
at comparable levels as with conventional delivery methods, which are limited to 
doses of 6,000 cGy to the tumor in most patients. 
 
In addition, an array of detectors mounted on the same rotating gantry and 
positioned directly opposed to the beam source, gives the HT delivery system two 
unique capabilities not found on any other delivery systems. First, these detectors 
allow for the generation of megavoltage CT (MVCT) images using the 6 MV 
beam. Resolution and contrast of MVCT is more than adequate to easily 
distinguish tissue planes and organ boundaries (26), as shown in the figure below. 
This allows the HT system to automatically align beam orientation to anatomic 
external landmarks and internal organs in 3 dimensions prior to each daily 
session, vastly improving the precision of radiation delivery. Second, these same 
arrays can be used to monitor output of the beam as it exits through the patient, 
providing an additional level of dose verification. In the future, it is anticipated 
that future software and hardware modifications will allow for this type of  
“adaptive radiotherapy” to occur in real time, constantly modulating beam output 
to account for minute-by-minute variations in tumor and organ motion. 
 
 
 
 

 
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Figure 1. Top row are soft tissue windows and bottom are lung windows 
  
University of Wisconsin 
TomoTherapy MVCT, 3 cGy   
GE PET/CT  
 
 
The advent of HT brings for the first time to the clinic the potential to deliver 
 
highly conforming dose distributions to large complex target shapes. For example, 
 
with HT shaping the dose to the entire pleural surface, while sparing lung 
 
parenchyma is now possible for patients with mesothelioma. 
  
At the City of Hope, TBI is often used as part of the preparatory regimen for 
many patients undergoing bone marrow transplants. Although TBI will effectively 
treat the target region which includes the marrow space, and, in some patients, 
extramedullary hematopoietic sites, such as spleen and lymph nodes, TBI also 
delivers the same dose to all other normal organs resulting in dose-limiting 
toxicity, such as nausea and vomiting, mucositis and pneumonitis. Working with 
collaborators at the University of Wisconsin and Tomotherapy, Inc. 
(manufacturers of HT), we have recently evaluated the feasibility of delivering 
conformal radiation doses to just the skeletal bone containing the marrow spaces 
as a possible alternative to TBI. Total marrow irradiation (TMI) using HT would 
dramatically reduce dose to normal tissues, reducing short-term and long-term 
toxicities.  Using whole body CT images captured on the COH Radiation 
Oncology Picker CT treatment planning system, normal organs and target skeletal 
bone compartments were contoured. After defining appropriate target and organ 
dose constraints, inverse planning using the HT planning station was used to 
generate dose distributions and dose volume histograms. An example of a TMI 
dose distribution plan is shown in the accompanying figure.  

 
H ig h  d o s e
L o w  d o s e
B re a s t 
L u n g  &  H e a rt
B ra in
G I tra c t
P h a ryn x  &  T h yro id
H ig h  d o s e
L o w  d o s e
B re a s t 
L u n g  &  H e a rt
B ra in
G I tra c t
P h a ryn x  &  T h yro id
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TBI remains a part of the preparatory regimen for many patients undergoing 
transplantation for hematologic malignancies. There have been a few clinical 
trials evaluating the feasibility of increasing TBI dose in an effort to improve 
outcomes. A phase III randomized trial compared 12 Gy + Cytoxan vs. 15.75 Gy 
TBI + Cytoxan in patients with AML.  The 3-year probability of relapse was 35% 
for the 12 Gy group and 12% for the 15.75 Gy group (1). A similar study was 
carried out by the same group of investigators for CML. The four year probability 
of relapse was 25% for the 12 Gy group and 0% for the 15.75 Gy group (2). 
However in both studies survival was not improved due to increased transplant 
related mortality at the higher TBI dose. Appelbaum concluded that relatively 
small changes in TBI dose can result in significant increases in anti-leukemic 
effects, but also resulted in increases in toxicities, primarily of the lung, mucus 
membranes and liver (3). Therefore benefit was established for dose escalation, 
but a more targeted form of radiation therapy was needed to allow for further dose 
escalation without excessive toxicities (3).  Multiple myeloma is also a 
radiosensitive malignancy with improved response rates after myeloablative 
therapies. However, incorporation of TBI into conditioning regimens has been 
challenging due to associated increased toxicities. 
 
The tables below compare TBI as currently done at COH with TMI. Dose 
estimates for COH conventional TBI (with 50% lung blocks and electron boost to 
the chest wall) and helical tomotherapy TMI were recently generated on our 
treatment planning stations in the same patient (adult female). Both plans used a 
prescribed dose of 1200 cGy. Table 1 compares the minimum dose for TBI vs. 
TMI for normal organs. There is a 1.4 to 10.6-fold reduction of minimum dose to 
normal organs with TMI compared to TBI.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1. Comparison of minimum dose to normal organs with TBI vs. TMI 
 
 
Structure 
TBI Minimum Dose (Gy) TMI Minimum Dose (Gy) TBI/TMI 
Right Lung 
5.5 
2.9 
1.9 
Left Lung 
5.6 
2.6 
2.2 
Esophagus 
12.3 
2.9 
4.2 
Oral Cavity 
9.5 
0.9 
10.6 
Breast 
4.5 
3.2 
1.4 
Kidneys 
12.0 
3.7 
3.2 
Liver 
10.2 
2.5 
4.1 
Heart 
5.6 
2.9 
1.9 
Brain 
10.7 
1.1 
9.7 
Parotids 
6.7 
2.7 
2.5 
GI Tract 
12.0 
1.9 
6.3 
Thyroid 
10.0 
2.0 
5.0 
Lens 
4.7 
1.5 
3.1 
 
 
Table 2 compares the median dose (Dose 50%) for TBI vs. TMI for normal 
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organs. There is a 1.6 to 5.4-fold reduction in normal organ median dose with 
TMI compared to TBI. Data from Table 2 show that one can escalate the 
prescribed dose with helical tomotherapy TMI by a factor of 1.8 before reaching a 
median lung dose comparable to standard TBI. Since median lung dose from TBI 
correlates to risk of lung toxicity (4) and since 2000 cGy is only 1.67 times higher 
than 1200 cGy, the risks of pulmonary toxicity should not be greater than standard 
TBI. Mucosal surfaces of the oral cavity and esophagus are reduced by a factor of 
3.2 to 5.4, which should result in reduced mucositis and esophagitis with the 
doses proposed compared to standard TBI. Median liver doses are reduced 3.3 
fold making the likelihood of hepatotoxicity less compared to TBI. Of note, in a 
review of radiation tolerance of the liver by Dawson et al. (5), the risk of radiation 
related hepatotoxicity was zero if mean liver doses were below 31Gy. In addition, 
if the volume of liver irradiated was < 1/3, the risk of hepatotoxicity for doses up 
to 90 Gy was estimated at 5%.  
 
 
 
 
 
 
 
 
 
 
 
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Table 2. Comparison of median dose (dose 50%) to normal organs with TBI 
vs. TMI 
 
Structure 
TBI 
(Gy) 
TMI 
(Gy) 
TBI/TMI Ratio 
Right Lung 
8.8 
5.0 
1.8 
Left Lung 
8.8 
5.0 
1.8 
Esophagus 
12.4 
3.9 
3.2 
Oral Cavity 
11.8 
2.2 
5.4 
Breast 
11.5 
5.8 
2.0 
Kidneys 
12.2 
3.7 
3.3 
Liver 
12.3 
4.0 
3.1 
Heart 
12.1 
7.7 
1.6 
Brain 
12 
5.3 
2.3 
Parotids 
11.8 
5.5 
2.1 
GI Tract 
12.2 
5.5 
2.2 
Thyroid 
12.1 
6.5 
1.9 
Lens 
11.3 
3.7 
3.1 
 
Finally the graph below shows dose volume histograms (DVH plots) for lung for 
3 scenarios: TBI to 1200 cGy (with 50% lung shielding and electron chest wall 
boost), TMI to 1200 cGy, and TMI to 2000 cGy. The DVH lung plots for TMI 
1200 are to the left of the DVH plots for TBI 1200, indicating a substantially 
lower dose to the lungs for TMI. When the TMI dose is escalated to 2000, the 
DVH plots shift right but still remain to the left of the TBI 1200 plots, indicating 
that almost the entire lung volume will receive a lower dose with TMI 2000 than 
TBI.  
 
 
 
 
 

 
 
The use of dose volume histograms is an established method of predicting lung 
toxicity for a given dose to lung, with multiple studies demonstrating minimal 
risks of radiation pneumonitis if 20-30% of the lung volume irradiated is kept at 
doses below 20-25 Gy (6).  Of note, most multi-institutional clinical lung cancer 
protocols now use these DVH limits as part of the protocol requirements (RTOG, 
SWOG, etc.). As shown in the graph above, for a patient receiving 2000 cGy 
TMI, the V20 (20 % of lung volume) receives approximately 8 Gy, well below 
the 20-25 Gy limit required by these protocols.  
 
Therefore, given all of the above, the planned highest dose level to marrow of 
2000 cGy TMI is felt to be appropriately conservative and should not result in 
toxicities that exceed TBI, but rather will likely result in reduced toxicities at least 
up to 2000 cGy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R
reference List 
Ad u lt F em ale L u n g  D V H
-2 0
0
2 0
4 0
6 0
8 0
1 0 0
0
5
1 0
1 5
2 0
2 5
3 0
G y
% Volume
T MI L t L u n g  1 2 G y
T MI R t L u n g  1 2 G y
T BI L t L u n g
T BI R t L u n g
T MI L t L u n g  2 0 G y
T MI R t L u n g  2 0 G y
TBI 1200
TMI 1200
TMI 2000
 
 
1  
Clift,R., Buckner,C.D., Appelbaum,F.R., Bearman,S., Petersen,F.B., Fisher,L.D., 
Anasetti,C., Beatty,P., Bensinger,W.I., Doney,K., Hill,R.S., McDonald,G.B., Martin,P., 
Sanders,J., Singer,J., Stewart,P., Sullivan,K.M., Witherspoon,R., Storb,R., Jansen,J.A. and 
Thomas,E.D. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first 
remission:  A randomized trial of two irradiation regimens,  Blood, 76: 1867-1871, 1990. 
 
2  
Clift,R.A., Buckner,C.D., Appelbaum,F.R., Bryant,E., Bearman,S.I., Peterson,F.B., 
Fisher,L.D., Anasetti,C., Beatty,P., Bensinger,W.I., Doney,K., Hill,R.S., McDonald,G.B., 
Martin,P., Meyers,J., Sanders,J., Singer,J., Stewart,P., Sullivan,K.M., Witherspoon,R., Storb,R., 
Hansen,J.A. and Thomas,E.D. Allogeneic marrow transplantation in patients with chronic myeloid 
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leukemia in the chronic phase:  A randomized trial of two irradiation regimens,  Blood, 77: 1660-
1665, 1991. 
 
3  
Appelbaum,F.R. The influence of total dose, fractionation, dose rate, and distribution of 
total body irradiation on bone marrow transplantation,  Seminars in Oncology, 20: 3-10, 1993. 
 
4  
Volpe,A.D., Ferreri,A.J.M., Annaloro,C., Mangili,P., Rosso,A., Calandrino,R., Villa,E., 
Lambertenghi-Deliliers,G. and Fiorino,C. Lethal pulmonary complications significantly correlate 
with individually assessed mean lung dose in patients with hematologic malignancies treated with 
total body irradiation,  Int.J.Radiation Oncology Biol.Phys., 52: 483-488, 2002. 
 
5  
Dawson,L.A., Ten Haken,R.K. and Lawrence,T.S. Partial irradiation of the liver,  Semin 
Rad Onc, 11: 240-246, 2001. 
 
6  
Rodrigues,G., Lock,M., Souza,D.D., Yu,E. and Van Dyk,J. Prediction of radiation 
pneumonitis by dose - volume histogram parameters in lung cancer - a systematic review,  
Radiotherapy and Oncology, 71: 127-138, 2004. 
 
In the proposed study we plan to deliver a TMI dose level of 1000 cGy, a starting 
dose below the traditional fractionated total body irradiation dose of 1200 cGy, 
and slightly above the 800 cGy usually administered together with 140 mg/m2 of 
melphalan.   The dose will then be escalated in cohorts of 3-6 patients per Phase I 
trial design as shown in the table below. If two fractions are delivered on the same 
day there must be a minimum of 6 hours between fractions. 
Day 1 
(cGy) 
Day 2 
(cGy) 
Day 3 
(cGy) 
Day 4 
(cGy) 
Day 5 
(cGy) 
Total Dose 
(cGy) 
200 
 
200 
200 
200 
200 
1000 
200 AM 
200 PM 
200 
200 
200 
200 
1200 
200 AM 
200 PM 
200 AM 
200 PM 
200 
200 
200 
1400 
200 AM 
200 PM 
200 AM 
200 PM 
200 AM 
200 PM 
200 
200 
1600 
200 AM 
200 PM 
200 AM 
200 PM 
200 AM 
200 PM 
200 AM 
200 PM 
200 
1800 
200 AM 
200 PM 
200 AM 
200 PM 
200 AM 
200 PM 
200 AM 
200 PM 
200 AM 
200 PM 
2000 
 
Conformal avoidance of dose is planned for lung, kidneys, heart, brain, thyroid gland, 
oral cavity, oropharynx, lens, GI tract, breasts, parotids, liver and spleen. 
 
2.5 
Maintenance Therapy 
 
In bone marrow samples of patients with active MM there is ample evidence for 
the presence of active angiogenesis (30); expression of certain adhesion molecules 
is also increased on the surface of such plasma cells in comparison to those from 
patients with MGUS. In at least one study, diminished vascularity following high-
dose therapy and PBPC seemed to be associated with better outcome (31). Alpha 
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interferon, an agent with possible antiangiogenetic and other activities, has been 
found to exhibit antitumor activity in the therapy of multiple myeloma. Data from 
our institution and from Europe have demonstrated prolonged disease-free and 
overall survival with maintenance interferon therapy, but compliance, and 
feasibility of delivering set doses at regular frequency and for the planned 
duration is questionable (32, 33).  Maintenance therapy with steroids has also 
been found to be effective following standard chemotherapy. (34) Thalidomide, 
an agent with possible antiangiogenesis potential, had been reported to induce 
tumor response-including short-lasting complete remissions- in heavily treated, 
relapsed patients with MM (35, 36). Hence, thalidomide, an agent effective in 
both salvage and first line therapeutic settings is a potentially promising tool in 
attempting further consolidation of the response/survival gains achieved following 
high-dose therapy and PBPC. More recently, Lenolidomide, which is approved 
for second line therapy of multiple myeloma, has shown great promise as a 
maintenance therapy. 
 
2.6 
Pamidronate or zoledronic acid in the therapy of multiple myeloma. 
 
Bisphosphonates– presumably by interfering with osteoclast-mediated bone 
resorption- are useful in reducing the incidence/complications of lytic metastases.  
Both pamidronate and zoledronic acid had been found effective in reducing the 
number skeletal complications, and may also alter the natural history of MM by a 
direct effect on the myeloma cells. (37, 38)  In a study evaluating the role of 
zoledronic acid to prevent osteoporosis, less frequent yearly or every 3 months, 
and monthly administration were found to be equally effective (39). 
 
2.7 
Chromosomal abnormalities as prognostic indicators in MM 
 
 
Cytogenetic abnormalities can be detected in significant numbers of MM cases; 
 
the presence of 11q, -13 and deletion 13q have been associated with worse 
 
survival (4); frequent abnormalities observed in MM include t(4;14) (p16;q32), 
 
t(11;14) (q13;q32), t(8;14) (q24;32), t(14;18) 9 q32;q21), 13q14 (Rb loss) and 
 
others.(40) One of these translocations, t(4;14) may lead to dysregulations of two 
 
separate oncogenes providing one of many potential targets for specific 
 
interventions in the future (40, 41). 
 
 
Autologous stem cell transplantation following high-dose chemo-/radiotherapy 
 
may contribute to the development of clonal hematopoietic evolution (or 
 
unmask/accelerate previously existing clonal abnormalities).  Hence, we will 
 
apply a unique assay (specific only in female patients) to detect the presence of 
 
clonal hematopoiesis prior to high-dose therapy as well as to monitor for the 
 
development of such clones following treatment, in female participants. 
 
 
2.8 
COHNMC experience with tandem cycle high-dose therapy in MM 
 
Between 5/94 and 3/03, we treated 104 patients with stages I-III multiple 
myeloma on 2 sequentially developed tandem cycle high-dose chemotherapy 

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trials.  Treatment consisted of cycle 1 of melphalan 150 mg/m2, and cycle 2 of 
oral busulfan 16 mg/kg x 4 days and cyclophosphamide 60 mg/kg x 2 days (46 
patients) followed by G-CSF primed PBPC on the first trial, and the same 
combination but using IV busulfan 0.8 mg/kg x 4 days and cyclophosphamide 
(1.5 gm/m2) and G-CSF primed PBPC support (58 patients), on the second trial.  
Patients with ≤ 10% bone marrow involvement in response, or with stable disease, 
and 2 prior treatment regimens, (first trial) and subsequently with ≤ 40% marrow 
involvement and inclusive of patients even with plasma cell leukemia, and up to 3 
prior treatment regimens (second trial) were eligible.  All patients were to receive 
maintenance therapy with intereferon -α 2, starting at 3 million units/m2, given 
subcutaneously, three-times/ week.  Patients enrolled on the second trial were to 
receive thalidomide up to 400 mg/day in addition to interferon, if they were not in 
complete remission by 6 months from initiating high-dose therapy.  The median 
age was 52-years, (range, 38-65), 2/3rd of patients were diagnosed with stage III 
myeloma, and 40% received prior radiation therapy.  The median number of prior 
treatment regimens was 1 (1-3).  Median time from diagnosis to high-dose 
therapy was 8 months (range, 2-74).  Eighty nine percent of patients received both 
cycles at a median interval of 75 days (29-134).  Among the 46 patients treated 
with oral busulfan there were 7 cases of venous-occlusive disease (VOD) with 3 
fatalities (Treatment-related mortality [TRM]: 7%).  Among 58 patients treated 
with IV busulfan, there were 6 cases of non-fatal VOD and one septic death 
(TRM: 1.7%).  Fifty-five percent of the 104 patient cohort achieved ≥ 90% 
response (complete response rate: 39%; very good partial response: 16%).  While 
92 % of patients tolerated at least 1 million unit/m2 of interferon 2-3 times/week, 
only 8 patients were able to tolerate concomitant administration of interferon and 
up to 200 mg of thalidomide beyond 3 months, with 2 patients converting into 
complete responders.   
 
 
 
 Three-year progression-free survival is 48.5% (95% CI, 38-59%) and overall 
survival is 74.4% (95%CI, 65-83%) for the entire group.  Progression-free 
survival and overall survival are 67% and 93.9% for the first and 38% and 64.5% 
for the second cohort of patients.  Possible explanations for the somewhat worse 
outcome for the second cohort are the inclusion of less responsive patients (≤ 40% 
vs. ≤ 10% bone marrow involvement), inclusion of patients with plasma cell 
leukemia, and up to 3 vs. 2 prior treatment regimens (33, 21). 
 
 
2.9 
Rationale for novel tandem high-dose chemotherapy and TMI followed by PBPC 
and lenalidomide/bisphosphonate maintenance. 
 
Based on the feasibility and possibly better complete response / very good partial 
response rate and progression-free survival of tandem cycles of melphalan and 
busulfan/cyclophosphamide followed by alpha interferon +/- thalidomide, and 
based on the positive data supporting tandem therapy in a randomized, 
prospective trial and in view of the encouraging, survival data in this relatively 
“low tumor bulk” population with responding, or stable multiple myeloma we 
propose to treat a larger cohort of patients with exposure to < 2 prior treatment 
regimens with tandem high-dose therapy.  

 
 
 
Patients will be eligible with up to < 10% marrow involvement provided that they 
are either responding to induction therapy or have stable disease. 
 
 
 
We will continue to incorporate cyclophosphamide both as a priming agent and to 
provide in vivo purging prior to Filgrastim priming.  
 
 
 
In view of the known therapeutic efficacy of radiation to myelomatous bone 
involvement, and with the availability of a likely safer method to deliver total 
marrow irradiation (TMI) with the potential to escalate the total dose, we propose 
to replace busulfan and cyclophosphamide as the conditioning regimen for cycle 
2.   Since the concomitant administration of conventionally delivered fractionated 
total body/marrow radiation has not been more effective than, and possibly 
compromised delivery of full dose melphalan, total marrow irradiation as a single 
therapeutic modality during cycle 2 will be tested in a phase I-II setting, followed 
by PBPC rescue. 
 
 
 
While the recently published data comparing tandem cycle melphalan/fractionated 
total body irradiation followed by melphalan seemed to yield better outcome in 
terms of progression-free and overall survival, with 80% of patients projected to 
progress by 7 years after tandem therapy, further improvements are badly needed. 
 
 
 
Based on recent data presented at the American Society of Hematology meetings 
in 2009 describing the potential benefit of Lenalidomide maintenance following 
an autologous stem cell transplant procedure from multiple groups but most 
specifically from the US Inter-group (Mc/carthy P, et.al. Phase III Inter-group 
study of Lenalidomide versus placebo maintenance therapy following single 
autologous stem cell transplant for multiple myeloma [CALGB 100104]: Initial 
report of patient accrual and adverse events. Blood ASH annual meeting abstracts, 
Nov 2009; 114:3416:)  
3/24/10 
 
 
 
In addition, bisphosphonates will be allowed to continue, or will be recommended 
to be administered, for a period of 2 years.  However, to avoid any potential 
adverse interactions between bisphosphonates and thalidomide, and in view of the 
lasting presence of bisphosphonates in the bone, pamidronate or zoledronate will 
be administered at a frequency of every 3 months (39, 43). 
 
 
 
Cytogenetic abnormalities by standard and FISH analysis to assess their role as 
predictors of response, monitors of residual disease and predictors of survival will 
be assessed.  Patients’ myeloma cells will be banked frozen/cell lines will be 
developed for future investigations of tumor biology, drug testing, and for the 
potential to assess efficacy of novel therapeutic agents. 
 
3.0 
THERAPEUTIC AGENTS  
 
3.1. 
Cyclophosphamide 
 
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3.1.1 Mechanisms of Action: This drug is biotransformed principally in the liver 
to active alkylating metabolites which prevent cell division by cross 
linking strands of DNA and it also inhibits DNA synthesis. 
 
3.1.2 Human Toxicity:  Toxicity from cyclophosphamide includes bone marrow 
suppression which usually occurs ten to twelve days after administration, 
nausea and vomiting, reversible alopecia, hemorrhagic cystitis which can 
frequently be prevented with increased hydration and co-administration of 
MESNA, and sterility and decreased gonadal function.  There are isolated 
reports of hemorrhagic colitis, oral mucosal ulceration, and jaundice. 
 
3.1.3 Pharmaceutical Data:  Formulation; Cyclophosphamide is supplied in 100 
mg, 200 mg, and 500 mg vials as a white powder.  The drug can re 
reconstituted in either normal saline or D5W. 
 
 
 
 
3.1.4 Administration:  The drug should be dissolved in about 500 cc of 
D5W and it is infused IV over 2 hours.  An added dose of IV fluids may 
help prevent bladder toxicity.  Cyclophosphamide 1.5 gm/m2 (based on 
actual body weight) will be administered for mobilization, prior to 
apheresis.  There will be no correction for extremely obese patients.   
8/8/07 
7/17/08
 
3.1.4 Supplier:  This drug is commercially available for purchase by the third 
party. 
 
3.2 
Melphalan (L-phenylalanine mustard, L-PAM, Alkeran) 
 
3.2.1 Mode of Action:  In common with other nitrogen mustards, melphalan 
reacts with DNA to produce either DNA-DNA or DNA-proteins cross-
linked products probably by binding at the N-7 position of guanine. 
 
 
 
3.2.2 Supply, Reconstitution and Administration:  Melphalan is commercially 
available by Burroughs Wellcome Company in sterile vials containing 50 
mg lyophilized drug as the hydrochloride salt.  It is formulated with 20 mg 
povidone per 50 mg vial.  Sterile diluent is supplied which contains per 10 
ml: sodium citrate 0.20 g, propylene glycol 6 ml, ethanol (95%) 0.526 ml, 
sterile water q.s. 10 ml. Reconstituted vials (undiluted solutions) are stable 
for 90 minutes.  Melphalan diluted in NS to 0.1-0.45mg/ml is stable for 
only 60 minutes.  Melphalan is unstable when diluted with NS to 2mg/ml.  
The rate of infusion should be 30 minutes or less. 
 
3.2.3 Toxicity:  The dose-limiting toxicity of melphalan is myelosuppression.  
Other toxicities after IV melphalan include mucositis, nausea, vomiting, 
and diarrhea.  Alopecia is generally seen only with high doses associated 
with bone marrow transplant settings.  Rarely reported reactions include 
pulmonary fibrosis, skin rash, vasculitis, and allergic reactions.  With high 
dose chemotherapy, gastrointestinal toxicity becomes dose limiting. At 
such high doses, elevated transaminases, syndrome of inappropriate 
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antidiuretic hormone secretion, depression, interstitial pneumonitis, and 
hepatic veno-occlusive disease have been reported. Acute nonlymphocytic 
leukemia and myeloproliferative syndromes may occur as secondary 
cancers from any alkylating agent such as melphalan. Amenorrhea, 
permanent in many cases, have been noted when melphalan was used in 
premenopausal women undergoing adjuvant therapy for breast cancer.  
Azoospermia would be expected, but is not well documented in the 
literature. 
 
3.3 
Filgrastim (r-metHuG-CSF) 
 
3.3.1 Description
 
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), 
produced by recombinant DNA technology.  NEUPOGEN® is the Amgen 
Inc. trademark for Filgrastim, recombinant methionyl human granulocyte 
colony stimulating factor (r-metHuG-CSF).  
 
Approximately 6,400 patients in U.S. and international based trials have 
participated in clinical trials of Filgrastim to date, and the worldwide 
commercial populations receiving Filgrastim totaled approximately 
190,000.  The drug has been found to be well tolerated at dosages up to 60 
µg/kg/day given IV or SC, with no toxic effects attributable to Filgrastim. 
A maximum tolerated dose has not yet been determined. 
 
3.3.2 Contraindications
 
NEUPOGEN® is contraindicated in patients with known hypersensitivity 
to E. coli-derived proteins, Filgrastim, or any component of the product. 
 
3.3.3 Adverse Reactions 
 
 
The only consistently observed clinical toxicity described with 
Neupogen® is medullary bone pain. Other clinical toxicities that have 
been described include skin rash, and cutaneous vasculitis.  Since 
commercial introduction of Neupogen®, there have been rare reports of 
allergic-type reactions.  Biochemical abnormalities that may occur include 
increases in alkaline phosphatase, uric acid, and lactate deydrogenase. 
 
3.3.4 Dilution and Storage 
 
 
If 
required, 
NEUPOGEN® 
may 
be 
diluted 
in 
5% 
dextrose.  
NEUPOGEN® diluted to concentrations between 5 and 15 mcg/mL 
should be protected from adsorption to plastic materials by addition of 
Albumin (Human) to a final concentration of 2 mg/mL.  Do not dilute with 
saline at any time; product may precipitate. 
 

NEUPOGEN® should be stored in the refrigerator at 2-8 degrees 
Centigrade (36-46 degrees Fahrenheit).  Do not freeze.  Avoid shaking.  
Prior to injection, NEUPOGEN® may be allowed to reach room 
temperature for a maximum of 24 hours.  Any vial left at room 
temperature for greater than 24 hours should be discarded.   
 
3.3.5 Supplier 
 
 
Commercial NEUPOGEN® is available in 1 mL and 1.6 mL vials at a 
concentration of 300 mcg/mL.  Discard unused portions.  Use only one 
dose per vial; do not reenter the vial.  Do not save unused drug for later 
administration. 
 
 
3.4  
Lenalidomide 
 
 
Common toxicities described for lenalidomide include: 
• Neurologic: Somnolence, dizziness, headache, confusion, tremor, loss of co-
ordination, 
asthenia, 
paresthesia, 
numbness, 
and 
leukoencephalopathy 
(radiographic findings). 
3/24/10 
• Hematologic: 
anemia, 
neutropenia, 
leucopenia, 
lymphoenia 
and 
thrombocytopenia; thromboembolic events (deep vein thrombosis and pulmonary 
embolism).   
• Gastrointestinal: Constipation, dehydration, dry mouth, diarrhea, dyspepsia, 
nausea, vomiting and stomatitis. 
• Constitutional: Weakness, insomnia, rigors, chills, sweating, weight loss and 
fever. 
• Reproductive: teratogenicity and miscarriage. 
• Musculoskeletal: arthralgia, back/neck pain, joint pain, muscle cramp and 
weakness. 
• Cardiac: hypotension. 
• Dermatologic: rash, dry skin, itching. 
• Endocrine: hypothyroidism. 
• Infection. 
• Pulmonary: cough, dyspnea. 
• Metabolic: hypokalemia, liver damage. 
• Renal: increased creatinine, renal failure. 
 
3.5 
Pregnancy reporting: 
 
Pregnancies occurring while the subject is on lenalidomide or within four weeks 
after the subject’s last dose of lenalidomide are considered expedited reportable 
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events.  If the subject is on lenalidomide, it is to be discontinued immediately and 
the subject is to be instructed to return any unused portion of lenalidomide to the 
Investigator.  The pregnancy must be reported within 24 hours of the 
Investigator’s knowledge of the pregnancy by phone and facsimile using the SAE 
Form.  
 
The Investigator will follow the subject until completion of the pregnancy, and 
must report the outcome as specified below.  The Investigator will provide this 
information as a follow-up to the initial SAE. 
 
If the outcome of the pregnancy meets the criteria for immediate classification as 
a SAE (i.e., spontaneous abortion [any congenital anomaly detected in an aborted 
fetus is to be documented], stillbirth, neonatal death, or congenital anomaly), the 
Investigator should follow the procedures report the event within 24 hours of the 
Investigator’s knowledge of the event). 
 
Any suspected fetal exposure to lenalidomide must be reported within 24 hours of 
being made aware of the event.  The patient should be referred to an 
obstetrician/gynecologist experienced in reproductive toxicity for further 
evaluation and counseling. 
 
All neonatal deaths that occur within 30 days of birth should be reported, without 
regard to causality, as SAEs.  In addition, any infant death after 30 days that the 
Investigator suspects is related to the in utero exposure to lenalidomide should 
also be reported. 
 
In the case of a live “normal” birth, the outcome should be reported as soon as the 
information is available.  
 
Other instructions related to lenalidomide: 
Only one cycle of therapy may be dispensed to the patient each month.  During 
maintenance a max of a 28-day supply may be dispensed.  Lenalidomide capsules 
should be swallowed whole, and should not be broken, chewed or opened.  If a 
dose of lenalidomide 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 taking 
more than the prescribed dose of lenalidomide should be instructed to seek 
emergency medical care if needed and contact study staff immediately.  See 
Appendices D (Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods) and E (Education and Counseling Guidance 
Document).   
 
3.6 
Total Marrow Irradiation (TMI) 
 
3.6.1 Administration: Ionizing radiation is an established and effective method 

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in treating multiple myeloma. Multiple myeloma is in general a 
radiosensitive disease. Total marrow irradiation will be delivered using a 
Helical 
Tomotherapy 
HiArt 
System 
(Tomotherapy, 
Inc). 
The 
administration schedule and dose escalation scheme are described below. 
 
3.6.2. Acute toxicities:  Toxicities from TMI may include bone marrow 
suppression, alopecia, fatigue, and skin erythema. Other acute toxicities, 
which occur with traditional total body irradiation and may also occur 
with TMI (but anticipated to be of lower frequency and/or less severity) 
include mucositis, esophagitis, enteritis, cystitis, proctitis, pneumonitis, 
nausea and vomiting and sterility.  
 
3.6.3. Potential Late Toxicities: Due to conformal avoidance of dose to normal 
organs, late toxicities from TMI are anticipated to be less frequent and/or 
severe compared with total body irradiation. Potential late toxicities may 
include 
sterility, 
endocrinopathies 
(i.e. 
hypothyroidism), 
cataract 
formation, pneumonitis, veno-occlusive disease, and second malignancy 
induction.  
 
 
3.7. 
Pamidronate 
 
3.7.1. Mechanism of Action:  Pamidronate is an inhibitor of bone resorption and, 
in addition may interfere with the release, deposition of metastatic tumor 
deposits. 
 
3.7.2. Toxicity:  Fatigue, fever, diarrhea, nausea, arthralgias, and rarely 
hypocalcemia, phlebitis at the site of injection have been observed. 
 
3.7.3. Pharmaceutical Data:  Pamidronate is supplied in 30, 60, and 90 mg vials 
as a freeze-dried powder.  Reconstitution can be done in 10 mL of sterile 
water, than the appropriate volume of pamidronate will be missed with 
normal (0.9%) saline to a total volume of 250 mL.  Pamidronate will be 
infused over 2 hours.  If the reconstituted solution is not used immediately, 
it can be stored at temperatures between 36-46 °F and can be used for up 
to 24 hours. 
 
3.7.4. Pamidronate is commercially available. 
 
3.8. Zoledronic Acid 
 
3.8.1. Mechanism of Action:  Zoledronic acid is an inhibitor of bone resorption 
and, in addition may interfere with the release, deposition of metastatic 
tumor deposits. 
 
3.8.2. Toxicity:  Fatigue, fever, diarrhea, nausea, arthralgias, and rarely 
hypocalcaemia, phlebitis at the site of injection have been observed. 
 

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3.8.3. Pharmaceutical Data:  Zoledronic acid is supplied in 5 mL vials which 
contains 4.264 mg zoledronic acid monohydrate, corresponding to 4 mg 
zoledronic acid on an anhydrous basis, 220 mg of mannitol, USP, water 
for injection and 24 mg of sodium citrate, USP.  Zoledronic acid will be 
infused over 15 or more minutes, in 100 mL normal saline. 
 
3.8.4. Zoledronic acid is stored at 25°C (77°F); excursions permitted to 15°C-
30°C (59°F-86°F). 
 
3.8.5. Zoledronic acid is commercially available. 
 
4.0 
STAGING CRITERIA  
 
4.1 
Criteria for Diagnosis of Multiple Myeloma (44) 
 
4.1.1 Major Criteria
 
Plasmacytomas on tissue biopsy. 
 
Bone marrow plasmacytosis with > 30% plasma cells. 
 
Monoclonal globulin spike on serum electrophoresis exceeding 3.5 gm% 
for G peaks or 2.0 gms for A peaks.  > 1.0 gm/24 hours of kappa or 
lambda light chain excretion on urine electrophoresis in the absence of 
amyloidosis. 
 
4.1.2 Minor Criteria
 
Bone marrow plasmacytosis 10% - 30%. 
 
4.1.3 Monoclonal globulin spike present, but less than the levels defined above. 
 
4.1.4 Lytic bone lesions. 
 
4.1.5 Normal lgM less than 50 mg%, lgA less than 100%, or lgG less than 600 
mg%. 
 
4.1.6 Diagnosis will be confirmed when any of the following features are 
documented in symptomatic patients with clearly progressive disease.  The 
diagnosis of myeloma requires a minimum of 1 MAJOR + 1 MINOR 
CRITERION or 3 MINOR CRITERIA which must include a+b, i.e.: 
 
4.1.6.1 l+b, l+c, l+d (l+a not sufficient) 
 
4.1.6.2 ll+b, ll+c, ll+d 
 
4.1.6.3 lll+a, lll+c, lll+d 

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4.1.6.4 a+b+c, a+b+d 
 
4.1.7 The presence of certain nonspecific disease features will support the 
diagnosis, particularly if of recent onset. 
 
4.1.7.1 Anemia 
 
4.1.7.2 Hypercalcemia 
 
4.1.7.3 Azotemia 
 
4.1.7.4 Demineralization and compression fractures 
 
4.1.7.5 Hypoalbuminemia 
 
4.1.8 Great care must be taken to distinguish between active myeloma as 
defined above and MGUS or indolent/smoldering myeloma (see Section 
4.2). 
 
4.2 
Criteria for Monoclonal Gammopathy of Undetermined Significance (MGUS), 
Indolent Myeloma and Smoldering Myeloma (Stage I or IIA) 
 
4.2.1 MGUS
 
4.2.1.1 Monoclonal gammopathy 
4.2.1.2 M-Component level 
 
 
 
 
 
4.2.1.2.1 
IgG < 3.5 gm% 
 
4.2.1.2.2 
IgA < 2.0 gm% 
 
4.2.1.2.3 
BJ  < 1.0 gm/24 hours 
 
4.2.1.3 Bone marrow plasma cells < 10% 
 
 
 
 
 
 
4.2.1.4 No bone lesions 
 
4.2.1.5 No symptoms 
 
4.2.2 Indolent Myeloma Criteria as for myeloma (see Section 4.2) except (all of 
the following): 
 
4.2.2.1 No or only limited bone lesions (< 3 lytic lesions); no 
compression fractures. 
 
4.2.2.2 M-component levels 

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4.2.2.2.1 
IgG < 7 gm% 
 
4.2.2.2.2 
IgA < 5 gm% 
 
4.2.2.3 No symptoms or associated disease features, i.e.: 
 
4.2.2.4 Performance status > 50% 
 
4.2.2.4.1 
Hemoglobin > 10 gm% 
 
4.2.2.4.2 
Serum calcium normal 
 
4.2.2.4.3 
Serum creatinine < 2.0 mg% 
 
4.2.2.4.4 
No infections 
 
4.2.3 Smoldering Myeloma  Criteria as for indolent myeloma except: 
 
4.2.3.1 NO bone lesions 
 
4.2.3.2 Bone marrow plasma cells < 30% 
 
4.3 
Assessment of Tumor Mass 
 
4.3.1 High Tumor Mass (Stage III) - One of the following abnormalities must be 
present: 
 
4.3.1.1 Hemoglobin < 8.5 gm%, hematocrit < 25 vol.%, or 
 
4.3.1.2 Serum calcium > 12 mg%, or 
 
4.3.1.3 Very high serum or urine myeloma protein production rates: 
 
4.3.1.3.1 
IgG peak > 7 gm% 
 
4.3.1.3.2 
IgA peak > 5 gm% 
 
4.3.1.3.3 
Bence Jones protein > 12 gm/day (24 hours), or 
 
4.3.1.3.4 
> 3 lytic bone lesions on bone survey (bone scan 
not acceptable) 
 
4.3.2 Low Tumor Mass (Stage I)  ALL of the following must be present: 
 
4.3.2.1 Hemoglobin > 10.5 gm% or hematocrit > 32 vol.% 
 

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4.3.2.2 Serum calcium normal 
 
4.3.2.3 Low serum myeloma protein production rates: 
 
4.3.2.3.1 
IgG peak < 5 mg% 
 
4.3.2.3.2 
IgA peak < 3 gm% 
 
4.3.2.3.3 
Bence Jones protein < 4 gm/day (24 hours) 
 
4.3.2.3.4 
Bone lesions scaled 0 (none) or 1 (osteoporosis) 
 
4.3.3 Intermediate Tumor Mass (Stage II)
 
All other patients who do not qualify specifically for high or low tumor 
mass categories are considered to have intermediate tumor mass. 
 
4.4 
Assessment of Renal Status 
 
 
 
4.4.1 A = Good Renal Function (creatinine < 2.0 mg%) 
 
 
 
4.4.2 B = Poor Renal Function (creatinine > 2.0 mg%) 
 
 
4.5 
Assessment of Myeloma Cell Mass 
 
 
STAGE III 
 
STAGE I 
 
STAGE II 
 
Cell Mass Category 
High
Low
Intermediate
# of myeloma cells 
> 1.2 x 1012/m2
< 0.6 x 1012/m2
0.6-1.2 x 102/m2
Requirements 
One of: A,B,C,D 
All of: A,B,C,D 
Neither High or 
Low 
Hemoglobin (gm%)       A  
(pretransfusion) 
< 8.5 
> 10.5 
> 8.5 
 
Serum calcium (mg%)   B 
> 12 
Normal 
< 12 
M-Component                C 
IgG > 7 gm% 
IgA > 5 gm% 
BJ  > 12 gm/day 
< 5 
< 3 
< 4 
< 7 
< 5 
< 12 
Bone lesions (on             D  
skeletal survey  
only; bone scan not 
acceptable) 
Scaled 3 
(> 3 lytic lesions) 
scaled 0 or 1 (no 
lesions or 
osteoporosis only) 
Scaled 0, 1, or 2 
 
NOTE:  The staging of patients with IgD or IgE monoclonal spikes is based upon other (non M-
component) criteria. 
 
5.0 
PATIENT ELIGIBILITY 
 

5.1 
Patients with multiple myeloma (stages I-III) will be eligible if they are either in 
response, or have stable disease. 
2/7/05
 
5.2 
Patients with smoldering myeloma are eligible if there is evidence of progressive 
disease requiring therapy (> 25% increase in M protein levels or Bence Jones 
excretion; Hgb < 10.5 g/dl; frequent infections; hypercalcemia; rise in serum 
creatinine above normal on two separate occasion) 
 
5.3 
Patients with non-quantifiable monoclonal proteins are eligible provided they 
meet other criteria for multiple myeloma, or smoldering myeloma, and they have 
evaluable or measurable disease by other (radiographic) means. 
 
5.4 
Unlimited prior chemotherapy regimens allowed. 
2/7/05
 
5.5 
KPS ≥ 70% 
 
5.6 
Patients with Waldenstrom’s macroglobulinemia are not eligible. 
 
2/7/05
5.7 
Less than 18 months since diagnosis. 
 
2/7/05
5.8 
Patients must be < 70 years old at the time of enrollment. 
 
5.9 
No contraindication to the collection of a minimum of 4 x 106 CD34+ cells/kg by 
apheresis. 
 
5.10 
All patients must have signed a voluntary, informed consent in accordance with 
institutional and federal guidelines. 
 
5.11 
Adequate hepatic function as demonstrated by bilirubin, < 1.5 mg/dl, and SGOT 
and SGPT < 2.5 x upper limits of normal. 
 
5.12 
Adequate renal function as demonstrated by: creatinine of measured or calculated 
creatinine clearance of > 50 cc/min. 
 
5.13 
Absolute neutrophil count of > 1000/µl, platelet count of > 100,000/µl. 
 
5.14 
Cardiac ejection fraction > 50% by MUGA scan and/or by echocardiogram. 
 
5.15 
Adequate pulmonary function as demonstrated by FEV1 > 60% and DLCO > 
50% of predicted lower limit.  
 
5.16 
Hepatitis B antigen, Hepatitis C RNA and HIV antibody tests negative. 
 
5.17 
No other medical, or psychosocial problems, which in the opinion of the primary 
physician or principal investigator would place the patient at unacceptably high 
risk from this treatment regimen. 
 
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5.18 
Females of reproductive age not using adequate birth control measures/ or who 
are pregnant are not eligible.   
 
5.19 
History of other malignancies within the last 3 years, as long as patients have 
remained in complete remission for at least 2 years, except for non-melanoma 
skin cancer and in situ carcinoma of the cervix. 
 
5.20 
Patients should have finished their prior chemotherapy at least 14 days prior to 
cyclophosphamide priming, and should have received their last dose of 
thalidomide, 
dexamethasone, 
or 
bisphosphonate 
>10 
days 
prior 
to  
cyclophosphamide priming.  
10/20/05
7/18/05
 
2/14/06
5.21 
Pre-treatment tests must have been performed within 6 weeks prior to initiation of 
cyclophosphamide.  A CBC, platelet count and comprehensive chemistry panel 
should be performed within 1 week prior to initiating cyclophosphamide priming. 
 
 
5.22 
Known hypersensitivity to Filgrastim or to E. coli derived proteins is an 
exclusion.  
 
5.23 
Inability to lie supine in a full body cast for approximately 30 minutes, the 
 
anticipated duration of each treatment session, is an exclusion. 
 
5.24 
Previous radiation therapy to more than 20% of bone marrow containing areas, or  
  
to any area exceeding 2000 cGy, is an exclusion.  
 
5.25 
Patients must be fully aware of the teratogenic potential of thalidomide and agree 
 
to fully comply with the mandated guidelines regarding contraception as stated in 
 
the informed consent and the patient warning document attached to the consent 
 
form.  Women of childbearing potential must have a negative pregnancy test 
 
performed within 24 hours prior to beginning thalidomide, except for woman who 
 
have been postmenopausal for at least 2 years, or underwent hysterectomy.  Use 
 
of effective means of contraceptive should be started at least 2 weeks prior to 
 
initiating thalidomide. 
 
6.0 
TREATMENT PLAN 
 
6.1 
Pre-treatment Evaluation
 
6.1.1 History and physical examination. 
 
6.1.2 Radiographic evaluation: MRI of the entire spine and pelvis and skeletal 
survey will be performed. 
 
6.1.3 Chest X-ray. 
 
 
 
6.1.4 Pulmonary function tests 
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6.1.5 MUGA scan or echocardiogram. 
 
 
6.1.6 CBC, differential count, platelet count, PT, PTT, SMA 18, Mg. 
 
 
6.1.7 Urine analysis. 
 
 
6.1.8 24-urine collection for total protein, protein electrophoresis, immune 
electrophoresis, and creatinine clearance. 
 
 
6.1.9 Hepatitis panel, HIV antibody, HSV and CMV antibody. 
 
6.1.10 Unilateral 
bone 
marrow 
biopsy 
and 
aspirate 
for 
morphology, 
cytogenetics/FISH.  Aspirate for HUMARA (females only). 
 
 
 
6.1.11 Peripheral blood for FISH (including clonal hematopoiesis markers), gene 
rearrangement, and for lymphocyte subset analysis. 
 
 
 
6.1.12 Serum protein electrophoresis, quantitative serum immunoglobulins, 
serum immunofixation electrophoresis 
 
6.1.13 Beta-2 Microglobulin level. 
 
6.1.14 Urine pregnancy test. 
 
6.1.15 HLA, ABO and Rh typing. 
 
6.1.16 Double lumen Hickman catheter will be placed (> 12 French catheter). 
 
6.2 
Patient Registration 
 
After all pre-treatment evaluations have been performed patients can be entered 
on study. Eligibility requirements must be reviewed by a member of the 
department of Biostatistics and the principal investigator. Patients may be 
screened for eligibility by calling the Department of Biostatistics at extension 
62468.
 
6.3 
Harvesting and Cryopreservation of Stem Cells  
 
 
 
Cyclophosphamide 1.5 gm/m2 (based on actual body weight) will be administered 
with 500 cc D5/W over 2 hours. Filgrastim 10 µg/kg (based on actual body 
weight) daily, sq or iv will be administered starting 24 hours after 
cyclophosphamide and continue through the completion of apheresis (total daily 
Filgrastim dose equals 10 µg/kg/day). 
 
Beginning day 10, provided that the peripheral blood white cell count is > 
1000/µL and rising, apheresis will commence and continue until a minimum of 4 
x 106 CD34+ cells/kg are collected.  For patients with good CD34+ cell yields 

during apheresis (once the minimum CD34+ requirements are secured), a target of 
> 10 x 106 will be set and no more than 10 apheresis are recommended. 
 
Filgrastim will continue to be given daily; Filgrastim dose will be held if the total 
white cell count is > 80,000/µl.  If the yield from the first 3 days of apheresis is < 
1 x 106/kg, the dose of Filgrastim will be increased to 10 µg/kg, bid. 
 
The collections will last 4 hours, or until a volume of 12 liters has been processed.  
Peripheral stem cells will be processed and cryopreserved following standard 
methods at the City of Hope National Medical Center. 
 
Patient who have already undergone mobilization and blood stem cell collection 
prior to signing this consent form, their physician will make a judgment to decide 
whether the quantity and quality of those previously collected blood stem cells is 
sufficient enough to proceed with the proposed treatment or alternatively, may 
have to undergo additional stem cell mobilization and leukopheresis. 
3/19/08 
 
6.4 
High-Dose Chemotherapy 
 
Cycle 1: Melphalan 
 
DAY –2  
 
7/18/05
 
 
Admission, history and physical, SMA 18, Mg, CBC, differential , VRF 
evaluation, and PLT count, urine analysis.  Review of required laboratory, 
screening and radiographic data, signing of consent form.   
 
Prophylactic IV, or p.o. fluconazole at 400 mg daily will be given to patients with 
AGC < 1000/µl. 
8/8/07 
 
Intravenous hydration with normal saline at 200 cc/hr and KCL 15 MeQ/1 will be 
started.  After 6 hours of hydration melphalan 100 mg/m2 will be infused in # 
30min. IV hydration will continue with normal saline at a rate of 200 cc/hr and 
KCL 15 MeQ/l for a total of at least 24 hours. 
 
Appropriate intravenous antiemetics will be given. 
 
When calculating chemotherapeutic dose, ideal body weight will be used.  
 
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DAY –1 
  
Melphalan 100 mg/m2 will be infused in # 30min. IV hydration will continue with 
normal saline at a rate of 200 cc/hr and KCL 15 MeQ/l for a total of at least 24 
hours. 
 
DAY  0 
 
 
Half of the previously collected CD34+ cells will be reinfused. 
DAY +5 
 
 
Filgrastim 5 µg/kg daily, IV, or SQ will be started.  Continue with Filgrastim until 
AGC > 1000/µl for 3 consecutive days 
 
Prophylactic IV, or p.o. fluconazole at 400 mg daily will be given to patients with 
AGC < 1000/µl. 
7/18/05 
8/8/07
 
Patients will be supported through iv hydration and red cell and platelet 
transfusions as needed. CBC, PLT and SMA7, SMA 12, and Mg and weekly 
chest x-ray as well as the necessary fever workup will be done.  Patients can be 
followed as outpatients unless they develop neutropenic fever, uncontrollable 
diarrhea or other problems requiring inpatient care.   All blood products will be 
filtered and radiated. 
 
Cycle 2: 
 
 
 
 
 
 
2/7/05
Total marrow radiation will start a minimum of 6 weeks and a maximum 18 
weeks from day 0 of cycle number 1. 
 
7/18/05 
DAY -6 
 
 
Admission to either outpatient, or inpatient unit, history and physical, SMA18, 
Mg, CBC, differential and PLT count, urine analysis, and VRE evaluation.   
Review of required laboratory, screening and radiographic data, check for signing 
of consent form.  
7/18/05 
 
DAY   -5 
200 cGy/D to 200 cGy BID 
03-19-08 
7/18/05 
 
 
 
DAY   -4 
200 cGy/D to 200 cGy BID 
 
 
 
DAY   -3 
200 cGy/D to 200 cGy BID  
 
 
 
DAY   -2 
200 cGy/D to 200 cGy BID 
 
 
 
DAY   -1 
200 cGy/D to 200 cGy BID 
 
TMI doses to previously irradiated regions will be limited to a total dose of no 
more than 1600 cGy.   
 
Prophylactic IV, or p.o. fluconazole at 400 mg daily will be given to patients with 
AGC < 1000/µl.   
7/18/05 
8/8/07 
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DAY 0 
 
Half of the previously collected CD34+ cells will be reinfused and 
5 µg/kg daily, IV, or SQ will be started.  Continue with hydration 
as needed.  Continue with Filgrastim until AGC > 1000/µl for 3 
consecutive days. 
Filgrastim  
 
Patients will be supported through iv hydration and TPN, red cell and platelet 
transfusions as needed.  Daily CBC, PLT and SMA7, every Monday, Wednesday, 
Friday SMA 18, and Mg and   weekly chest x-ray, biweekly PT, PTT as well as 
the necessary fever workup will be done.  Patients can be followed in the 
outpatient unit unless they develop neutropenic fever, uncontrollable diarrhea or 
other problems requiring inpatient care.   All blood products will be filtered and 
radiated according to standards at the COH. 
 
 
Maintenance Therapy  
Starting no sooner than 30 days from day 0 of the second cycle (TMI), 
Lenalidomide 10 mg/d will be initiated daily for 3 months, and should the patient 
tolerate this dosing, the dose will be escalated to 15 mg/d for a total duration of 3 
years unless the patient cannot tolerate this medication or his or her disease 
progression. (See section 6.5.2 for dose modifications.) 
2/14/0
 
Aredia 90 mg iv every 12 weeks, or zoledronic acid 4 mg IV every 12weeks will 
be administered and will be continued for 36 months. 
 
6.5 
Dose Adjustments 
 
6.5.1 Melphalan 
 
There will be no dose adjustments for melphalan  
 
Pre-cycle 2 requirements should be met prior to initiating the second 
cycle. 
 
 
6.5.2 Lenalidomide 
 
Dose Modifications – In the instance of more than one observed toxicity, 
the greatest dose reduction should be applied 
 
 
 
 
Hematologic Dose Modification Months 1-3 
 
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• 
If on 2 capsules per day, the ANC is < 500/µL or the platelet count is 
<30,000/µL, then the study drug may be held for up to 8 weeks. Study 
drug may be re-instituted at 1 capsule per day if ANC is > 500/µL or the 
platelet count is under > 30,000/µL. If, however, after an 8 week treatment 

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delay, the ANC remains < 500/µL or the platelet count < 30,000/µL, the 
patient will be removed from protocol therapy. 
• 
If on 1 capsule per day, the ANC is < 500/µL or the platelet count is < 
30,000/µL, then the study drug may be held for up to 8 weeks. If ANC > 
500/µL or the platelet count is > 30,000/µL, then study drug may be re-
instituted at 1 capsule per day for 21 of 28 days. If, however, after an 8 
week treatment delay, the ANC remains < 500/µL or the platelet count < 
30,000/µL, the patient will be removed from protocol therapy. 
• 
If on 1 capsule per day for 21 of 28 days, the ANC is < 500/µL or the 
platelet count is < 30,000/µL, then the patient will be removed from 
protocol therapy. 
 
 
 
 
 
Hematologic Dose Modification beyond Month 3 
 
• 
If on 3 capsules per day, the ANC is < 500/µL, then the study drug may e 
held for up to 8 weeks. Study drug may be re-instituted at 2 capsules per 
day if ANC is > 500/µL or platelet count is > 30,000/µL. If, however, after 
an 8 week treatment delay, the ANC remains < 500/µL or platelet count < 
30,000/µL, the patient will be removed from protocol therapy. 
• 
If on 2 capsules per day, the ANC is < 500/µL or the platelet count is < 
30,000/µL, then the study drug may be held for up to 8 weeks. If ANC is > 
500/µL or the platelet count is > 30,000, then study drug may be re-
instituted at 1 capsule per day. If, however, after an 8 week treatment 
delay, the ANC remains < 500/µL or the platelet count < 30,000/µL, the 
patient will be removed from protocol therapy. 
• 
If on 1 capsule per day, the ANC is < 500/µLor the platelet count is < 
30,000/µL, then the study drug may be held for up to 8 weeks. If ANC > 
500/µL or the platelet count is > 30,000/µL, then study drug may be re-
instituted at 1 capsule per day for 21 of 28 days. If, however, after an 8 
week treatment delay, the ANC remains < 500/µL or the platelet count < 
30,000/µL, the patient will be removed from protocol therapy. 
• 
If on 1 capsule per day for 21 of 28 days, the ANC is < 500/µL or the 
platelet cunt is < 30,000/µL, then the patient will be removed from 
protocol therapy. 
 
 
 
 
 
Dose Escalation beyond Month 3 
 
If a dose reduction has occurred and ANC > 1000/µL and platelet count is 
> 75.000/µL, the study drug dose may be re-escalated by one level (i.e., 
one capsule every day to two capsules every day, etc.). Hematologic 
parameters must remain at these threshold values for one month before 
another dose escalation may occur. Maximum study drug dose will be 3 
capsules per day. 
 
If for any reason, a patient is not able to be dose escalated, dose escalation 
should be attempted by the time of the next re-staging. If at next restaging, 

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the patient has not recurred or progressed, and the patient is not able to be 
dose escalated, patient may continue on treatment at current dose level. 
If for any reason the drug is held for a non-grade 3 hematologic toxicity, 
the drug will be held until the toxicity resolves and the drug started at one 
dose level lower. The drug should be re-escalated to the original dose 
within 4 weeks. The drug should be escalated as per the criteria listed 
above. 
 
Non-Hematologic Toxicity Dose Modifications 
 
 
 
 
 
Neurologic Toxicity 
 
 
• 
If on 3 capsules per day, a patient experiences > grade 3 neurologic 
toxicity, then the study drug may be held for as many as 8 weeks. If 
toxicity resolves to < grade 1, then study drug may be re-instituted at 2 
capsules per day. If, however, after an 8 week treatment delay, the toxicity 
does not resolve to < grade 1, the patient will be removed from protocol 
therapy. 
• 
If on 2 capsules per day, a patient experiences > grade 3 neurologic 
toxicity, then the study drug may be held for as many as 8 weeks. If 
toxicity resolves to < grade 1, then study drug may be re-instituted at 1 
capsule per day. If, however, after an 8 week treatment delay, the toxicity 
does not resolve to < grade 1, the patient will be removed from protocol 
therapy. 
• 
If on 1 capsule per day, a patient experiences > grade 3 neurologic 
toxicity, then the study drug may be held for as many as 8 weeks. If 
toxicity resolves to < grade 1, then study drug may be re-instituted at 1 
capsule per day for 21 of 28 days. If, however, after an 8 week treatment 
delay, the toxicity does not resolve to < grade 1, the patient will be 
removed from protocol therapy. 
• 
If on 1 capsule per day for 21 of 28 days, a patient experiences > grade 3 
neurologic toxicity, then the patient will be removed from protocol 
therapy. 
 
 
Cardiac Toxicity 
 
• 
If on 3 capsules per day, a patient experiences > grade 2 cardiac toxicity, 
then the study drug may be held for as many as 8 weeks. If toxicity 
resolves to < grade 1, then study drug may be re-instituted at 2 capsules 
per day. If, however, after an 8 week treatment delay, the toxicity does not 
resolve to < grade 1, the patient will be removed from protocol therapy.  
• 
If on 2 capsules per day, a patient experiences > grade 2 cardiac toxicity, 
then the study drug may be held for as many as 8 weeks. If toxicity 
resolves to < grade 1, then study drug may be re-instituted at 1 capsule per 
day. If, however, after an 8 week treatment delay, the toxicity does not 
resolve to < grade 1, the patient will be removed from protocol therapy. 

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• 
If on one capsule per day, a patient experiences > grade 2 cardiac 
toxicity, then the study drug may be held for as many as 8 weeks. If 
toxicity resolves to < grade 1, then study drug may be re-instituted at 1 
capsule per day for 21 of 28 days. If, however, after an 8 week treatment 
delay, the toxicity does not resolve to < grade 1, the patient will be 
removed from protocol therapy. 
• 
If on one capsule per day for 21 of 28 days, a patient experiences > 
grade 1 cardiac toxicity, then the patient will be removed from protocol 
therapy. 
 
 
Other Non-Hematologic Toxicity 
 
• 
For other grade 3 non-hematologic toxicity, hold CC-5013 until toxicity 
resolves to < grade 2, then the study drug should be resumed at the next 
lower close level. 
• 
For patients who develop grade < non-hematologic toxicity, an attempt 
will be made to maintain the patient at that dose level. If the patient cannot 
tolerate this dose level, the treating physician should decrease the dose to 
the next lower dose level. 
• 
For other grade 4 non-hematologic toxicity, discontinue study drug and 
contact the Study Chair or Co-Chair. 
 
 
In the event of any grade 1 or 2 toxicity that the patient finds 
intolerable, the study drug may be held until the toxicity resolves and the 
study drug resumed at the next lower dose level. Alternatively, the study 
drug may be continued at the next lower dose level without cessation of 
study drug. However, study drug should be held for the occurrence of a 
resh consistent with evolving Stevens-Johnson syndrome or toxic 
epidermal necrolysis (bullous, blistering that is purpuric in nature) until 
appropriate evaluation is made. Study drug may be held for up to 8 weeks. 
Contact the Study Chair or Co-Chair for consultation. 
Venous Thrombosis 
 
Patients who develop signs of symptoms suggestive of thrombosis should 
be evaluated and treated as clinically indicated. CC-5013 should be held 
for patients with venous thrombosis CC-5013 may resume when patient is 
adequately anticoagulated. Patients with recurrent thrombosis despite 
adequate anticoagulation should ge removed from protocol therapy. 
 
Renal Toxicity 
 
• For creatinine clearance (CrCI) < 30 mL/min skip Lenalidomide and 
reassess in four weeks. If CrCI remains < 30 Ml/min after four weeks, 
then discontinue Lenalidomide. 
• For CRCI < 60 mL/min but > 30 mL/min: 
o If on 3 capsules per day, decrease Lenalidomide to 1 capsule 
alternating with 2 capsules daily (1 capsule on day, followed by 2 

capsules the next day…etc.). Reassess after four weeks and 
attempt to re-escalate Lenalidomide. 
o If on 2 capsules per day, decrease Lenalidomide to 1 capsule per 
day. Reassess after four weeks and attempt to re-escalate 
Lenalidomide. 
o If on 1 capsule per day, decrease Lenalidomide to 1 capsule per 
day for 21 of 28 days. Reassess after four weeks and attempt to re-
escalate Lenalidomide. 
 
 
 
 
6.5.4 Pamidronate or zoledronic acid 
 
There will be no dose adjustments.  Pamidronate or zoledronate can be 
premedicated with a non-steroidal anti-inflammatory agent, or with 
acetaminophen, if fever or constitutional symptoms occur following 
administration. 
 
7.0 
EVALUATION AND TOXICITIES 
 
Physical evaluation, laboratory and radiographic evaluation will be performed as outlined below.  
When evaluating toxicity CTCAE version 3 will be used. 
 
7.1. 
Patients will be examined and graded by the treating physician for subjective and                          
objective evidence of toxicities according to the Common Terminology Criteria 
for Adverse Events v3.0 (CTCAE), which can be found at: 
<http://ctep.cancer.gov/reporting/ctc.html> daily during both the first and second 
treatment cycle through recovery, monthly for the first year and then yearly for 
the first three years.   
 
7.2 
Dose Limiting Toxicity (DLT): 
 
Dose Limiting Toxicity (DLT) will be based on toxicities observed following the 
second cycle: TMI followed by PBPC  
 
Toxicity grading will be based on the NCI CTCAE version 3.0 which can be 
found at http://ctep.cancer.gov/reporting/ctc.html. 
 
To be fully treated and fully followed for toxicity, a patient must receive both 
cycles of the tandem transplant (cycle 1: melphalan, followed by cycle 2: TMI) at 
the planned doses and be observed for at least 4 weeks after the start TMI, or have 
experienced DLT following the second cycle.  All patients who are not fully 
treated and fully followed for toxicity will be replaced before dose escalation is 
permitted. 
 
Toxicity will be graded according to the NCI common toxicity criteria (CTCAE 
v3.0).  Dose limiting toxicity (DLT) in a given patient is defined as: 
 
7.2.1 Any Grade 3, non-hematologic unexpected toxicity (not reversible to 
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grade 2 or less within one week from the onset). 
 
7.2.2 Grade 4 thrombocytopenia, if it lasts beyond 28 days 
 
7.2.3 Grade 4 neutropenia associated with fever or infection and lasting beyond 
three weeks, or grade 4 neutropenia lasting for more than 28 days. 
 
 
7.2.4 The following will not be considered DLT:  
  
 
 
 
7.2.4.1 > Grade 3 nausea or > Grade 3 vomiting that occurs following 
non-compliance with protocol prescribed antiemetic therapy 
 
 
7.2.4.2 > Grade 3 diarrhea that occurs following non-compliance with 
protocol prescribed therapy 
 
 
7.1.5.3 any Grade 3 fatigue 
 
7.3 
Dose Escalation Rules: 
 
A Phase I Tracking log will be completed and kept by the Clinical Research 
Associate (CRA) and the Statistician from the Department of Biostatistics. 
 
Rules for dose escalation and expansion in cohorts of patients are based on DLT 
occurring following each patient’s second transplant in the tandem. Patients who 
drop out prior to the second cycle will be considered inevaluable. Three patients 
will be treated at each new dose level.  If 0/3 patients experience DLT attributable 
to the study treatment, 3 patients will be treated at the next dose level.  If DLT 
attributable to the treatment (i.e. definitely, probably, or possibly attributed) is 
experienced in exactly 1/3 of patients, 3 more patients (for a total of 6) will be 
treated at that dose level.  If no additional DLT, attributable to the treatment, is 
observed at the expanded dose level (i.e. 1/6 with DLT), the dose will be 
escalated.  Escalation will terminate as soon as two or more patients experience 
any DLT attributable to the study treatment, at a given dose level or a treatment 
related death is observed following the 2nd cycle.  The Phase I trial will be closed 
when 6 patients have been treated at the next lower dose level, and at most 1/6 
patients experience DLT.  If more than 1/6 patients experience DLT, the next 
lower dose will be expanded. 
 
Once the MTD has been determined, additional accrual at the MTD will 
commence, beginning the phase II portion of the study (the initial 6 patients 
treated at the MTD during the dose escalation will be counted in the phase II 
portion). 
 

 
8.0 
STUDY PARAMETERS 
 
 
Within 6 
Wks Pre-
Cytoxan 
Pre-
Cycle 
1 
Cycle 1
Pre-
Cycle 
2 
Cycle 2
30 
days** 
Q 6 
mos#
Q 
yr+
History and Physical 
X 
X 
 
X 
X 
X 
X#**
X 
CBC, DIFF, 
PLT/SMA7 
X^ 
X 
Daily  
X 
 Daily  
X 
X#**
X 
SMA 18, MG++
X^ 
X 
M,W,F 
X 
M,W,F 
X 
X#**
X 
PT, PTT 
X 
X 
 
X 
QO 
Week 
 
 
X 
Urinalysis, Creat 
Clearance 
X 
 
 
X 
 
 
 
 
Chest X-ray 
X 
 
Q 
Week 
X 
Q 
Week 
 
 
 
MRI of axial skeleton 
or PET scan as 
clinically indicated by 
bone x-rays 
X 
 
 
 
 
 
X ** 
X 
SPEP, IEP, Beta-2 
Microglobulin 
X 
 
 
X 
 
X‡
X#**
X 
24 hr urine for PEP, 
IEP, total protein, 
creatinine clearance 
X 
 
 
X 
 
X‡
X#**
X 
MUGA Scan/ or echo 
X 
 
 
X 
 
 
 
X 
** 
VRE Evaluation (by 
Swab or Stool 
 
X 
 
 
X 
 
 
 
EKG 
X 
 
 
X 
 
 
 
X 
** 
PFT 
X 
 
 
 
 
 
 
 
AB, RH, HLA Typing 
X 
 
 
 
 
 
 
 
BM, ASP, BX,  
morphology, 
cytogenetics, FISH,  
clonal hematopoiesis, 
(two cyto tubes and 
three green tops) 
vascular density 
establishing cell lines- 
X 
 
 
X 
 
X‡
X#**
X 
Blood for 
Cytogenetics,FISH 
and clonal 
hematopoiesis  
(Humara- two green 
tops) 
X 
 
 
 
 
 
X#**
X 
2/14/06 
2/7/05
2/7/05
2/7/05
2/7/05
8/8/07
2/14/06
2/7/05
2/7/05
2/7/05
2/7/05
7/18/05
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Within 6 
Wks Pre-
Cytoxan 
Pre-
Cycle 
1 
Cycle 1
Pre-
Cycle 
2 
Cycle 2
30 
days** 
Q 6 
mos#
Q 
yr+
PBPC product for 
cytogenetics, FISH 
clonal hematopoiesis 
two cytogenetic tubes. 
 
X 
 
 
 
 
 
 
Urine Pregnancy Test  
(For female patients) 
X 
 
 
 
 
 
 
 
HIV, Hepatitis Panel 
to include A,B,C; 
Herpes and CMV Titer 
X 
 
 
 
 
 
 
 
 
#Counting from day 0 of cycle 2 only during the first year.  
* (pre-Lenalidomide) and 4 months from day 0 of cycle 1; 
**During the first year if the MRI/PET scans are positive pre-study initiation and/or as clinically indicated; 
‡ At 30 days from day 0 of cycle 2 
^ within a week prior to cyclophosphamide priming 
 
2/7/05
2/7/05
2/14/06 
7/18/05 
9.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
The following definitions will be used for this study.  Response can be defined as a 50% 
or better reduction in serum myeloma protein production and further categorized as 
completed and partial.   
 
9.1 
Response Gradations: 
 
9.1.1 Complete response: Defined as the absence of bone marrow or blood 
findings of multiple myeloma on at least 2 measurements at a minimum of 
a 6 week interval.  Thus all evidence of serum and urinary M-components 
must disappear on electrophoresis as well as by immunofixation studies.  
The follow-up bone marrow may not contain more than 5% plasma cells 
on aspiration or core biopsy and no evidence of increasing anemia.  
Skeletal X-rays must either show recalcification or no change in osteolytic 
lesions. Resolution of soft tissue plasmocytomas. 
 
9.1.2 Partial Response:  Sustained decrease of the monoclonal serum protein by 
> 50% reduction) on at least two measurements of at least 6 week interval.  
A response is clear-cut for patients who achieve a 75% or greater 
reduction in the serum myeloma protein concentration without evidence of 
increasing anemia.  Responding patients must also have a sustained 
decrease in 24-hour urine M-component to less of the initial prestudy 
value, and to less than 0.2 gm/day on at least two measurements at three-
week intervals.  For a response to be confirmed, a marked reduction in 
both serum myeloma protein and in Bence-Jones protein excretion must be 
present.  Bone marrow plasma cells should be reduced by at least 50% 
from the pretreatment level, and soft tissue plasmocytomas should be 
reduced by ≥ 50%. 
 

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Very Good Partial Response:  Defined as reduction  of bone marrow or 
blood findings of multiple myeloma on at least 2 measurements at a 
minimum of a 6 week interval By ≥ 90%  
 
9.1.3 In all complete, and responding patients, the size and number of lytic 
skeletal lesions must not increase, and the serum calcium must remain 
normal.  Any of the following ancillary data will support the conclusion 
that an objective response has occurred, but are not required to confirm 
response:  1) recalcification of lytic skull or pelvis lesions (occurs in about 
20% of responding patients with lytic lesions); 2) significant increase in 
depressed normal immunoglobulins, as in lgM increments exceeding 20 
mg%, lgA exceeding 40 mg%, and lgG exceeding 400 mg% (occurs in 
about 15% of responding patients); 3) fall in the level of the serum beta-2 
microglobulin to the normal range (less than 1.0 mg/dl). 
   
9.2 
Minor response:  Patients with 25 - 49% tumor mass regression without new 
symptoms or signs of myeloma with declines in the serum myeloma protein 
production of 25% to 49% , or 50-89% reduction in 24 hour urinary light chain 
excretion, which still exceeds 200 mg/24 hours, and maintained for a minimum of 
6 weeks. 
 
9.3 
Stable disease:  Is defined as a lack of progression (change of < 25% myeloma 
protein) for a minimum duration of 3 months. 
 
9.4 
Progression:  Any of the following: patients with a > 25% increase in myeloma 
protein production and confirmed at least once on repeated examination within 2-
4 weeks, or other signs of disease such as hypercalcemia > 11.5 mg/dL, or new 
bone/plasmocytoma lesions.  >25% increase in bone marrow biopsy of  plasma 
cells, with a minimum of 10% involvement.    
 
9.5 
Relapse:  This is defined by the unequivocal objective evidence and constitutes 
the earliest of any of the following:  1) an increase by more than 100% from the 
lowest level of the serum myeloma protein production; 2) an increase above the 
response level of the myeloma peak (i.e., relapse to more than 25% of the baseline 
myeloma protein production); 3) reappearance of the myeloma peaks that had 
disappeared with the treatment; 4) definite increase in the size and number of lytic 
bone lesions recognized on radiographs; 5) Newly developed soft tissue 
plasmocytoma; 6)  >25% increase in bone marrow biopsy of plasma cells, with a 
minimum of 10% involvement.  Compression fractures per se do not constitute a 
relapse.   
 
9.6 
Performance Status:  Karnofsky Performance status will be recorded. 
 
10.0 
REPORTING DATA 
 

All primary data will be maintained by the Department of Biostatistics, City of Hope 
National Medical Center. This includes on study flow sheets, consent forms and off-study 
forms. 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
STUDY DESIGN FOR THE PHASE I PART OF STUDY AND RULES FOR 
DOSE ESCALATION 
 
 
Rules for dose escalation, dose expansion, and termination of escalation are given 
 
below. 
 
 
For each patient, the enrollment, course initiation, dose, and adverse event data 
 
must be submitted on case report forms within two weeks of the end of the first 
 
course, as these data will form the basis for dose escalation decisions.  No 
 
additional patients may be enrolled at an escalated dose until all patients from the 
 
current dose level have been fully followed, and their data collection forms have 
 
been received and the escalation has been approved by the PI and study 
 
coordinator. 
 
11.2 
Dose Limiting Toxicity (DLT) will be based on toxicities observed following the 
 
second cycle: TMI followed by PBPC  
 
Toxicity grading will be based on the NCI CTCAE version 3.0.   
 
To be fully treated and fully followed for toxicity, a patient must receive both 
cycles of the tandem transplant (cycle 1:melphalan, followed by cycle 2:TMI) at 
the planned doses and be observed for at least 4 weeks after the start TMI, or have 
experienced DLT following the second cycle.  All patients who are not fully 
treated and fully followed for toxicity will be replaced before dose escalation is 
permitted. 
 
Toxicity will be graded according to the NCI common toxicity criteria (CTCAE 
v3.0).   Dose limiting toxicity (DLT) in a given patient is defined as: 
 
11.2.1 Any Grade 3, non-hematologic unexpected toxicity (not reversible to 
grade 2 or less within one week from the onset). 
7/12/06
 
11.2.2 Any Grade 4 non-hematologic toxicity 
 
11.2.3 Grade 4 thrombocytopenia, if it lasts beyond 28 days 
 
11.2.4 Grade 4 neutropenia associated with fever or infection and lasting beyond 
three weeks, or grade 4 neutropenia lasting for more than 28 days. 
 
11.2.5 The following will not be considered DLT:   
 
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11.2.5.1  > Grade 3 nausea or > Grade 3 vomiting that occurs  
 
 
following non-compliance with protocol prescribed  
 
 
antiemetic therapy 
 
11.2.5.2 
> Grade 3 diarrhea that occurs following non-compliance 
 
with protocol prescribed therapy 
 
11.2.5.3 
any Grade 3 fatigue 
 
 
11.3 
Maximum Tolerated Dose (MTD) 
 
The maximum tolerated dose (MTD) is defined as the highest dose tested in 
which there is no treatment related mortality and none or only one patient 
experienced DLT attributable to the study drug(s), when at least six patients were 
fully treated at that dose and fully followed for toxicity.  The MTD is one dose 
level below the lowest dose tested in which 2 or more patients experienced DLT 
attributable to the treatment or there was a treatment related death.  At least 6 
patients will be treated at the MTD.   
 
 
11.4 
Dose Escalation Schedule 
 
The dose of melphalan is fixed.   The dose of the helical radiation will follow the 
dose escalation according to the schedule given below.   
 
Level 
Day 1 
(cGy) 
Day 2 
(cGy) 
Day 3 
(cGy) 
Day 4 
(cGy) 
Day 5 
(cGy) 
Total Dose 
(cGy) 
1 
200 
 
200 
200 
200 
200 
1000 
2 
200 AM 
200 PM 
200 
200 
200 
200 
1200 
3 
200 AM 
200 PM 
200 AM 
200 PM 
200 
200 
200 
1400 
4 
200 AM 
200 PM 
200 AM 
200 PM 
200 AM 
200 PM 
200 
200 
1600 
5 
200 AM 
200 PM 
200 AM 
200 PM 
200 AM 
200 PM 
200 AM 
200 PM 
200 
1800 
6 
200 AM 
200 PM 
200 AM 
200 PM 
200 AM 
200 PM 
200 AM 
200 PM 
200 AM 
200 PM 
2000 
If at any time during the dose escalation part of this study, a treatment related 
mortality is observed, that dose level will be closed and the dose below will either 
be declared the MTD or further patients will be accrued at that lower dose level if 
less than 6 evaluable patients have been accrued to that level. 
 
 
11.5 
Numbers of Patients and Rules for Dose Escalation 
 
 
Rules for dose escalation and expansion in cohorts of patients are based on DLT 
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occurring following each patient’s second transplant in the tandem. Patients who 
 
drop out prior to the second cycle will be considered inevaluable. Three patients 
 
will be treated at each new dose level.  If 0/3 patients experience DLT attributable 
 
to the study treatment, 3 patients will be treated at the next dose level.  If DLT 
 
attributable to the treatment (i.e. definitely, probably, or possibly attributed) is 
 
experienced in exactly 1/3 of patients, 3 more patients (for a total of 6) will be 
 
treated at that dose level.  If no additional DLT, attributable to the treatment, is 
 
observed at the expanded dose level (i.e. 1/6 with DLT), the dose will be 
 
escalated.  Escalation will terminate as soon as two or more patients experience 
 
any DLT attributable to the study treatment, at a given dose level or a treatment 
 
related death is observed following the 2nd cycle.  The Phase I trial will be closed 
 
when 6 patients have been treated at the next lower dose level, and at most 1/6 
 
patients experience DLT.  If more than 1/6 patients experience DLT, the next 
 
lower dose will be expanded. 
 
 
Once the MTD has been determined, additional accrual at the MTD will 
 
commence, beginning the phase II portion of the study (the initial 6 patients 
 
treated at the MTD during the dose escalation will be counted in the phase II 
 
portion).   
 
 
 
 
 
11.6 
This is a Phase I/II study of tandem high-dose therapy consisting of melphalan 
(cycle 1) and then TMI (cycle 2) for patients with multiple myeloma.   During the 
dose escalation, the melphalan dose will be held constant, and the radiation dose 
will be escalated to find the maximum tolerated dose, which will also be deemed 
the recommended dose.   
 
 
11.7 
This study is expected to accrue a minimum of 31 evaluable patients, with an 
expected accrual of 53-75 patients. The study should be completed by early 2013 
the latest with a projected minimum yearly accrual of 6 patients per year.  
 
11.8 
Analysis of Clinical Endpoints of Phase I portion: The design of the Phase I 
 
portion of the trial is described above, together with the definition DLT, and 
 
MTD. 
 
 
 
The toxicities observed at each dose level will be summarized in terms of type 
(organ affected or laboratory determination such as absolute neutrophil count), 
severity (by NCI Common Toxicity Criteria (version 3) and nadir or maximum 
values for the laboratory measures), time of onset (i.e. course number), duration, 
and reversibility or outcome.  Tables will be created to summarize these toxicities 
and side effects by dose and by course.  Baseline information (e.g. the extent of 
prior therapy) and demographic information will be presented, as well, to describe 
the patients treated in this study.  All responses will be reported.  Survival and 
time to failure will be summarized both by pooling across dose levels and by dose 
level, although the primary outcome of the phase II portion will include only the 
patients accrued at the MTD. 
 
11.9 
Study design and sample-size for Phase II portion of study:  

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11.9.1 Sample-size for Phase II portion: For the purpose of this analysis the rate 
response is defined as sum of a near CR (Very Good Partial Response) or 
a CR as described in the response criteria. To estimate the response rate a 
two stage minimax design suggested by Simon will be used [ref 2].  It is 
assumed that a true response rate less than 50% would not warrant further 
study of this regimen.  It is also assumed that a response rate of 68% 
would be considered promising for further studies.  In the first stage, 28 
evaluable patients will be entered.  If less than 14 responses are observed, 
the accrual will stop with the conclusion that the regimen is not promising 
for further study.  If 15 or more responses are observed in the first 28 
patients, an additional 22 patients will be accrued during the second stage 
of the phase II accrual. 30 or more responses out of 50 patients will be 
considered as evidence warranting further study of the regimen providing 
other factors, such as toxicity and survival, also appear favorable.  If less 
than 30 responses out of 50 patients are observed, further study of the 
regimen would not be warranted.  The probability of falsely declaring an 
agent with a 50% response probability as warranting further study is 0.1 
(alpha) and the probability of correctly declaring an agent with a 68% 
response probability as warranting further study is 90% (power). As 
evaluation of response takes several months, it is likely that accrual will 
exceed the interim stopping point prior to being able to evaluate the first 
28 patients. If that is the case, curtailed sampling will be employed two 
months after the first 28 patients have been treated to estimate the 
probability of passing the required threshold. If the probability of failing to 
meet the required threshold exceeds 50% under the promising response 
rate assumption, accrual will cease until additional follow-up is obtained 
on the 28 patients (up to 6 months may be required for a confirmation of a 
response). With 50 patients the true probability of response can be 
estimated with a maximum standard error equal to 7%. 
 
11.9.2 Accrual to the Phase II portion: Based on the current referral patterns to 
the City of Hope, it was expected that approximately 20 patients per year 
will be eligible for this study. With a goal of 50 patients treated at the 
MTD. The protocol will need to remain open through 2013. As the 
majority of relapses are expected to occur within 3 years, and it will take 
approximately 1 year to find the MTD, this study will continue to allow 
for sufficient follow-up for the secondary goal of analyzing disease 
progression and survival. 

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11.9.3 Early Stopping Rules: 
 
Number of Patients Accrued at MTD 
Number of treatment-related deaths Permitted 
20 
<2 
30 
<3 
40 
<3 
 
11.9.4 Specifically, if there are 2 treatment related deaths in the first 20 patients, 
the study will be stopped. If there are 3 treatment related deaths in the first 
40 patients, the study will be stopped.   Due to the follow-up time, if there 
are two treatment related deaths in the first 20 patients, but the treatment 
related deaths occur when there are a total of 30 patients accrued, no 
further accrual will occur, until six months of follow-up are obtained on 
the 30 patients. If there are no further treatment related deaths, accrual will 
recommence.  Additional safe guards/stopping rules include: Grade 4 
thrombocytopenia lasting beyond 28 days, Grade  4 neutropenia associated 
with fever or infection and lasting beyond 3 weeks, or  grade 4 
neutropenia lasting beyond 28 days without fever in more than 2 of 20 
patients, or more than 3 of 30 patients, or  more than 4 of 40 patients 
during the second phase of the study.  
 
11.9.5 This stopping rule provides a 41% probability of stopping at 20 patients if 
the true TRM rate is 7%, and provides a greater than 50% chance of 
stopping prior to completion of accrual. If the true TRM rate is 1.5%, there 
is less than a 4% chance of stopping at 20 patients, and less than a 10% 
chance of stopping prior to the completion of accrual. 
 
11.9.6 Survival Analysis: If our accrual goal is met with no premature 
termination due to significant toxicity or lack of response, a secondary 
goal of assessing progression-free survival (PFS) and overall survival 
(OS) will be carried out. Survival estimates will be made using the 
product-limit method of Kaplan and Meier, with 95% confidence limits 
calculated using the logit transformation. These estimates will be 
contrasted with the historical rates at the City of Hope of 48.5% PFS and 
74.4% OS at three years, although formal hypothesis testing will not be 
conducted.  
 
12.0 
GENDER AND ETHNICITY STATEMENT 
 
The City of Hope has a plan in place to increase minority recruitment to our studies in 
compliance with the National Institute of Health policy for recruitment of women and 
minorities. 
 
The table below shows the distribution by sex and race of the patients accrued to 
therapeutic clinical studies at City of Hope for the past five years with the same primary 
site of disease targeted for this protocol (breast).  Our goal is to maintain our high accrual 
of women while continuing to increase the accrual of minority subjects. 

 
Accrual Goal by Sex and Ethnicity  
 
 
By Sex 
By Ethnicity 
Site 
Accrual 
Goal 
Female 
Male 
White 
Hispanic 
Black 
Asian/ 
Other 
Unknown
Multiple 
Myeloma 
 
367 
172 
(47%) 
195 
(53%) 
213 
(58%) 
66 
(18%) 
70 
(19%) 
14 
(4%) 
4 
(1%) 
 
 
13.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
This study is to be approved by the Institutional Review Board of the City of Hope.  All 
patients will have signed an informed consent for participation in research activities, and 
will have been given a copy of the Experimental Subject's Bill of Rights. 
 
When results of this study are reported in medical journals or at meetings, identification 
of those taking part will be withheld.  Medical records of patients will be maintained in 
strictest confidence, according to current legal requirements.  However, they will be 
made available for review, as required by the Food and Drug Administration (FDA) or to 
other authorized users such as the National Cancer Institute (NCI) under the guidelines 
established by the Federal Privacy Act. 
 
2/14/06
14.0 
DATA AND SAFETY MONITORING 
14.1  
Definition of Risk Level 
  
This is a Risk Level 3 study, as defined in the “Guidance, Policy and Procedures for 
Data and Safety Monitoring for In-House Trials at City of Hope”, 
http://www.infosci.coh.org/gcrc/doc/dsmp.doc because it is a Phase I/II clinical trial 
where the risks are at least balanced by the potential benefit to subjects and the 
importance of the knowledge that may result. 
 
14.2 
Monitoring and Personnel Responsible for Monitoring 
 
The Protocol Management Team (PMT) consisting of the PI, Collaborating 
Investigator, CRA, protocol nurse, and statistician is responsible for monitoring the 
data and safety of this study, including implementation of stopping rules for safety.  
 
Reporting of data to the DSMB during the Phase I portion will occur at each decision 
to escalate a dose, and a Phase I tracking log will be submitted in addition to the 
toxicity summaries to the DSMB.  During the Phase II portion, reporting of data will 
occur at intervals separated by no more than six months, 10 patients or a treatment 
related death. This report (the PMT report) will include a summary of accrual, 
adverse events and treatment related mortality.  
 
   
 
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Type of Adverse Event 
When Reported 
● UNEXPECTED & SERIOUS ADVERSE EVENTS 
≥  GRADE 3 
that are possibly, probably or definitely related to the study 
procedures  
Within 5 business days 
(The report will be forwarded to the IRB concurrent with 
the DSMB review.  The report and the DSMB review will 
also be forwarded to the CPRMC when the DSMB review is 
complete.) 
● UNEXPECTED & SERIOUS ADVERSE EVENTS 
> GRADE 4 
that are unrelated or unlikely related to the study procedures 
Within 10 business days 
(The report and the DSMB review will be forwarded to the 
IRB and the CPRMC when the DSMB review is complete.) 
● EXPECTED & SERIOUS ADVERSE EVENTS 
≥  GRADE 4 
Cancer Therapeutic Trials without dose escalation:  
thrombocytopenia and non-hematologic events ≥ Grade 4 
Cancer Therapeutic Trials with dose escalation: neutropenia, 
thrombocytopenia and non-hematologic events ≥ Grade 4 
Non-Cancer Studies: All events ≥ Grade 4 
Within 10 business days 
(The report and the DSMB review will be forwarded to the 
IRB and the CPRMC when the DSMB review is complete.) 
 
14.3 
 Adverse Events 
 
14.3.1. Reporting: Adverse events must be reported to the COH DSMB, IRB, and 
GCRC (if GCRC supported) according to definitions and guidelines at 
http://www.infosci.coh.org/gcrc/doc/dsmp.doc and 
http://resadmin.coh.org/doc/irb3810.doc, which are defined below.  SAEs 
will be monitored by the PMT. Less than serious adverse events will be 
reported only at the time of protocol continuation reports. In the event that an 
SAE is categorized as an “unacceptable toxicity” or “treatment related 
mortality”, the tables in section 11 will be checked to verify that no toxicity 
based stopping condition has been met.    
 
14.3.2. Adverse Event - An adverse event (AE) is any untoward medical experience 
or change of an existing condition that occurs during or after treatment, 
whether or not it is considered to be related to the protocol intervention. All 
AEs occurring during this study, whether observed by the physician, nurse, or 
reported by the patient, will be recorded on the City of Hope National 
Medical Center Adverse Events (COH AER) form 
(http://resadmin.coh.org/doc/irb3820.doc).  
 
14.3.3 Serious Adverse Event- A serious adverse event (SAE) is defined as any 
expected or unexpected adverse event (AE, generally equivalent to 
CTCAE grades 3, 4 or 5) that is related or unrelated to the intervention 
that results in any of the following outcomes: 
 
• Death 
• A life-threatening event 
• In-patient hospitalization (not required as part of the treatment) or   
             
prolongation of existing hospitalization 

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• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
• Causes cancer 
• Is an overdose 
 
Certain medical events that may not result in death, be life-threatening, or 
require hospitalization, may also be considered a serious adverse event when 
appropriate medical or surgical intervention is necessary to prevent one of the 
outcomes listed above. 
 
14.3.4 Unexpected Adverse Event – Any event in which the severity or specificity is 
not consistent with the risk information described in the protocol, and the 
event is not anticipated from the subject's disease history or status. 
 
14.3.5. Expected Adverse Event - Any event in which the severity or specificity is 
consistent with the risk information described in the protocol or is anticipated 
based on the subject's medical history. 
 
14.3.6. Attribution - For reporting purposes, attribution is the assessment of the 
likelihood that an AE is caused by the research agent or protocol intervention.  
The attribution is assigned by the Principal Investigator after considering the 
clinical information, the medical history of the subject, and past experience 
with the research agent/intervention.  This is recorded using the Adverse 
Event Report (COH AER) form (http://resadmin.coh.org/doc/irb3820.doc) in 
one of 5 categories scored as the following: 5=related, 4=probably related, 
3=possibly related, 2=unlikely related and 1=unrelated.  The attribution is 
subject to change as follow-up information becomes available, and it can be 
changed by the DSMB or by the IRB in the process of review. 
 

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14.0 
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