Conditions: Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
This phase II trial studies how well panobinostat, carfilzomib, and dexamethasone work in treating patients with multiple myeloma that has come back (relapsed) or does not respond to treatment (refractory). Panobinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as carfilzomib and dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Using multiple myeloma cells from patients' blood samples, the researchers will do laboratory tests to look at how well each of the drugs, alone and in different combinations, kill multiple myeloma cells. If the laboratory tests work well, they may be used in the future to help plan treatment for future patients.

Detailed description:
PRIMARY OBJECTIVE:

I. To correlate in vitro drug sensitivity testing with clinical response by determining the rate of in vitro drug sensitivity to panobinostat, carfilzomib, and dexamethasone singly and in combination, doublets and triplets.

SECONDARY OBJECTIVE:

I. To monitor response rates (partial response \[PR\], very good partial response \[VGPR\], and complete response) using the International Myeloma Working Group Uniform Response Criteria for Multiple Myeloma.

EXPLORATORY OBJECTIVE:

I. Progression free survival and overall survival will be assessed for up to 3 years after last dose.

OUTLINE:

Patients receive panobinostat orally (PO) on days 1, 3, 5, 15, 17, and 19. Patients also receive carfilzomib intravenously (IV) and dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and/or bone marrow samples for testing via in vitro chemosensitivity assay.

After completion of study treatment, patients are followed up every 3 months for up to 3 years.

Arms:
arm 1: Patients receive panobinostat PO on days 1, 3, 5, 15, 17, and 19. Patients also receive carfilzomib IV and dexamethasone PO on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood and/or bone marrow samples for testing via in vitro chemosensitivity assay.

Interventions: intervention 1: Carfilzomib intervention 2: Chemosensitivity Assay intervention 3: Dexamethasone intervention 4: Laboratory Biomarker Analysis intervention 5: Panobinostat
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo in vitro chemosensitivity testing intervention 3: Given PO intervention 4: Correlative studies intervention 5: Given PO

Protocol document:
Prot_SAP_001.pdf: 
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University of Washington 
Fred Hutchinson Cancer Research Center 
Seattle Cancer Care Alliance 
 
Previous Version: 4.0 13 January 2020 
Current Version: 5.0 23 December 2020 
 
CLBH589DUS108T: Panobinostat with Carfilzomib and Dexamethasone for 
Relapsed/Refractory Multiple Myeloma: Correlation with In Vitro 
Chemosensitivity Testing 
 
Principal Investigator:  
Andrew Cowan, MD 
Professor of Medicine 
University of Washington 
825 Eastlake Ave East 
Seattle, WA 98109 
Tel: 206-667-4551 
Email: ajcowan@seattlecca.org 
 
 
IRO received 11/18/21
FHCRC IRB Approval  
DEC 22 2021 
Document Released Date


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Table of Contents 
Section 
Page 
1. Study Overview 
1.1. 
Study Objectives .................................................................................................... 4 
2. Background and Study Rationale ......................................................................................... 4 
3. Eligibility Criteria ................................................................................................................. 5 
3.1. 
Inclusion Criteria ................................................................................................... 5 
3.2. 
Exclusion Criteria .................................................................................................. 7 
4. Patient Registration............................................................................................................... 8 
5. Drug Information .................................................................................................................. 8 
5.1. 
Panobinostat .......................................................................................................... 8 
5.2. 
Carfilzomib .......................................................................................................... 11 
5.3. 
Dexamethasone .................................................................................................... 12 
6. Study Design and Treatment Plan ...................................................................................... 13 
6.1. 
Study Design........................................................................................................ 13 
6.2. 
Chemosensitivity Assay 
 .............................................................. 14 
6.3. 
Treatment ............................................................................................................. 14 
6.4. 
Treatment Courses ............................................................................................... 14 
6.5. 
Dose Reduction/Modification.............................................................................. 14 
7. Study Procedures ................................................................................................................ 16 
8. Criteria for Response .......................................................................................................... 18 
9. Document Retention ........................................................................................................... 18 
10. Regulatory and Reporting Requirements ........................................................................... 18 
10.1.    Adverse Event Monitoring and Reporting ........................................................... 18 
10.2.    Serious Adverse Events ....................................................................................... 19 
10.3.    Expedited Reporting Requirements ..................................................................... 19 
10.4     Pregnancy Reporting Requirements .................................................................... 20  
10.5 Concomitant Medications ................................................................................. 20 
11. Data and Safety Monitoring and Reporting ........................................................................ 20 
12. Statistical Considerations ................................................................................................... 21 
13. References .......................................................................................................................... 22 
APPENDICES 
Appendix A: Performance Status Criteria ................................................................................ 25 


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Appendix B: Schedule of Events .............................................................................................. 26 
Appendix C: International Myeloma Working Group Uniform Response Criteria for Multiple 
Myeloma ................................................................................................................................. 27 
  
       


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1. STUDY OVERVIEW 
1.1. Primary Objective 
To correlate in vitro drug sensitivity testing with clinical response we will determine rate of in vitro 
drug sensitivity to panobinostat, carfilzomib, and dexamethasone singly and in combination, doublets 
and triplets. We will determine parameters that predict that patients will achieve ≥ VGPR after 
clinical regimen. 
1.2. Secondary Objective 
To monitor response rates (partial response (PR), very good partial response (VGPR), and complete 
response) using the International Myeloma Working Group Uniform Response Criteria for Multiple 
Myeloma (Appendix C). 
1.3. Exploratory Objective 
Progression free survival and overall survival will be assessed for up to 3 years after last dose. 
2. BACKGROUND AND STUDY RATIONALE 
 
Several classes of drugs have proven efficacy in multiple myeloma and drug combinations have 
resulted in synergistic responses that have improved efficacy. The novel drug classes have included 
immunomodulatory drugs (IMiDS), proteasome inhibitors, monoclonal antibodies, and histone 
deacetylase inhibitors.  These agents have been combined with each other and conventional cytotoxic 
agents and steroids to comprise highly effective regimens, with a very high proportion of response in 
newly diagnosed and relapsed patients.   There are approved agents in each of the drug classes, and 
ongoing investigation of new agents.  
Histone deacetylase inhibitors have been shown to be effective agents in hematologic malignancies.  
Their mechanism of action is alteration of chromatin structure, leading to growth arrest, apoptosis and 
differentiation. Both vorinostat and panobinostat were used in clinical trials in multiple myeloma. The 
latter agent, panobinostat, was extensively studied in phase I, II and III trials, leading to FDA 
approval.  Rocilinostat (ACY1215) is a selective HDAC6 inhibitor and clinical trials in multiple 
myeloma are ongoing.  
Panobinostat is a histone deacetylase inhibitor with activity against Class I, II and IV nonhistone and 
histone deacetylases.  A dose escalation study of panobinostat in combination with bortezomib 
established a maximum tolerated dose of 20 mg of panobinostat administered three times a week in 
combination with bortezomib at 1.3 mg/m2/dose (San Miguel et al 2013).  A phase 3 trial 
demonstrated that panobinostat plus bortezomib and dexamethasone was superior to placebo plus 
bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma in terms of 
progression free survival (San Miguel et al 2014). This result led to the FDA approval of panobinostat 
in patients with relapsed, refractory multiple myeloma. In a phase 3 trial, 60.7% of patients responded 
to the combination, including 27.6% complete responses (San- Miguel et al 2014).   
 
Bortezomib was the first proteasome inhibitor that was approved for multiple myeloma, initially for 
relapsed patients, and subsequently, new diagnosis.  It is highly active, and combinations of 


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bortezomib with many other agents have been extensively studied, including 3 and 4 drug regimens.  
One of the most active regimens that is highly utilized upfront is the combination of lenalidomide and 
bortezomib with dexamethasone (Richardson et al., 2010) with a ≥ VGPR rate of 74%.  However, the 
combination of carfilzomib with lenalidomide and dexamethasone has also been highly effective in 
the upfront setting, with response rate of ≥ near complete remission (nCR) of 82% by 8 cycles, and 
100% ≥ nCR by 16 cycles (Dytfeld et al., 2014). Moreover, the depth of response was remarkable, 
with 35% stringent complete responses (sCR) by 8 cycles and 78% by 16 cycles.   Furthermore, 
carfilzomib has a much lower rate of neuropathy.  Based on these features, carfilzomib was then 
studied in combination with panobinostat.  
Panobinostat and carfilzomib were combined in a phase I/II trial for relapsed, refractory patients 
(Berdeja et al, 2015).  Four combinations of carfilzomib and panobinostat were utilized in this phase 
I/II trial of the combination to assess toxicity and efficacy. The maximum tolerated dose used for the 
phase II expansion was 30 mg panobinostat and 20 then 45 mg/m2 carfilzomib (Berdeja et al, 2015).  
 
Another comparison of additional doses of this combination demonstrated that panobinostat 20 mg on 
days 1,3,5,15,17,19 and carfilzomib 20 mg/m2 then 56 mg/m2/dose days 1,2,8,9,15,16 each cycle 
resulted in an overall response rate of 84% (34% ≥ VGPR, 50% ≥ PR) (Berdeja et al, 2015 abstract). 
      We now understand that there is a plethora of mutations associated with the development of multiple 
myeloma, and that there are gene expression signatures associated with prognosis. Each patient 
appears to have a unique pattern of mutations and gene expression. Given this heterogeneity, it might 
be predicted that individuals would have wide variability in response to standard drug combination s, 
and this is indeed the case. But when a new patient presents, or at the time of relapse, we do not yet 
have in hand the tools with which we might predict response with certainty.  A test that could predict 
which patients might be expected to respond to specific agents might enable clinicians to optimize 
therapy for individual patients. 
 
We have developed an in vitro assay (CLIA certified for AML thus far, including these drugs) for 
testing cancer cells that are adherent in 384 well plates. 
 
We propose to assay in vitro sensitivity of purified multiple myeloma cells obtained just prior to 
clinical treatment on a clinical trial, then perform statistical analysis to determine if the test was 
predictive of response.  The test will include 8 concentrations of the individual drugs, then 
combinations of the concentrations of each pair of drugs, and the triple drug combination. The assay 
will define combinations that lead to additive vs. synergistic cytotoxicity [analysis by isobolograms 
(Berenbaum, 1978; Steel and Peckham, 1979)].   We hope to define parameters of drug sensitivity to 
the individual drugs and/or drug combinations in vitro that correlate with clinical response. 
3. ELIGIBILITY 
3.1. Inclusion Criteria 
1. 
Age 18 or older 
2. 
Diagnosis of multiple myeloma refractory to or relapsed after ≥ 1 line of prior therapy 
(IMWG criteria) 


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3. 
Measurable disease, as indicated by one of the following: 
a. 
Serum M-protein ≥ 1.0 g/dL 
b. 
Elevated involved free light chain ≥ 10 mg/dL as per IMWG criteria, and abnormal 
ratio 
c. 
Urine Bence Jones protein >200mg/24 hr 
4. 
Adequate blood counts 
a. 
ANC ≥ 750/uL 
b. 
Platelet count ≥ 75,000/uL 
c. 
Hemoglobin ≥ 7 g/dL 
5. 
Adequate renal and hepatic function: 
 
a. 
Creatinine ≤ 2.0 mg/dL or calculated creatinine clearance ≥ 30mL/min 
b. 
Total bilirubin ≤ 1.5xULN unless elevation is thought to be due to Gilbert’s    
syndrome 
c. 
SGOT (AST) and SPGT (ALT) ≤ 2.5x ULN 
6. 
Patients must avoid consumption of grapefruit, pomegranates, starfruit, Seville oranges or 
products containing the juice of each during the entire study and preferably 7 days before the 
first dose of study medications, due to potential CYP3A4 interaction with the study 
medications. Orange juice is allowed. 
7. 
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, should have a pregnancy test prior to the initiation of treatment and use 
highly effective methods of contraception during and for 3 months post study treatment. 
Highly effective contraception methods include total abstinence, female sterilization, male 
sterilization, use of oral, injected, or implanted hormonal methods of contraception or 
placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of 
hormonal contraception that have comparable efficacy. Women using hormonal 
contraceptives should additionally use a barrier method of contraception. Women are 
considered post-menopausal and not of child-bearing potential if they have had 12 months of 
natural amenorrhea or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks ago.   
8. 
Sexually active males must use a condom during intercourse while taking study drug and for 
6 months after stopping treatment. Males should not father a child in this period. A condom 
is required to be used also by vasectomized men as well as during intercourse with a male 
partner. Female partners of sexually active men should also use an effective contraception 


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during treatment and for 6 months after their male partner has stopped taking the drug. 
 
3.2. Exclusion Criteria 
1. 
Another bone marrow malignancy 
2. 
Another cancer with expected survival of < 2 years 
3. 
Active viral, bacterial, or fungal infection progressing on current treatment 
4. 
Clinically significant uncontrolled heart disease and/or recent cardiac event within 6 months 
prior to enrollment, such as: 
a. 
History of angina pectoris, symptomatic pericarditis, or myocardial infarction 
b. 
History or presence of any significant, uncontrolled, or persistent cardiac arrhythmias, 
e.g. ventricular, supraventricular, nodal arrhythmias or conduction abnormality. Stable 
atrial fibrillation within 6 months prior to randomization is permitted. 
c. 
Presence of unstable atrial fibrillation (ventricular response rate > 100 bpm).  
NOTE: patients with stable atrial fibrillation can be enrolled provided they do not meet 
other cardiac exclusion criteria. 
d. 
Resting heart rate < 50 bpm 
e. 
Complete left bundle branch block (LBBB), bifascicular block 
f. 
Congenital long QT syndrome 
g. 
Any clinically significant ST segment and/or T-wave abnormalities 
h. 
Corrected QT (QTcF) > 450 msec for males and > 470 msec for females using 
Fridercia’s correction on screening Electrocardiogram (ECG)  
i. 
History of documented congestive heart failure (New York Heart Association 
functional classification III-IV) 
j. 
Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 150 mmHg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mmHg with or without antihypertensive 
medication.  
NOTE: initiation or adjustment of antihypertensive medication(s) is allowed prior to 
screening. 
k. 
Other clinically significant heart disease or vascular disease 
5. 
Currently taking medications that have known or definite risk of prolonging the QT interval 
or inducing Torsades de pointes (TdP). The medication must be discontinued or switched to 
a safe alternative medication prior to starting treatment. Specific exception is allowed for 


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patients on long-standing medications that have risk of prolonging QT interval or inducing 
TdP if screening ECG does not indicate a prolonged QT abnormality. For a list of drugs 
known to risk prolonging QT interval or inducing TdP, please refer to the published list of 
drugs at https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf 
6. 
Impairment of gastrointestinal (GI) Function or GI disease that may significantly alter the 
absorption of panobinostat or dexamethasone (e.g. ulcerative disease uncontrolled nausea, 
vomiting, malabsorption syndrome, obstruction, or stomach and/or small bowel resection) 
7. 
Unresolved diarrhea ≥ CTCAE grade 2 or a medical condition associated with chronic 
diarrhea (such an irritable bowel syndrome, inflammatory bowel disease) 
8. 
Major surgery ≤ 14 days prior to starting study treatment or side effects of surgery that have 
not recovered to < CTCAE grade 2 
4. PATIENT REGISTRATION 
Patients who fulfill eligibility criteria and who signed consent will be enrolled by the study 
coordinator.  
5.  DRUG INFORMATION 
 
5.1. Panobinostat 
1. 
Mechanism of Action 
Panobinostat (LBH589) is a deacetylase inhibitor (DACi) belonging to a structurally novel cinnamic 
hydroxamic acid class of compounds.  It is a potent class I/II pan-DAC inhibitor (pan-DACi) that has 
shown anti-tumor activity in pre-clinical models and cancer patients. Deacetylases (DAC) target 
lysine groups on chromatin and transcription factors and various non-histone proteins such as p53, 
tubulin, HSP90 and Rb. Panobinostat is formulated as an oral capsule. Inhibition of DAC provides a 
novel approach for cancer treatment.  Histones are part of the core proteins of nucleosomes, and 
acetylation and deacetylation of these proteins play a role in the regulation of gene expression.  
Highly charged deacetylated histones bind tightly to the phosphate backbone of DNA, inhibiting 
transcription, presumably, by limiting access of transcription factors and RNA polymerases to DNA.  
Acetylation neutralizes the charge of histones and generates a more open DNA conformation.  This 
conformation allows transcription factors and associated transcription apparatus access to the DNA, 
promoting expression of the corresponding genes.  The opposing activities of two groups of enzymes, 
histone acetyltransferase (HAT) and HDAC control the amount of acetylation.  In normal cells a 
balance exists between HAT and DAC activity that leads to cell specific patterns of gene expression.  
Perturbation of the balance produces changes in gene expression 
Several lines of evidence suggest that aberrant recruitment of HDAC and the resulting modification of 
chromatin structure may play a role in changing the gene expression seen in transformed cells.  For 
example, silencing of tumor suppressor genes at the level of chromatin is common in human tumors 
(Herman 1994, Pratt 1994, Szyf 1994, Herman 1995, Merlo 1995, Herman 1996, 


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Cameron 1999) and HDAC complexes have been shown to be crucial to the activity of the AML-
specific fusion proteins PLZF-RAR-α, PML-RAR-α, and AML1/ETO (Gelmetti 1998, Grignani 
1998, Lin 1998, Redner 1999).  DAC inhibitors (DACi) have been shown to induce differentiation, 
cell cycle arrest or apoptosis in cultured tumor cells, and to inhibit the growth of tumors in animal 
models (Yoshida 1987, Yoshida 1988, Itazaki 1990, Yoshida 1990, Sugita 1992, Yoshida 1992, 
Medina 1997).  In addition, DACi have been shown to induce expression of p21, a key mediator of 
cell cycle arrest in G1 phase and cellular differentiation (Biggs 1996, Nakano 1997, Sowa 1997, 
Sambucetti 1999). 
Tumor growth inhibition and apoptosis in response to DACi treatment may also be mediated through 
changes in acetylation of non-histone proteins (e.g., HSP90, p53, HIF-1α, α-tubulin).  For example, 
the chaperone protein HSP90 has been shown to be acetylated in cells treated with DACi (Yu 2002, 
Fuino 2003, Nimmanapalli 2003).  Acetylation of HSP90 inhibits its ability to bind newly synthesized 
client proteins, thus preventing proper client protein folding and function.  In the absence of HSP90 
function, misfolded proteins are targeted for degradation in the proteasome.  Many proteins that 
require HSP90 association are critical to cancer cell growth, including ErbB1, ErbB2, AKT, Raf, 
KDR, and BCR-ABL.  Acetylation of HSP90 in cells treated with DACi inhibits the chaperone 
function of HSP90, leading to degradation of the client proteins and eventual cell death. 
In Feb 2015, panobinostat (Farydak®) has received approval from the FDA for the treatment of 
patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib 
and an immunomodulatory agent. 
2. 
Pharmacokinetics 
After oral administration, panobinostat is rapidly absorbed with no observed lag phase. Maximum 
plasma concentrations were generally reached within 1 hour after oral dosing. The absolute 
bioavailability was 30% (data on file) and the mean (SD) half-life of panobinostat was comparable 
following i.v. and oral dosing ~15.0 (5) hours. Moderate drug accumulation was observed with oral 
three-times-a-week schedule but not with the weekly i.v. schedule (1.4-fold drug accumulation with 
oral three-times-a-week dosing), consistent with the terminal half-life of 15 hours and dosing interval. 
 
Different degrees of renal impairment (mild, moderate and severe) did not alter panobinostat plasma 
exposure, whereas, mild hepatic dysfunction increased panobinostat plasma exposure by 43% and 
moderate hepatic impairment marginally increased panobinostat plasma exposure by 105% in cancer 
patients. 
 
In vitro experiments suggested that the hepatic oxidative metabolism of panobinostat is mediated 
primarily by cytochrome P450 (CYP) 3A4, and to a lesser extent by CYP2D6 and CYP2C19. In 
addition to monooxygenation, hydrolysis of the hydroxamic sid chain (M43.5) were also found to be 
mediated (at least in-part) by the CYPs. These same metabolic pathways were also observed in the 
recent human ADME and mass balance study [CLBH589B218]. 
 


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3. 
Toxicities and Adverse Events 
Clinical development of panobinostat focuses on the oral formulation. The clinical program for the 
i.v. formulation is completed with no further company-sponsored studies currently planned. As of 31 
December 2013, 36 clinical studies, including clinical pharmacology (CP), Phase I and Phase II trials, 
as well as two randomized Phase III studies have either been completed or are ongoing. A total of 
2428 patients were enrolled, 235 for i.v. and 2193 for oral, who received at least one dose of 
panobinostat either as a single agent or in combination with other agents.  
Patients were treated with panobinostat either TIW QW (666 patients) or TIW QOW (96 patients) in 
single agent oral panobinostat clinical trials. These patients comprise the pooled safety population 
experiencing AEs during study treatment. The most frequent non-hematologic toxicity included GI 
events (diarrhea, nausea, vomiting), mostly of Grade 1-2, in both groups. Blood and lymphatic system 
disorders were the second most often reported specific system organ class, with dose-related 
thrombocytopenia being the most frequent AE. Fatigue, mostly Grade 1-2, was also common among 
patients treated for TIW QW and TIW QOW. 
Thyroid function, as monitored by the measurement of TSH and free T4, did not reveal overt hyper- 
or hypo- thyroidism, with fluctuations in TSH values being within normal limits. 
AEs regardless of causality for TIW QW dosing were reported in 664 patients, 99.7% of the safety 
population for this dosing schedule. The most commonly reported AEs across doses were 
gastrointestinal (GI), i.e., diarrhea in 406 patients (61.0%) and nausea in 372 patients (55.9%). 
Thrombocytopenia was the third most frequent AE in 359 patients (53.9%) with the highest frequency 
in the 40 mg dose level (137 patients; 84%). Fatigue also was commonly seen across dose levels in 
326 patients (48.9%) overall. Of note hypothyroidism was reported in 12.9% of patients treated at the 
dose level of 40 mg, mostly deriving from study [CLBH589E2214] in HL patients who are known to 
have an increased risk for hypothyroidism. 
Grade 3-4 AEs regardless of causality were reported in 534 patients, 80.2% of the safety population 
for the QW schedule. The most commonly reported Grade 3-4 AEs across doses were 
thrombocytopenia in 272 patients (40.8%), neutropenia in111 patients (16.7%), anemia in 103 
patients (15.5%), fatigue in 82 patients (12.3%) and febrile neutropenia in 46 patients (6.9%). 
There were more Grade 3-4 hematologic AEs at higher dose levels, with the highest incidences at 
40 and 60 mg. The highest incidence of febrile neutropenia was seen at the dose level of 60 mg 
(27.4%) compared to the other dose levels where the incidence was ≤ 3.7%. This could be because 
this dose level was only tested in leukemia patients, in whom febrile neutropenia is a common AE. 
Grade 3-4 thrombocytopenia, Grade 3-4 neutropenia and Grade 3-4 anemia accounted for 75.7% 
(272/359), 82.8% (111/134) and 52.8% (103/195) of their respective all grade events. Grade3-4 
diarrhea, Grade 3-4 vomiting and Grade 3-4 nausea accounted for less than 10% of their respective 
all grades events. For the TIW QOW dosing schedule, AEs regardless of causality were reported in 
96 patients, which is 100% of the safety population. The most commonly reported AEs (all grades) 
across doses were diarrhea in 65 patients (67.7%), nausea in 60 patients (62.5%), fatigue in 54 patients 
(56.3%), vomiting in 42 patients (43.8%), thrombocytopenia in 41 patients (42.7%), pyrexia in 35 
patients (36.5%) and anorexia in 33 patients (34.4%). 


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In the TIWQOW schedule, Grade 3-4 AEs regardless of causality were reported in 81 patients, 
84.4% of the safety population. The most commonly reported Grade 3-4 AEs across doses were 
thrombocytopenia in 35 patients (36.5%), neutropenia in 25 patients (26.0%), fatigue in 14 patients 
(14.6%), diarrhea in 11 patients (11.5%), anemia in 10 patients (10.4%), and febrile neutropenia 
in 8 patients each (8.3%). 
Overall, the most frequent Grade 3-4 AEs regardless of causality for both schedules (TIWQW 
and TIWQOW) were ascribed to the same SOC, namely blood and lymphatic system disorders. 
5.2. Carfilzomib 
1. 
Mechanism of Action 
Carfilzomib is a modified peptide epoxyketone, an analog of the natural products epoxomicin and 
eponemycin, that irreversibly binds to the chymotrypsin-like activity of the 20S proteasome. The 
peptide portion selectively binds in the proteasome with high affinity and the epoxy ketone interacts 
with the threonine-containing active sites to irreversibly inhibit enzyme activity. The cellular 
consequences of this inhibition include the accumulation of proteasome substrates and induction of 
apoptosis. (Demo 2007). 
2. 
Pharmacokinetic 
Intensive PK sampling with single- and multiple-dose PK characterization was evaluated in Studies 
PX-171-005 and PX-171-007. Following repeated doses of carfilzomib at 15 and 20 mg/m2 , 
systemic exposure and half-life were similar on Days 1 and 15 or 16 of Cycle 1, suggesting there was 
no systemic carfilzomib accumulation. At doses between 20 and 36 mg/m2 , there was a dose-
dependent increase in exposure. The mean steady-state volume of distribution of a 20 mg/m2 dose of 
carfilzomib was 28 L. When tested in vitro, the binding of carfilzomib to human plasma proteins 
averaged 97% over the concentration range of 0.4 to 4 micromolar. Peptide fragments and the diol of 
carfilzomib were the predominant metabolites measured in human plasma and urine, suggesting that 
peptidase cleavage and epoxide hydrolysis were the principal pathways of metabolism. Cytochrome 
P450-mediated mechanisms played a minor role in overall carfilzomib metabolism. 
A pharmacokinetic study was conducted in which 43 multiple myeloma patients who had various 
degrees of renal impairment (mild, moderate, and severe) had no effect on the clearance or exposure 
of carfilzomib. No pharmacokinetic studies were performed with carfilzomib in patients with hepatic 
impairment. 
In an in vitro study using human liver microsomes, carfilzomib showed modest direct and time-
dependent inhibitory effect on human cytochrome CYP3A4/5. In vitro studies indicated that 
carfilzomib did not induce human CYP1A2 and CYP3A4 in cultured fresh human hepatocytes. 
Cytochrome P450-mediated mechanisms play a minor role in the overall metabolism of carfilzomib. 
Carfilzomib is not expected to inhibit CYP3A4/5 activities and/or affect the exposure to CYP3A4/5 
substrates. 
 
 


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3. 
Toxicities and Adverse Events 
Safety data for single-agent carfilzomib have been analyzed for 526 patients with advanced multiple 
myeloma who took part in one of 4 phase II studies. The most common adverse events of any grade 
included fatigue (55.5%), anemia (46.8%), and nausea (44.9%). Grade 3/4 non-hematologic AEs were 
uncommon (<10% Grade 3 and <1% Grade 4).  Thrombocytopenia (23.4%), anemia (22.4%), 
lymphopenia (18.1%), and pneumonia (10.5%) were the most common AEs Grade 3 or 
over.  Common serious AEs (SAEs) included pneumonia (9.9%), acute renal failure (4.2%), pyrexia 
(3.4%), CHF (3.4%), dyspnea (2.1%), hypercalcemia (2.1%), and pathological fracture (2.1%). AEs 
related to study treatment included fatigue (41.4%), nausea (35.2%), thrombocytopenia (28.3%), 
anemia (26.8%), diarrhea (22.4%), and dyspnea (20.3%).  there were 37 deaths on study or within 30 
days of last dose across all 4 studies. Of the 37 deaths 7 were considered possibly related by the 
investigator, these included: cardiac arrest (n=2), hepatic failure (n=1), dyspnea (n=1), multi-organ 
failure (n=1), cardiac disorder (n=1), and unknown (n=1).A total of 8 cardiac-related deaths were 
deemed possibly related to carfilzomib per sponsor assessment.  The frequency of Grade 3 or over 
peripheral neuropathy observed with carfilzomib is low (1.3%) (Siegel 2013). Carfilzomib does not 
induce neurodegeneration in vitro via a proteasome-independent mechanism (Arastu-Kapur 2011)  
5.3. Dexamethasone 
1. 
Mechanism of Action 
Dexamethasone is a synthetic adrenocortical steroid with glucocorticoid activity.  It is one of the most 
active glucocorticoids and has both anti-inflammatory and immunosuppressant activity.  
Unbound dexamethasone crosses cell membranes and binds to specific cytoplasmic glucocorticoid 
receptors; this complex in turn binds to DNA elements, resulting in a modification of transcription 
and protein synthesis.  Anti-inflammatory responses include inhibition of leukocyte infiltration at the 
site of inflammation, interference in the function of mediators of inflammatory response, suppression 
of humoral immune responses, and reduction in edema or scar tissue. 
2. 
Pharmacokinetics 
Dexamethasone is quickly absorbed after oral administration, achieving peak plasma concentrations 
after one hour.  Binding to plasma proteins occurs more quickly than for most other corticosteroids.  
The biological half-life is approximately 190 minutes.  
The drug penetrates tissue and cerebrospinal fluids.  The metabolism of dexamethasone occurs in 
most tissues but is primarily done in the liver.  Inactive metabolites are excreted through renal 
functions.  
3. 
Toxicities/Adverse Events 
Dexamethasone has been in use for decades; as such, the toxicities and expected adverse events are 
well-documented. 
Allergic reactions: Anaphylactoid reaction, anaphylaxis, angioedema 


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Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory 
collapse, congestive heart failure, fat embolism, hypertension, myocardial rupture following recent 
myocardial infarction, edema, pulmonary edema, syncope, tachycardia, thromboembolism, 
thrombophlebitis, vasculitis 
Dermatologic: Acne, allergic dermatitis, dry scaly skin, ecchymoses and petechiae, erythema, 
impaired wound healing, increased sweating, rash, striae, suppression of reactions to skin tests, thin 
fragile skin, thinning scalp hair, urticarial 
Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, 
hyperglycemia, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral 
hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, 
secondary adrenocortical and pituitary unresponsiveness 
Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, 
hypokalemic alkalosis, potassium loss, sodium retention 
Gastrointestinal: Abdominal distention, elevation in serum liver enzyme levels (usually reversible 
upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with 
possible perforation and hemorrhage, perforation of the small and large intestine (particularly in 
patients with inflammatory bowel disease), ulcerative esophagitis 
Metabolic: Negative nitrogen balance due to protein catabolism 
Musculoskeletal: Aseptic necrosis of femoral and humeral heads, loss of muscle mass, muscle 
weakness, osteoporosis, pathologic fracture of long bones, steroid myopathy, tendon rupture, and 
vertebral compression fractures 
Neurological/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, 
increased intracranial pressure with papilledema (pseudotumor cerebri) usually following 
discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality 
changes, psychic disorders, vertigo 
Ophthalmic: Exophthalmos, glaucoma, increased intraocular pressure, posterior subcapsular cataracts 
Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased 
motility and number of spermatozoa, malaise, moon face, weight gain. 
 
6. STUDY DESIGN AND TREATMENT PLAN 
6.1. Study Design 
This is a phase 2, open labeled, non-randomized trial that will correlate in vitro drug sensitivity 
testing with clinical outcomes of multiple myeloma patients receiving panobinostat with carfilzomib 
and dexamethasone. Enrollment is projected as 40 patients over 3 years at a single site.  
 


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6.2. Chemosensitivity Assay 
Multiple myeloma cells will be procured from the patient blood (if circulating) and bone marrow. 
Myeloma cells will be isolated after density depletion, and there will be enrichment by magnetic bead 
separation (CD138+ column).  Cells are added to matrix protein coated non-tissue culture-treated 
384-well plates at a density of 5,000 cells per well in 50μL of complete media using a Thermo 
Scientific Matrix WellMate, and incubated overnight to allow attachment.  Compounds (50nL) are 
added (ranging from 5 pM to 100 μM) to patient samples using the CyBio CyBi-Well Vario and 
incubated at 37°C, 5% CO2 for 96 hours. CellTiter- Glo (Promega) is dispensed into the individual 
wells with the WellMate. Following 20 minutes incubation on an orbital shaker. luminescence is 
measured on a Perkin Elmer EnVision Multi-label plate reader.  Percentage cell viability is reported 
as relative to the DMSO solvent control.  IC50 values are calculated by fitting data using least squares 
method to the standard four-parameter logistic model. Curve fitting is performed using IDBS XLFit 
software (Microsoft Excel).  
The results are obtained within 1 week following the specimen collection, and the drug sensitivity 
curves and effective concentrations that kill 50% of the cells (EC50) are available.  
6.3. Treatment 
Panobinostat will be dosed at 20mg PO every other week on days 1, 3, 5, 15, 17, and 19 of a 28-day 
cycle. Carfilzomib will be administered at 20 mg/m² IV on days 1 and 2; then 45 mg/m² IV on days 8, 
9, 15, and 16 of the first 28-day cycle. For all subsequent 28-day cycles, carfilzomib will be 
administered at 45 mg/m² IV on days 1, 2, 8, 9, 15, and 16. Dexamethasone will be dosed at 20mg PO 
on days of carfilzomib.  
Dosing  
(4-week cycles) 
Week 1  
(Day 1-7) 
Week 2  
(Day 8-14) 
Week 3  
(Day 15-21) 
Week 4  
(Day 22-28) 
Panobinostat 
1 
 
3 
 
5 
 
 
Rest period 
15 
 
17 
 
19 
 
 
Rest period 
Carfilzomib 
1 
2 
 
 
 
 
 
8 
9 
 
 
 
 
 
15 
16 
 
 
 
 
 
Rest period 
Dexamethasone 
1 
2 
 
 
 
 
 
8 
9 
 
 
 
 
 
15 
16 
 
 
 
 
 
Rest period 
 
NOTE: Adjustments of ± 1 day on days 1, 8, and 15 will be permitted for administrative/scheduling 
flexibility, as long as infusions are given on two consecutive days each week and there are 6-8 days 
between the start of each week. Treatment will be initiated in approximately 28-day cycles (+ 14 days).  
6.4. Treatment Courses 
Patients will be treated until disease progression, patient withdrawal, PI or sponsor decision, or a 
maximum of 12 cycles. 
6.5. Dose Reductions/Modifications 
For patients who do not tolerate the protocol-specified dosing schedule, dose modifications 
(dose interruptions, dose delays, dose reductions, or changes to the dosing scheme) are 
permitted in order to allow the patient to continue the study treatment. Patients can return to a 
previous dose level after a dose reduction has been made, per investigator discretion.  


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1. 
Panobinostat 
Panobinostat dose reduction levels for toxicity: 
Dose Level 
Dose 
Starting dose 
20mg TIW, Days 1, 3, and 5, and 15, 17, and 19 
1st reduction 
15mg TIW, Days 1, 3, and 5, and 15, 17, and 19 
2nd reduction 
10mg TIW, Days 1, 3, and 5, and 15, 17, and 19 
3rd reduction 
10mg BIW, Days 1 and 5, and 15 and 19 
 
If permanent discontinuation of panobinostat is required, patients must discontinue all components of 
study treatment. If a dose of panobinostat is missed, it can be taken up to 12 hours after the scheduled 
dose. If more than 12 hours have passed, then missed dose should be skipped and treatment continues 
with next scheduled dose. If vomiting occurs, dose should not be repeated but should be taken at the next 
usual scheduled time.   
2. 
Carfilzomib 
 Carfilzomib dose reduction levels for toxicity: 
 
 
 
 
 
If permanent discontinuation of carfilzomib is required, patients must discontinue all components of 
study treatment. 
3. 
Dexamethasone 
Dexamethasone dose reduction levels for toxicity: 
Dose level 
Dose 
Starting Dose 
20mg on days 1, 8, 15 and 20mg on days 2, 9, 16 
1st dose reduction 
20mg on days 1, 8, 15 and 4mg on days 2, 9, 16 
2nd dose reduction 
4mg on days 1, 8, 15 and 4mg on days 2, 9, 16 
 
The above dose reduction table is a suggested reduction order. Dexamethasone dose reduction does not 
have to exactly follow the above dose reduction order. If patients have an intolerance to dexamethasone, 
the dose can be reduced to any level at any point in the study, per the treating physician’s discretion. 
Study records will document the actual dexamethasone doses. Patients unable to tolerate the minimum 
dose level of dexamethasone may discontinue dexamethasone and continue study treatment.  
 
 
Dose level 
Dose 
Starting dose  
45 mg/m² 
1st reduction 
36 mg/m² 
2nd reduction 
27 mg/m² 
3rd reduction 
Permanently discontinue study treatment 


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7. STUDY PROCEDURES 
7.1. Screening Evaluations/Procedures 
1. 
Signed, written informed consent: Consent must be completed prior to performing any study-
related procedures.  
2. 
The following standard of care evaluations will be reviewed to determine eligibility for the 
study 
a. 
Medical history: Detailed documentation of disease and treatment history with 
outcomes 
b. 
ECOG performance status (Appendix A) 
c. 
Concurrent medical conditions. 
d. 
Hematology: CBC with differential and platelet count  
e. 
Serum chemistries: Electrolytes (sodium, potassium, magnesium, phosphorus, 
chloride, and bicarbonate), blood urea nitrogen (BUN), creatinine, glucose, and liver 
function tests (aspartate aminotransferase (AST) and/or alanine aminotransferase 
(ALT), alkaline phosphatase (ALP), total bilirubin  
f. 
Initial standard of care diagnostic bone marrow reports, including hematopathology, 
cytogenetics / FISH, flow cytometry and mutation status. 
g. 
Serum protein electrophoresis, serum free light chains, and 24-hour urine protein 
electrophoresis as defined by disease characteristics 
3. 
ECG: 12 lead ECG  
4. 
Serum Pregnancy Test: for women of child-bearing potential. Post-menopausal women must 
have been amenorrhoeic for ≥ 12 months in order to be considered “of non-childbearing 
potential.” 
5. 
A research bone marrow aspirate and core biopsy sample, to occur either at the same time as 
or independent of a standard of care bone marrow evaluation. If the aspirate and core biopsy 
contain an inadequate number of plasma cells, another bone marrow aspirate and core biopsy 
may be obtained with patient approval. Investigator discretion will be used for analyzing the 
adequacy of the cell counts.  
If multiple myeloma is present in a location other than the bone marrow, a sample of fluid or 
a biopsy from that location (for example, plasmacytoma biopsy, pleural fluid, blood) may be 
sent to the research laboratory for testing in the assay. To avoid the risk of another invasive 
procedure to procure a new sample, samples from locations other than the bone marrow that 
were procured under other protocols (including, but not limited to, 1757, 7606, 9673) can be 
used for the chemosensitivity assay if samples are available and viably cryopreserved.  


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7.2. On Study Evaluations/Procedures 
1. 
Adverse events will be collected from the time therapy is started through 30 days after the 
last day therapy in administered. 
2. 
Hematology: CBC with differential and platelet count and peripheral blood smear at 
frequency per standard of care. Bone marrow aspirations by standard practice. 
3. 
Serum chemistries: Electrolytes (sodium, potassium, magnesium, phosphorus, chloride, and 
bicarbonate), BUN, creatinine, glucose, and liver function tests (AST, ALT, ALP, total 
bilirubin, LDH) per standard of care. 
4. 
Serum protein electrophoresis, serum free light chains, and 24-hour urine protein 
electrophoresis as defined by disease per standard practice. 
5. 
ECG: 12-lead ECGs will be performed every 3rd cycle and at the end of treatment. The 
patient should be resting for approximately 10 minutes prior to each ECG collection 
timepoint.  
6. 
Serum Pregnancy Test 
7.3. Follow-Up Evaluations 
1. 
Response data. All reports for bone marrow evaluations done as standard of care following 
this treatment, including morphology, flow cytometry, cytogenetics/FISH and mutation 
studies, will be collected. 
2. 
Subsequent complete blood count, renal function, liver function, SPEP, free light chains, 
24hr urine tests obtained for clinical reasons for a period of up to one month post the last 
dose of chemotherapy, as needed to define toxicity or duration of response. 
3. 
Reports on each patient’s course post stem cell transplant, if applicable, will be reviewed to 
determine response and duration of remission. 
4. 
Disease free and overall survival data will be assessed by contacting the referring MD or the 
patient for the first three years. 
8. CRITERIA FOR RESPONSE 
Response will be evaluated using International Myeloma Working Group Uniform Response Criteria 
for Multiple Myeloma, which is outlined in Appendix C. 
9. DOCUMENT RETENTION 
Case report forms, diagnostic pathology reports, and laboratory test results will be kept in a secure 
location that protects confidential information or electronically with secure access. Follow-up 
information regarding survival and information about time of relapse and subsequent therapy will also 
be maintained. Once the last patient has finished the long-term follow-up and all data has been 


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reviewed, study documents may go to long-term storage, where they will be retained for at least 2 
years after the investigation is completed, according to local and federal regulations. 
10.  REGULATORY AND REPORTING REQUIREMENTS 
10.1. Adverse Event Monitoring and Reporting 
Information about all adverse events, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be 
collected and recorded and followed as appropriate. 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related to 
study drug. Medical conditions/diseases present before starting study drug are only considered 
adverse events if they worsen after starting study drug. Abnormal laboratory values or test results 
constitute adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the patient at each 
visit during the study. Adverse events also may be detected when they are volunteered by the patient 
during or between visits or through physical examination, laboratory test, or other assessments. As far 
as possible, each adverse event should be evaluated to determine: 
1. 
The severity grade (mild, moderate, severe) or (grade 1-4) 
2. 
Its relationship to the study drug(s) (suspected/not suspected) 
3. 
Its duration (start and end dates or if continuing at final exam) 
4. 
Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization) 
5. 
Whether it constitutes a serious adverse event (SAE) 
All adverse events should be treated appropriately. Such treatment may include changes in study drug 
treatment including possible interruption or discontinuation, starting or stopping concomitant 
treatments, changes in the frequency or nature of assessments, hospitalization, or any other medically 
required intervention. Once an adverse event is detected, it should be followed until its resolution, and 
assessment should be made at each visit (or more frequently, if necessary) of any changes in severity, 
the suspected relationship to the study drug, the interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be found in 
the Panobinostat Investigator Brochure (IB) or will be communicated between IB updates in the form 
of Investigator Notifications. This information will be included in the patient informed consent and 
should be discussed with the patient during the study as needed. 
The principal investigator is responsible for monitoring the safety of patients who enroll in this study.  
All non-hematologic toxicities ≥ grade 3 occurring after any administration of the study drug through 
30 days after the last administration of therapy will be recorded and followed until resolution.  The 


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descriptions and grading scales found in the most current available NCI CTCAE version will be used 
for adverse event reporting.  
10.2. Serious Adverse Events 
A serious adverse event (SAE) is any adverse event that occurs that results in any of the following 
outcomes: 
• Death. 
• Life threatening adverse event. 
• Hospitalization or prolongation of hospitalization* 
• Persistent of significant disability/incapacity. 
• A congenital anomaly/birth defect. 
• Requires surgical intervention to prevent one of the outcomes listed above. 
For the purposes of this study, hospitalizations or prolongation of hospitalizations for protocol-
scheduled procedures, blood product transfusions, or for social reasons (i.e. awaiting transport home) 
will not be considered a SAE.  
10.3. Expedited Reporting Requirements 
Every SAE, regardless of suspected causality, occurring after the patient has provided informed 
consent and until at least 30 days after the patient has stopped study treatment must be reported to 
Secura Bio within 24 hours of learning of its occurrence. The form must be faxed within 24 hours to 
securabio@parexel.com.  
Additionally, any Panobinostat study drug misuse or abuse must be reported to 
securabio@parexel.com.  
In accordance with FHCRC/UW Cancer Consortium IRB policy, all adverse events (AEs; whether 
occurring on-site or off-site), which in the opinion of the principal investigator are (1) unexpected, 
and (2) related or possibly related to the research, and (3) serious or suggests that the research places 
research participants or others at a greater risk of physical or psychological harm than was previously 
known or recognized, will be submitted to the IRB within 10 calendar days of learning of the 
problem. 
AEs that do not meet the requirement for expedited reporting will be reported to the IRB as part of the 
annual renewal of the protocol. 
10.4. Pregnancy Reporting Requirements 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must be 
reported to Secura Bio within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 


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Pregnancy should be reported by the investigator to Secura Bio and should include the period of 
gestation at the time of exposure, dates of drug exposure, an assessment of the possible relationship to 
the panobinostat. Any SAE experienced during pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study treatment 
in this study. Consent to report information regarding these pregnancy outcomes should be obtained 
from the mother. 
10.5. Concomitant Medications  
Concomitant medications are all medications or treatments other than the study drugs that are taken or 
received by the subject. Concomitant medications will be assessed and recorded from the time of first 
dose of study drug through the end of treatment.  
 
11.  DATA AND SAFETY MONITORING PLAN 
The Principal Investigator will carry out ongoing trial oversight and will meet frequently with the 
study team to review recently acquired data and adverse events. The data recorded within the 
research charts and protocol database is compared with the actual data that is available from the 
medical record and/or clinical histories. All investigators on the protocol have received formal 
training in the ethical conduct of human research. The Principal Investigator will receive monitoring 
support as described below. Institutional support of trial monitoring will be in accordance with the 
FHCRC/University of Washington Cancer Consortium Institutional Data and Safety Monitoring 
Plan. Under the provisions of this plan, FHCRC Clinical Research Support coordinates data and 
compliance monitoring conducted by consultants, contract research organizations, or FHCRC 
employees unaffiliated with the conduct of the study. Independent monitoring visits occur at 
specified intervals determined by the assessed risk level of the study and the findings of previous 
visits per the institutional DSMP. In addition, protocols are reviewed at least annually and as needed 
by the Consortium Data and Safety Monitoring Committee (DSMC), FHCRC Scientific Review 
Committee (SRC) and the FHCRC/University of Washington Cancer Consortium Institutional 
Review Board (IRB). The review committees evaluate accrual, adverse events, stopping rules, and 
adherence to the applicable data and safety monitoring plan for studies actively enrolling or treating 
patients. The IRB reviews the study progress and safety information to assess continued acceptability 
of the risk-benefit ratio for human subjects. Approval of committees as applicable is necessary to 
continue the study. The trial will comply with the standard guidelines set forth by these regulatory 
committees and other institutional, state and federal guidelines. 
12. STATISTICAL CONSIDERATIONS 
The primary objective of this study is to compare the in vitro sensitivity of various single agents as 
well as combinations of these agents between patients who respond to their treatment and patients 
who do not respond to their treatment.  Towards this end, we will use the IC50 as a measure of 
“sensitivity”, and in doing so; we will then compare the mean sensitivity in responders to the mean 
sensitivity in non-responders.  We plan to enroll a total of 40 patients, and we expect a response rate 
of approximately 30%, thereby yielding roughly 12 responders and 28 non-responders.  With 40 


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patients and this projected response rate, we’ll have 90% power to detect a statistically significant 
difference (at the one-sided significance level of .05) if the true mean IC50 for responders and non-
responders are 1.03 standard-deviation units apart.   
This power calculation was done using the two-sample t-test, but when the data are analyzed we will 
potentially use either a transformation or use the rank-sum test as appropriate. 
If there is sufficient evidence to suggest that the true probability of death exceeds 5%, the study will 
be suspended pending a detailed review by a DSMB.  Sufficient evidence will be taken to be an 
observed proportion with a lower one-sided 80% confidence limit in excess of 5%.  These proportions 
will be examined after every 10th patient is enrolled and evaluable.  Any of the following would 
trigger such a rule: 2 of the first 10 (or fewer) patients, 3 of the first 30 or fewer, 4 of the first 40 or 
fewer.  If the true probability of death is .01, then the probability of such a trigger occurring after 20 
or 40 patients is approximately .007 and .009, respectively.  If the true probability is .16, the 
probability of such a trigger after 20 or 40 patients is approximately .70 and .93, respectively 
(probabilities estimated from 5,000 simulations). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDICES 
Appendix A: Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


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Appendix B: Schedule of Events 
 The following table is a representation of what may occur during participation on this trial, variations 
from this schedule will be done per physician discretion and will not be considered a protocol deviation. 
 
 
 
 
Procedure 
Screening 
Treatment 
Follow-Up 
28-day cycle (+ 14 days) 
 
Informed Consent 
x 
 
 
Physical Exam w/ 
ECOG 
x 
Medical History 
x 
Pregnancy Test 
x 
x 
CBC 
x 
x 
x 
Serum Chemistries 
x 
x 
x 
Tumor Markers  
x 
x 
x 
Chemosensitivity 
Assay 
x 
 
 
Bone Marrow 
Evaluations 
x 
 
x  
(only required if needed to 
determine response) 
Electrocardiograms 
x 
x 
(every 3 months) 
x 
Study Agent 
Therapy 
 
x 
AE Assessment 
 
x 
x 
Concomitant Meds 
x 
x 
x 
Survival 
 
x 


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Appendix C: International Myeloma Working Group Uniform Response Criteria for 
Multiple Myeloma 
 
Response 
IMWG Criteria 
sCR 
• CR as defined below, plus  
• Normal FLC ratio, and  
• Absence of clonal cells in bone marrow3 by 
immunohistochemistry or immunofluorescence4 
CR 
• Negative immunofixation on the serum and urine, and 
• Disappearance of any soft tissue plasmacytomas, and  
• < 5% plasma cells in bone marrow3 
VGPR 
Serum and urine M-protein detectable by immunofixation but not 
on electrophoresis, or 
• ≥ 90% reduction in serum M-protein plus urine M-protein level 
<100 mg/24 h 
PR 
• ≥ 50% reduction of serum M-protein and reduction in 24 hours 
urinary M-protein by ≥ 90% or to < 200 mg/24h 
• If the serum and urine M-protein are not measurable,5 a ≥ 50% 
decrease in the difference between involved and uninvolved FLC 
levels is required in place of the M-protein criteria 
• If serum and urine M-protein are not measurable, and serum free 
light assay is also not measurable, ≥ 50% reduction in plasma cells 
is required in place of M-protein, provided baseline bone marrow 
plasma cell percentage was ≥ 30% 
• In addition to the above listed criteria, if present at baseline, a ≥ 
50% reduction in the size of soft tissue plasmacytomas is also 
required 
MR 
• ≥ 25% but < 49% reduction of serum M protein and reduction in 
24-hour urine M protein by 50-89%, which still exceeds 200 mg 
per 24 hour 
• In addition to the above criteria, if present at baseline, 25-49% 
reduction in the size of soft tissue plasmacytomas is also required 
• No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response) 
No 
change/Stable 
disease 
• Not meeting criteria for CR, VGPR, PR, MR, or progressive disease 


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Progressive 
Disease 
• Increase of ≥ 25% from lowest response value in any one or more 
of the following: 
o Serum M-component (the absolute increase must be 
≥ 0.5 g/dL)6, and/or 
o Urine M-component (the absolute increase must be 
≥ 200 mg/24 h), and/or 
• Only in patients without measurable serum and urine M-protein 


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Response 
IMWG Criteria 
levels: the difference between involved and uninvolved FLC levels. 
The absolute increase must be > 10 mg/dL 
• Only in patients without measurable serum and urine M-protein 
levels and without measurable disease by FLC levels: bone 
marrow plasma cell percentage (absolute percentage must be ≥ 
10%)7 
• Definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in the size of existing bone 
lesions or soft tissue plasmacytomas 
• Development of hypercalcemia (corrected serum calcium > 11.5 
mg/dL or 2.65 mmol/L) that can be attributed solely to the plasma 
cell proliferative disorder 
Relapse 
Clinical relapse requires one or more of: 
• Direct indicators of increasing disease and/or end organ dysfunction 
(CRAB features).6 It is not used in calculation of time to 
progression or progression-free survival but is listed here as 
something that can be reported optionally or for use in clinical 
practice 
• Development of new soft tissue plasmacytomas or bone lesions 
• Definite increase in the size of existing plasmacytomas or bone 
lesions. A definite increase is defined as a 50% (and at least 1 cm) 
increase as measured serially by the sum of the products of the 
cross-diameters of the measurable lesion 
• Hypercalcemia (> 11.5 mg/dL) [2.65 mmol/L] 
• Decrease in hemoglobin of ≥ 2 g/dL [1.25 mmol/L] 
• Rise in serum creatinine by 2 mg/dL or more [177 mol/L or more] 
Relapse from 
CR5 (to be 
used only if 
the endpoint 
studied is 
DFS)8 
Any one or more of the following: 
• Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis 
• Development of ≥ 5% plasma cells in the bone marrow7 
• Appearance of any other sign of progression (i.e., new 
plasmacytoma, lytic bone lesion, or hypercalcemia) 
Overall Responders:  PR, VGPR, CR, sCR Clinical Benefit Rate: Overall 
responders + MR 
Adapted from Durie BGM, et al. Leukemia 2006; 20: 1467-1473; and Kyle RA, 
Rajkumar SV. Leukemia 2008;23:3-9. 
Note: A clarification to IMWG criteria for coding CR and VGPR in patients in 
whom the only measurable disease is by serum FLC levels: CR in such 
patients is defined as a normal FLC ratio of 0.26–1.65 in addition to CR 
criteria listed above. VGPR in such patients is defined as a >90% decrease in 
the difference between involved and uninvolved free light chain (FLC) levels. 
3 Confirmation with repeat bone marrow biopsy not needed. 
 Presence/absence of clonal cells is based upon the kappa/lambda ratio. An 
abnormal kappa/lambda ratio by immunohistochemistry and/or 
immunofluorescence requires a minimum of 100 plasma cells for analysis. An 
abnormal ratio reflecting presence of an abnormal clone is kappa/lambda of > 


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4:1 or < 1:2. 
All relapse categories require two consecutive assessments made at any time 
before classification as relapse or disease progression and/or the institution of 
any new therapy. In the IMWG criteria, CR patients must also meet the criteria 
for progressive disease shown here to be classified as progressive disease for 
the purposes of calculating time to progression and progression-free survival. 
The definitions of relapse, clinical relapse and relapse from CR are not to be 
used in calculation of time to progression or progression free survival 
For progressive disease, serum M-component increases of ≥1 gm/dL are 
sufficient to define relapse if starting M-component is ≥5 g/dL. 
Relapse from CR has the 5% cut-off versus 10% for other categories of relapse. 
For purposes of calculating time to progression and progression-free survival, 
CR patients should also be evaluated using criteria listed above for progressive 
disease.