Conditions: DS Stage I Plasma Cell Myeloma DS Stage II Plasma Cell Myeloma DS Stage III Plasma Cell Myeloma Refractory Plasma Cell Myeloma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 50
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the side effects and best dose of carfilzomib when given together with melphalan and to see how well they work in treating patients with multiple myeloma before stem cell transplant. Carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving carfilzomib together with melphalan may kill more cancer cells.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of carfilzomib that can be added to high dose melphalan as part of conditioning chemotherapy for myeloma. (Phase I) II. To determine the efficacy of the combination in patients with myeloma undergoing stem cell transplantation, as defined by achievement of complete response (CR). (Phase II)

SECONDARY OBJECTIVES:

I. To examine the toxicities associated with addition of carfilzomib to high dose melphalan in patients with multiple myeloma (MM).

II. To determine the progression free rate at 1 and 2 years post registration.

TERTIARY OBJECTIVES:

I. To determine the proportion of patients achieving a minimal residual disease (MRD) negative status.

II. To assess the HevyLite assay prior to and during treatment.

OUTLINE: This is a phase I, dose-escalation study of carfilzomib followed by a phase II study.

CONDITIONING: Patients receive carfilzomib intravenously (IV) over 30 minutes on days -6, -5, -2, and -1. Patients also receive melphalan IV over 1 hour on days -4 and -3.

TRANSPLANT: Patients undergo autologous stem cell transplant on day 0.

After completion of study treatment, patients are followed up at day 30, day 100, and then every 90 days for up to 5 years.

Arms:
arm 1: CONDITIONING: Patients receive carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive melphalan IV over 1 hour on days -4 and -3.

TRANSPLANT: Patients undergo autologous stem cell transplant on day 0.

Interventions: intervention 1: Autologous Bone Marrow Transplantation intervention 2: Autologous Hematopoietic Stem Cell Transplantation intervention 3: Carfilzomib intervention 4: Laboratory Biomarker Analysis intervention 5: Melphalan
Intervention descriptions: intervention 1: Undergo autologous stem cell transplant intervention 2: Undergo autologous stem cell transplant intervention 3: Given IV intervention 4: Correlative studies intervention 5: Given IV

Protocol document:
Prot_SAP_000.pdf: 




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


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Schema 
 
Phase I MTD ( Dose level 3, 56 mg/m2 Carfilzomib and 100 mg/m2 Melphalan) has been 
reached and phase I permanently closed 12/29/2015 
 
Phase II will open with the activation of Addendum 6 
 
 
 
 
 
 
 
   
 
     
 
 
 
 
 
 
 
 
 
 
 
 
1. Conditioning Regimen-Cycle 1: cycle = 6 days (days -6 to -1) 
2. Stem Cell Transplant-Cycle 2: cycle = 31 days (days 0-30) 
3. Post SCT Cycle 3: cycle = 70 days (days 31-100) 
4. Post Day 100 Cycles 4 onwards: Every cycle will be 90 days 
5. With Addendum 8, patient follow-up no longer required 
 
 
 
 
 
 
 
 
 
 
 
Generic name:   Carfilzomib 
Brand name(s): 
Mayo Abbreviation:  CARMIB    
Availability:   Onyx Pharmaceuticals, Inc. 
Generic name:    Melphalan 
 
Brand name(s): Alkeran® 
Mayo Abbreviation:  LPAM 
  
Availability:   Commercial 
Registration 
Treatment 
CONDITIONING REGIMEN1 
Carfilzomib given on Days -6, -5, -2, -1  
Melphalan Days -4, -3  
 
 
STEM CELL TRANSPLANT2 
Transplant Day 0 (see Section 7.3) 
Observation3, 4 
Unacceptable adverse events  
                Event              
Patient refusal                                                     Monitoring      
PD at any time 
Subsequent treatment for myeloma  
Event-
Monitoring5 


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1.0 
Background 
 
1.1 
High dose therapy and stem cell transplantation (SCT) remain the standard of 
care for patients with myeloma (MM) who are eligible to undergo the 
procedure.(Attal, Harousseau et al. 1996; Child, Morgan et al. 2003; Kumar 
2009) It is an effective therapy, with improvement in overall survival and quality 
of life (time without symptoms and treatment) compared to conventional 
therapies. However, patients with MM undergoing SCT invariably suffer disease 
relapse after a median duration of 24 to 30 months. This is not surprising given 
that only a third of the patients achieve a complete response following induction 
therapy and SCT. Patients with high proliferative rates of tumor cells, those with 
high International Staging System (ISS) stage and those with adverse cytogenetic 
profile, such as presence of t(4;14) and t(14;16) are at a higher risk.(Gertz, Lacy 
et al. 2005) Strategies to improve the duration of response to SCT can contribute 
to improved patient wellbeing and potentially improve survival, and become an 
integral part of the therapeutic approach to MM. The high dose chemotherapy 
allows significant tumor control and the ability to overcome drug resistance. The 
condition regimen most commonly used for autologous transplantation is the 
melphalan 200 mg/m2, which has not changed significantly in the past decade. 
Attempts to improve upon the conditioning by escalating the dose to 280 mg/m2, 
or by adding amifostine to the melphalan, have met with no success.  Single arm 
studies of bone targeting radiation using radioisotopes like samarium have shown 
interesting results. Several classes of new drugs have become available for the 
treatment of MM. Proteasome inhibitors, in particular, have been successful in 
terms of their efficacy in this disease.  
 
1.2 
Proteasome inhibitors for MM: The proteasome is a multi-catalytic proteinase 
complex that is responsible for degradation of a wide variety of protein substrates 
within normal and transformed cells.  Intracellular proteins targeted for 
degradation by the proteasome are first ubiquitinated via the ubiquitin 
conjugation system.  Ubiquitinated proteins are cleaved within the proteasome by 
one or more of three separate threonine protease activities: a chymotrypsin-like 
activity, a trypsin-like activity, and a caspase-like activity.   
 
1.3 
Studies have shown that addition of proteasome inhibitors to alkylating agents, 
such as cyclophosphamide or melphalan, can produce considerable synergy 
leading to better transplant outcomes in patients. In addition, at least 2 published 
trials have examined the role of adding bortezomib to melphalan 
conditioning.(Lonial, Kaufman et al. 2010; Roussel, Moreau et al. 2010) In both 
these single arm trials, the combination was well tolerated with no unexpected 
adverse events. In the Intergroupe Francophone du Myelome (IFM) phase 2 
study, 54 untreated patients were enrolled to receive bortezomib (1 mg/m (2) x 4) 
and melphalan (200 mg/m (2)) as the conditioning regimen (Bor-
HDM).(Roussel, Moreau et al. 2010) Overall, 70% of patients achieved at least a 
very good partial response (VGPR), including 17 patients with a complete 
response (CR) (32%) after SCT. No toxic deaths were observed. Bortezomib did 
not increase hematologic toxicity. Only one grade 3 to 4 peripheral neuropathy 
was reported. A matched control analysis was conducted comparing this cohort 
with patients from the IFM 2005-01 trial, which used melphalan alone. Patients 
were matched for response to induction therapy and type of induction: CR was 
higher in the Bor-HDM group (35% vs 11%; P = .001), regardless of induction 


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therapy. Lonial, et al conducted a randomized phase I/II trial designed to evaluate 
the safety and efficacy of combining the proteasome inhibitor bortezomib with 
high-dose melphalan as the conditioning for high-dose therapy and autologous 
transplant for myeloma.(Lonial, Kaufman et al. 2010) The study enrolled patients 
who did not achieve a very good partial remission (VGPR) following one or 
more induction regimens, and were randomized to receive a single escalating 
dose of bortezomib (1.0, 1.3, or 1.6 mg/m (2)), either 24 hours before or 24 hours 
after high-dose melphalan. Dose escalation was based on the escalation with 
overdose control, a Bayesian statistical model. Among 39 randomized patients, 
20 received bortezomib after melphalan and 19 received bortezomib before -
similar between the arms. The overall response rate for all patients was 87%, 
with 51% achieving a VGPR or better. Pharmacodynamic studies showed greater 
plasma cell apoptosis among patients who received bortezomib following 
melphalan. A single dose of bortezomib administered after high-dose melphalan 
was safe, with data suggesting improved efficacy. 
 
1.4 
Carfilzomib (PR-171) is a tetrapeptide keto-epoxide-based inhibitor specific for 
the chymotrypsin-like active site of the 20S proteasome.(Kuhn, Chen et al. 2007; 
Parlati, Lee et al. 2009; Khan and Stewart 2011)  Carfilzomib is structurally and 
mechanistically distinct from the dipeptide boronic acid proteasome inhibitor, 
bortezomib (Velcade®).  In addition, when measured against a broad panel of 
proteases, including metallo-, aspartyl, and serine proteases, carfilzomib 
demonstrated less reactivity against non-proteasomal proteases when compared 
to bortezomib.(Demo, Kirk et al. 2007; Arastu-Kapur, Shenk et al. 2008) 
 
1.5  
CARFILZOMIB Toxicology Studies: In the initial Good Laboratory Practice 
(GLP)-compliant toxicity studies done by the drug maker, Onyx, carfilzomib was 
administered to rats and monkeys as two complete two-week cycles of QD for 
five days, with nine days rest.(Kirk, Jiang et al. 2008)  The administration of 
12 mg/m2 to rats, which was the toxic dose in 10% of animals (STD10), resulted 
in > 90% proteasome inhibition in red blood cells one hour after dosing.  Overall, 
stronger inhibition of the proteasome and longer duration of inhibition was 
tolerated with carfilzomib compared with bortezomib.  Daily administration of 
bortezomib at anti-tumor doses is not tolerated in animals and, therefore, daily 
bortezomib has not been given in the clinic.  A dose-dependent decrease in 
proteasome activity was demonstrated in animals, and equivalent levels of 
proteasome inhibition were achieved with administration of carfilzomib, as either 
an intravenous (IV) push or an IV infusion.  The dose-limiting toxicities (DLTs) 
of carfilzomib, in both the rat and monkey 28 day GLP toxicity studies, included 
toxicities to the gastrointestinal tract, bone marrow, pulmonary, and 
cardiovascular systems.  No behavioral or histopathological signs of 
neurotoxicity were observed, and carfilzomib does not cross the blood-brain 
barrier. 
 
In 6-month rat and 9-month chronic toxicity studies, carfilzomib was 
administered on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle, mimicking the 
active anti-tumor regimen being used in ongoing Phase II studies in MM and 
solid tumors3.  Tolerability was excellent, with no evidence of peripheral (or 
central) neurotoxicity, including neuropathology, even at high doses.  This is in 
stark contrast to that observed with bortezomib.(Bross, Kane et al. 2004)  The 
DLTs of carfilzomib included effects on the gastrointestinal, renal, pulmonary, 


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and cardiovascular systems and appeared to be related to Cmax effects.  Of note, 
neutropenia was not observed; rather, transient neutrophilia was seen following 
acute dosing.  The renal, cardiovascular and gastrointestinal toxicities were 
similar to those observed with bortezomib.  Finally, cyclical thrombocytopenia, 
likely due to inhibition of platelet budding from megakaryocytes, was similar to 
that seen with bortezomib.  Proteasome inhibition in the blood in excess of 90% 
was achievable at well-tolerated doses, which contrasts with the ~70% 
proteasome inhibition achievable with bortezomib at its maximum tolerated dose 
(MTD).  In summary, these animal toxicity studies support the tolerability of 
carfilzomib in clinical studies, even on intensive dosing schedules, and at doses 
achieving proteasome inhibition in excess of what can be achieve with 
bortezomib at its MTD, on a less intensive schedule. 
 
1.6  
Carfilzomib Preclinical Antitumor Activity: Based upon the results of in vitro 
and in vivo studies, it is anticipated that the more intense and longer duration of 
proteasome inhibition that can be achieved with carfilzomib will result in 
enhanced anti-tumor activity relative to bortezomib.  Continuous (72 hr) 
exposure to carfilzomib is associated with potent cytotoxic and pro-apoptotic 
activity across a broad panel of tumor-derived cell lines in culture.(Demo, Kirk et 
al. 2007; Kuhn, Chen et al. 2007) Incubation of hematologic tumor cell lines with 
carfilzomib for as little as one hour leads to rapid inhibition of proteasome 
activity, followed by accumulation of polyubiquitinated proteins and induction of 
apoptotic cell death.  Carfilzomib has also been demonstrated to be cytotoxic in 
bortezomib-resistant tumor cell lines. (Demo, Kirk et al. 2007; Kuhn, Chen et al. 
2007) 
 
The anti-tumor efficacy of carfilzomib has been tested in immunocompromised 
mice implanted with a variety of tumor cell lines.  In a human colorectal 
adenocarcinoma model HT-29, administration of carfilzomib on a twice-weekly 
Day 1, Day 2 schedule resulted in a significant reduction in tumor size and was 
superior to a twice-weekly Day 1, Day 4 schedule using the same dose of 
carfilzomib, and a once-weekly dosing schedule using twice the dose level.  
Bortezomib at its MTD has no activity in this xenograft model using the standard 
Day 1, Day 4 schedule(Demo, Kirk et al. 2007). 
 
1.7  
Phase I Experience with Carfilzomib as a Monotherapy: A Phase I clinical 
trial, PX-171-002, testing carfilzomib in subjects with relapsed/refractory 
hematologic malignancies, is being completed.(Alsina, Trudel et al. 2007) 
During the dose escalation portion of the trial, 36 subjects received carfilzomib 
on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle.  Subjects with MM, Non-
Hodgkin’s Lymphoma (NHL), Waldenström’s Macroglobulinemia (WM), and 
Hodgkin’s Lymphoma (HL) were enrolled on the study.   
 
No dose limiting toxicities (DLTs) were observed in the initial seven cohorts 
(doses ranged from 1.2 to 15 mg/m2) of three subjects each.  At the 20 mg/m2 
dose level, one of eight patients had a Grade 3 renal failure at Cycle 1, day 2, 
which was considered possibly related to study drug and lasted for six days.  The 
patient continued on study for the remainder of Cycle 1 before having disease 
progression.   At the 27 mg/m2 dose level, one of six subjects experienced a DLT 
during Cycle 1, consisting of severe hypoxia with pulmonary infiltrates following 
Day 2 of dosing.  In subjects where the 27 mg/m2 dose was efficacious, a “first 


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dose effect” was seen that included a constellation of findings that appeared to be 
the clinical sequelae of rapid tumor lysis syndrome (TLS) and/or cytokine 
release.  This effect was notable for fever, chills, and/or rigors occurring during 
the evening following the first day of infusion.  On the second day, three of five 
subjects with MM experienced an increase in creatinine to Grade 2 (including the 
subject with the DLT).  This elevation was rapidly reversible and all three 
subjects were re-challenged with carfilzomib without recurrence of the events.  
Interestingly, all three subjects had a rapid decline in serum and/or urine M-
protein levels; two subjects achieved a partial response (PR), and the third 
subject achieved a minimal response (MR).  There were no consistent changes in 
potassium, calcium, phosphorous, or uric acid levels, although some increases in 
LDH and other markers of tumor lysis were noted.  Because of the possible TLS 
and reversible creatinine elevations, hydration and very-low dose dexamethasone 
prophylaxis were instituted in subsequent studies and have essentially eliminated 
clinically significant TLS/creatinine elevations and the other “first-dose” effects.   
 
Hematologic toxicities were primarily mild or moderate.  The thrombocytopenia 
reported with carfilzomib is cyclical and similar to that reported with bortezomib.  
The cause and kinetics of the thrombocytopenia following treatment are different 
from those of standard cytotoxic agents.  To maximize the likely benefit of 
carfilzomib, subjects with thrombocytopenia should be supported as clinically 
indicated, rather than having treatment reduced due to thrombocytopenia. 
 
Of the 36 evaluable patients enrolled in PX-171-002, 20 had MM.(Alsina, Trudel 
et al. 2007)  Four MM patients achieved a partial response (PR), one of two at the 
15 mg/m2 dose, one of six at the 20 mg/m2 dose, and two of five at the 27 mg/m2 
dose.  The responses have been rapid in onset, beginning in some subjects after 
1-2 doses.  The duration of response (DOR) ranged from 134 to 392 days. The 
minimal effective dose was 15 mg/m2, wherein >80% proteasome inhibition in 
peripheral blood and mononuclear cells was observed one hour after dosing.  The 
median number of prior therapies for subjects on this trial was five, and 
responses were seen in subjects who had relapsed from (including some 
refractory to) bortezomib and/or immunomodulatory agents.  Stable disease also 
occurred in four NHL and five MM subjects, with subjects on therapy for up to 
409 days.  Such prolonged therapy, at “full” twice-weekly doses, is not possible 
with bortezomib.  These results led to the initiation of two Phase II studies. 
 
1.8  
Phase II Experience with Carfilzomib as a monotherapy: Two Phase II 
clinical studies are ongoing with carfilzomib in MM patients, PX-171-003-A0 
(N=46) in relapsed and refractory MM, and PX-171-004 (N=39) in relapsed MM.  
In both studies, patients were dosed with 20 mg/m2 on Days 1, 2, 8, 9, 15, and 16 
on a 28 day schedule.  In these studies, there were four cases of suspected or 
documented TLS prior to institution of the prophylaxis guidelines.  Since these 
guidelines were implemented, no further cases of TLS have been reported, 
including in >350 additional patients with relapsed or refractory MM treated in 
ongoing Phase II studies.  In both studies, the most common adverse events were 
fatigue, anemia, thrombocytopenia (primarily cyclical), gastrointestinal, and 
dyspnea.  Almost all were Grades 1 or 2.  There were reported cases of increases 
in serum creatinine that were primarily < Grade 2, and were transient, rapidly 
reversible, and non-cumulative.  A very low rate of treatment-emergent 
peripheral neuropathy, 2.2%, Grade 3/4, was observed in PX-171-003-A0, 


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despite the fact that 78% of patients had Grade 1/2 neuropathy upon study 
entry.(Jagannath, Vij et al. 2010) 
 
The response rate in PX-171-003-A0 was 18% PR, 7% MR and 41% SD in these 
patients that entered the study with progressive disease, and were refractory to 
their most recent therapy, often including bortezomib and/or an 
immunomodulatory drug (usually lenalidomide).  The median time to 
progression on the PX-171-003-A0 study was 5.1 months, with a DOR of 7.4 
months (mean follow up of 7.6 months). (Jagannath, Vij et al. 2010) 
 
A “stepped up” dosing schedule, referred to as 20/27 mg/m2, has subsequently 
been incorporated into the PX-171-003 study (referred to as PX-171-003-A1) in 
order to maximize the clinical benefit of carfilzomib.  Patients receive 20 mg/m2 
for the first cycle and 27 mg/m2 thereafter.  The study completed enrollment of 
266 patients by the end of 2009, and may form the basis for an accelerated 
approval NDA filing by the end of 2010.  To date, this dosing schedule has been 
well tolerated.7 An independent Safety Oversight Group (SOG) evaluated the 
safety data from the 40 of 250 patients to be enrolled on the 20/27 schedule and 
agreed that the trial should proceed without modification.  No cases of TLS were 
observed, and rates of BUN and creatinine elevation dropped sharply, with Grade 
3/4 renal impairment dropping to 2.2% in A1 (from 15% in A0), most likely due 
to hydration and very low dose dexamethasone.  The other most common adverse 
events were similar to the A0 portion of the study.  Treatment-emergent 
peripheral neuropathy remains low on this portion of the study, with 15% Grade 
1/2 and one (0.7%) Grade 3/4 event reported to date on PX-171-003-A1. In 
addition, anemia rates in the PX-171-003-A1 (higher dose) were lower than those 
reported in the PX-171-003–A0 portion of the study, possibly indicating that the 
higher dose of carfilzomib is achieving better clearing of neoplastic cells in the 
bone marrow, allowing for superior normal marrow reconstitution.  Rates of 
thrombocytopenia and neutropenia were similar between the two cohorts, with 
Grade 3 neutropenia in ~5%, without any Grade 4 neutropenia to date.  
 
In PX-171-004, a first cohort of patients received 20 mg/m2.  The subset of 
patients (N=54) that had not seen bortezomib had an ORR of 46% (2% CR, 9% 
VGPR and 35% PR), while the bortezomib treated patients (N=33), had an ORR 
of 18% (3% CR, 3% VGPR, and 12% PR).(Siegel, Wang et al. 2009; Wang, 
Siegel et al. 2009) The median time to progression (TTP) was 7.6 and 5.3 months 
in these two groups, respectively.  Thus, carfilzomib can induce very high levels 
of response in patients who have not previously been treated with bortezomib 
and, even in bortezomib-treated patients, substantial anti-tumor activity is 
observed.  Of note, disease control (PR + MR (minimal response) + (stable 
disease) SD) was achieved in ~65% of patients with progressive MM entering the 
study.  Patients on these studies have been treated for >12 cycles with good 
tolerability and no cumulative toxicities (e.g., bone marrow, severe fatigue, or 
neuropathy) have been observed. The protocol was amended to allow patients to 
increase to 27 mg/m2 in Cycle 2 or later based on tolerability, similar to that used 
in PX-171-003 – A1.  Further information about the Phase II studies is presented 
in the Investigator’s Brochure. 
 
1.9a 
Dose Rationale: Preliminary data suggest that carfilzomib as a single agent can 
produce substantial response rates in myeloma subjects across a variety of dosing 


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cohorts.  Responses were seen over a wide therapeutic window, from 15 to 27 
mg/m2.  Maximum proteasome inhibition was seen at doses 11 mg/m2 and higher 
in whole blood samples taken 1 hour after the first dose.  The final analysis of the 
human pharmacokinetic (PK) data is ongoing, but appears to be rapid and similar 
to the results from the animal studies.  Carfilzomib is rapidly cleared from 
plasma, with an elimination half life of < 60 minutes at the 20 mg/m2 dose.  
Large, single arm studies of the 27 mg/m2 dose are ongoing and suggest that this 
dose is very well tolerated, with patients being treated for >10 cycles without 
cumulative toxicities. 
 
By the end of 2009, 269 patients with relapsed and refractory multiple myeloma 
have been enrolled in the PX-171-003-A1 study. The goal of escalating the dose 
to 27 mg/m2, beginning with Cycle 2, is to improve ORR, DOR, and TTP. 
 
In multiple preclinical studies, the tolerability of carfilzomib in rats has been 
shown to be significantly higher when administered as a 30 min infusion, as 
compared to a rapid IV bolus.  Toxicities observed with IV bolus injection of 
carfilzomib above the MTD at a dose of 48 mg/m2, include evidence of prerenal 
azotemia (transient increases in BUN > creatinine), as well as lethargy, 
piloerection, dyspnea, and gastrointestinal bleeding. Notably, death occurred in 
~50% of animals at 48 mg/m2 when carfilzomib was given as a bolus. 
Administration of the same dose (48 mg/m2) as a 30 min continuous infusion was 
well tolerated, with no changes in BUN and creatinine and substantially reduced 
signs of lethargy, piloerection, or dyspnea.  Moreover, all animals in the infusion 
treatment groups survived.  The only toxicity observed following infusion of 
carfilzomib for 30 min was gastrointestinal bleeding.  The reduced toxicity seen 
with dosing by infusion may reflect the reduced Cmax of carfilzomib vs that with 
bolus dosing.  Inhibition of the pharmacological target of carfilzomib (the 
chymotrypsin-like activity of the proteasome) was equivalent in the bolus and 
infusion treatment groups.   
 
In the clinic, the MTD of carfilzomib has not been reached in the MM setting, 
particularly when administered as a 30 minute infusion.  27mg/m2 of carfilzomib 
(bolus administration over 2-10 min.) is well tolerated in MM patients overall 
and can be tolerated for >12 cycles in late stage MM patients with substantial 
comorbidities.  
 
A phase I dose escalation study (PX-171-007) of single agent carfilzomib is 
ongoing, and as of 10 July 2009, over 65 patients with solid tumors had started 
treatment in the initial Phase II portion of the study at 36 mg/m2 (bolus 
administration over 2-10 min). A review of the tolerability of 36 mg/m2 
carfilzomib in these patients  indicates that this regimen was very well tolerated, 
with only one DLT (fatigue) and an overall adverse event profile similar to that 
seen with the 27mg/m2 carfilzomib experience with bolus dosing (see IB for 
details). Three patients completed > 12 cycles of therapy at 36 mg/m2, with no 
evidence of cumulative toxicity.  There were no significant DLTs observed; the 
majority of discontinuations on the study were due to progressive disease. 
Because of the long-term tolerability carfilzomib, the Phase 1b portion of this 
study was reopened, and a separate arm for MM was added.  
 


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In the PX-171-007 trial, more recently patients have been treated with 
carfilzomib given as a 30-minute infusion in order to potentially minimize Cmax-
related infusion events. The protocol was amended and doses of 20/36 (20 mg/m2 
given on Days 1 and 2 of Cycle 1 only; followed by 36 mg/m2 for all subsequent 
doses), 20/45, 20/56 mg/m2, and so forth, are being investigated.  Doses of 20/56 
mg/m2 are currently being given in two separate cohorts of patients with 
advanced MM and advanced solid tumors; the lower doses were well tolerated.  
Preliminary tolerability information at this dose level (20/56 mg/m2) have 
indicated that it is reasonably well tolerated, with minimal infusion reactions.  In 
some cases at 20/56mg/m2, dexamethasone was increased from 4 mg/dose to 8 
mg with the 56 mg/m2 doses, in order to reduce fevers and hypotension.  As of 
March 20, 2010, seven patients have received 20/56 mg/m2 and are tolerating it.  
Patients with advanced, refractory MM being treated at 36 mg/m2 and 45 mg/m2 
have shown very good tolerability (>6 months in some cases), with documented 
minimal and partial responses in these heavily pretreated patients. These data 
indicate that carfilzomib 30-minute infusion can be given at very high levels, 
with >95% inhibition of blood proteasome levels achievable and with (at least) 
acute tolerability.  All protocols using ≥ 36 mg/m2 carfilzomib are now 
administering the drug as a 30-minute infusion. 
 
In addition to the above observations, a phase I study of carfilzomib in patients 
with relapsed and refractory multiple myeloma was reported in abstract form at 
the 2009 American Society of Hematology meeting, which demonstrated that 
carfilzomib can be safely administered to patients with substantial renal 
impairment (CrCl < 30 mL/min, including patients on dialysis), without dose 
adjustment.(Badros, Vij et al. 2009)  These data indicate that carfilzomib does not 
exacerbate underlying renal dysfunction, and confirms the “pre-renal” etiology of 
the BUN/creatinine elevations observed with IV bolus carfilzomib. 
 
1.9b 
Study Rationale: Given the existing data, it is reasonable to consider the 
combination of carfilzomib, a new generation of proteasome inhibitors, with 
melphalan, as conditioning therapy for autologous stem cell transplant in 
myeloma. We have designed this phase I/II study of a novel conditioning 
regimen incorporating multiple anti-myeloma agents for patients with MM 
undergoing autologous stem cell transplantation.  The phase I portion of the 
study is designed to determine the MTD of carfilzomib as part of the 
conditioning regimen.  The phase II portion of the study is designed to assess the 
efficacy and toxicity of this approach. 
 


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2.0 
Goals    
 
2.1 
Primary 
 
2.11  
Phase I: To determine the MTD of carfilzomib that can be added to high 
dose melphalan as part of conditioning chemotherapy for myeloma 
 
2.12 
Phase II: To determine the efficacy of the combination in patients with 
myeloma undergoing stem cell transplantation, as defined by 
achievement of complete response (CR). 
 
2.2 
Secondary 
 
2.21 
To examine the toxicities associated with addition of carfilzomib to high 
dose melphalan in patients with MM. 
 
2.22 
To determine the progression free rate at 1 and 2 years post registration. 
 
2.3 
Correlative Research 
 
2.31 
To determine the proportion of patients achieving a minimal residual 
disease (MRD) negative status. 
 
2.32      To assess the HevyLite assay prior to and during treatment. 
 
3.0 
Patient Eligibility 
 
3.1 
Inclusion Criteria  
 
3.11 
Age 18 years. 
3.12 
The following laboratory values obtained  14 days prior to registration:   
 
Serum Creatinine ≤ 2 mg/dL 
 
Absolute neutrophil count 1000/μL 
 
Platelet count  50,000/μL 
 
Hemoglobin ≥ 8.0 g/dL 
 
3.13 
Diagnosis of symptomatic MM. 
 
3.14     Measurable disease of multiple myeloma at the time of baseline values 
for disease assessment (see section 11.11) as defined by at least one of 
the following: 
 
Serum monoclonal protein ≥1.0 g/dL (see Section 11.1 for 
definition) 
 
≥200 mg of monoclonal protein in the urine on 24 hour 
Electrophoresis 
 
Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal 
serum immunoglobulin kappa to lambda free light chain ratio. 
 
Bone marrow plasma cells ≥ 30% 
 
NOTE: For patients with no relapse prior to transplant, measurable 
disease at the time of diagnosis. 
 


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MCCC Addendum 9 
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NOTE: For patients who have had a disease relapse prior to transplant, 
measurable disease at the time of the most recent relapse immediately 
prior to transplant.  NOTE:  If the patient had treatment for the relapsed 
disease prior to transplant, the patient must have measurable disease at 
the time of relapse prior to this therapy.  
 
3.15 
Patient is considered for autologous stem cell transplantation with full 
dose melphalan (200 mg/m2).  
 
3.16 
ECOG performance status (PS) 0, 1 or 2 (Appendix I). 
 
3.17 
Recovered from toxicity of previous chemotherapy (excludes grade 1 
neurotoxicity and hematological toxicity). 
 
3.18 
Provide informed written consent. 
 
3.19a 
Adequate cardiopulmonary function  
 
Ejection fraction  45%    
 
Corrected pulmonary diffusion capacity of greater than or equal to 
50%  
 
FEV1  50% 
 
FVC  50% 
 
3.19b Negative pregnancy test performed ≤7 days prior to registration, 
for women of childbearing potential only. 
 
3.19c 
Willing to return to Mayo Clinic Rochester, Mayo Clinic Arizona, Mayo 
Clinic Florida for treatment. 
 
Note:  During the Active Monitoring Phase of a study (i.e., active 
treatment and observation), participants must be willing to return to the 
consenting institution for follow-up. 
 
3.19d Willing to provide blood and bone marrow samples for correlative 
research purposes (see Sections 6.31 and 14.0). 
 
3.2 
Exclusion Criteria 
 
3.21  
Prior autologous or allogeneic bone marrow/peripheral blood stem cell 
transplant. 
 
3.22 
More than two prior regimens for therapy of MM. 
 
3.23 
Myocardial infarction within 6 months prior to enrollment, or has New 
York Heart Association (NYHA) Class III or IV heart failure, 
uncontrolled angina, severe uncontrolled ventricular arrhythmias, or 
electrocardiographic evidence of acute ischemia or active conduction 
system abnormalities. NOTE: Prior to study entry, any ECG abnormality 
at screening has to be documented by the investigator as not medically 
relevant. 
 


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3.24 
Seroreactivity for HIV, HTLV I or II, HBV, HCV. 
 
3.25 
Other active malignancy < 2 years prior to registration.  EXCEPTIONS:  
Non-melanotic skin cancer or carcinoma-in-situ of the cervix.  NOTE:  
If there is a history or prior malignancy, they must not be receiving other 
specific treatment for their cancer.  
 
3.26 
Any of the following: 
 
Pregnant women or women of reproductive capability who are 
unwilling to use effective contraception 
 
Nursing women  
 
Men who are unwilling to use a condom (even if they have 
undergone a prior vasectomy) while having intercourse with any 
woman, while taking the drug and for 28 days after stopping 
treatment. 
 
3.27 
Other co-morbidity, which would interfere with patient's ability to 
participate in the trial, e.g. uncontrolled infection, uncompensated lung 
disease. 
 
3.28 
Concurrent chemotherapy, radiotherapy, or any ancillary therapy 
considered investigational.  NOTE: Bisphosphonates are considered to 
be supportive care rather than therapy, and are thus allowed while on 
protocol treatment. 
 
3.29  
Known allergies to any of the components of the investigational 
treatment regimen or required ancillary treatments. 


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4.0 
Test Schedule  
 
 
                              Active Monitoring                                      
 
Days Prior to 
Registration 
 
 
 
End of 
Cycle 1 
(Day -1) 
 
 
 
End of 
Cycle 2 
(Day 30)1 
 
 
Observation 
 
 
30 days 
14 days 
End of 
Cycle 3 
(Day 
100)10  
Every 90 
days 1, 5, 11 
Complete medical history 
X 
 
 
 
 
 
Adverse Event monitoring 
 
X 
X 
X 
X 
X12 
Physical exam, including weight and 
vital signs 
 
X 
X 
X 
X 
 
Height 
 
X 
 
 
 
 
Performance status (ECOG scale)  
 
X 
X 
X 
X 
X 
CBC with differential (neutrophil, 
platelets, hemoglobin) 
 
X 
X 
X 
X 
X 
Prothrombin time (PT) 
X 
 
 
 
 
 
Chemistry group to include sodium, 
potassium, glucose, alkaline 
phosphatase; total and direct bilirubin; 
SGOT (AST); serum creatinine, 
calcium, albumin, urates, phosphorus 
 
 
X 
 
X 
 
X 
 
X 
 
X 
LDH, Beta2-microglobulin,  C-reactive 
protein, Plasma cell assessment 
X 
 
 
 
 
 
Electrophoresis of serum and urine 
 
X 
 
X 
X 
X 
Affected serum immunoglobulin8 
 
X 
 
X 
X 
X 
Immunofixation serum and urine 
X 
 
  
X 
X2 
X2 
Immunoglobulin serum free light chains 
 
X 
 
X6 
X6 
X6 
Test Schedule continued on the following page.


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                              Active Monitoring                                      
 
Days Prior to 
Registration 
 
 
 
End of 
Cycle 1 
(Day -1) 
 
 
 
End of 
Cycle 2 
(Day 30)1 
 
 
Observation 
 
 
30 days 
14 days 
End of 
Cycle 3 
(Day 
100)10  
Every 90 
days 1, 5, 11 
Metastatic skeletal survey 
X 
 
 
 
X 4 
X 4 
Bone marrow aspirate and biopsy, 
myeloma FISH, metaphase 
cytogenetics, plasma cell proliferation, 
and flow cytometry9   
X 
 
 
 
X 
X7 
Chest x-ray, ECHO, PFT 
X 
 
 
 
 
 
Serum pregnancy test 
 
X3 
 
 
 
 
Research Bone marrow aspirateR 
X 
 
 
 
X 
X7 
Research bloodR 
X 
 
 
 
X 
X7 
 
1)  14 days 
2) Immunofixation (IF) needed only in the absence of M-spike. 
3) For women of childbearing potential only.  Must be done ≤7 days prior to registration. 
4) Every 168 days (6 months).  This is not required for patients unable to return to the study site for follow-up visits. 
5)   For up to 1 year from the time of registration, or until progression or subsequent treatment after transplant, whichever occurs first 
6)   Only required to document stringent CR or for patients who are followed by light chains for response. 
7)  At physician’s discretion at time of suspected CR.  This is not required for patients unable to return to the study site for follow-up visits. 
8) Affected immunoglobulin refers to the baseline M-protein type, that is, IgM, IgG, IgA, or IgD.  Not applicable if patient “non-
secretory”, or if patient has no heavy chain, i.e. light chain MM or AL. 
9) FISH and cytogenics are required only at baseline. 
10)  40 days 
11) May be performed by local MD and results faxed to study site if patient is unable to return to the study site for follow-up visits. 
12) Patient who is completing local labs – a nurse will contact to assess AEs and medication changes. 
 
R Research funded (see Section 19.0).  Will be charged to study and not to patient’s account. 
 


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MCCC Addendum 9 
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5.0 
Grouping Factor:  
 
5.1 
Phase: I (Dose Escalation Group, permanently closed 12/29/15) vs. II (MTD) 
 
6.0  
Registration Procedures 
 
6.1 
Phase I – Mayo Clinic Institutions Only 
 
Prior to discussing protocol entry with the patient, call the MCCC Registration 
Office 
 for dose level and to insure that a place on the protocol is 
open to the patient.  
 
6.11 
Registration Procedures 
 
6.111 To register a patient, 
 a completed eligibility checklist 
to the Mayo Clinic Cancer Center (MCCC) Registration Office between 
8 a.m. and 4:30 p.m. central time Monday through Friday.   
6.2 
Phase II 
 
6.21  
Mayo Clinic Institutions Registration Procedures 
 
6.211 To register a patient, access the Mayo Clinic Cancer 
Center (MCCC) web page and enter the remote 
registration/randomization application.  The 
registration/randomization application is available 24 
hours a day, 7 days a week.  Back up and/or system 
support contact information is available on the Web site.  
If unable to access the Web site, call the MCCC 
Registration Office at 
 between the hours 
of 8 a.m. and 5:00 p.m. Central Time (Monday through 
Friday). 
 
The instructions for the registration/randomization application are 
available on the MCCC web page 
 
and detail the process for completing and confirming patient registration.  
Prior to initiation of protocol treatment, this process must be completed 
in its entirety and a MCCC subject ID number must be available as noted 
in the instructions.  It is the responsibility of the individual and 
institution registering the patient to confirm the process has been 
successfully completed prior to release of the study agent.  Patient 
registration via the registration/randomization application can be 
confirmed in any of the following ways: 
 
Contact the MCCC Registration Office 
.  If the 
patient was fully registered, the MCCC Registration Office staff can 
access the information from the centralized database and confirm the 
registration. 
 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 


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MCCC Addendum 9 
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6.3 
Phase I and II 
 
6.31 
Correlative Research 
A mandatory correlative research component is part of this study, the patient 
will be automatically registered onto this component (see Sections 3.19c and 
14.0). 
 
6.32 
Prior to accepting the registration, registration/randomization application will 
verify the following: 
 
IRB approval at the registering institution 
 
Patient eligibility 
 
Existence of a signed consent form 
 
Existence of a signed authorization for use and disclosure of protected health 
information  
 
6.33 
Documentation of IRB approval must be on file in the Registration Office before 
an investigator may register any patients.  
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
  If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 
 
6.34 
At the time of registration, the following will be recorded: 
 
Patient has/has not given permission to store and use his/her sample(s) for 
future research of Multiple Myeloma at Mayo. 
 
Patient has/has not given permission to store and use his/her sample(s) for 
future research to learn, prevent, or treat other health problems. 
 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
 
6.35 
Treatment on this protocol must commence at Mayo Clinic Rochester, Mayo 
Clinic Arizona, Mayo Clinic Florida under the supervision of a 
hematologist/oncologist. 
 
6.36 
Treatment cannot begin prior to registration and must begin  14 days after 
registration.  Exception: If therapy must be started when the MCCC Registration 
Office is closed, the registration office must be notified immediately upon the 
next business day.  Under no circumstances will un-registered patients be 
retrospectively eligible for the study.   
 


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6.37 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.38 
All required baseline symptoms (see Section 10.5) must be documented and 
graded. 
 
6.39b Study drug is available on site.  
 
7.0 
Protocol Treatment 
 
7.1 
Treatment Schedule: The treatment phase of the protocol consists of 2 distinct cycles, 
with a total duration of 37 days. 
 
 
Duration 
Transplant day number 
 
Cycle 1 
6 days 
-6 to -1 
Conditioning regimen 
 
Cycle 2 
31 days 
0 to +30 
Hematopoietic stem cell 
infusion and engraftment.  
Assessment of DLT for 
Phase I and toxicity for 
Phase II 
Disease assessment. 
 
7.11 
Cycle 1 (Days -6 to -1) (Conditioning for stem cell transplant) 
 
Phase I (Dose Escalation phase)  
 
Agent 
Dose 
Route 
Day 
Cycle length 
 
Carfilzomib1 
 
As assigned by 
MCCC 
Registration 
Office 
IV 
 
-6, -5, -2, and -1 
 
 
Melphalan2 
 
100 mg/m2 
 
IV 
-4 and -3 
1  Carfilzomib is administered as a continuous IV infusion in 50 mL or 100 mL of 5% 
dextrose in water over 30 minutes after pre-hydration with 500 mL NS iv over 1 hour. On 
day -6, Solu-Medrol 125 mg iv should be administered 1 hour prior to carfilzomib. 
2  Melphalan is administered as a continuous IV infusion in 1000 mL of 0.9% sodium 
chloride over 1 hour. 


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MCCC Addendum 9 
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Phase II (Phase II studies at MTD) 
 
Agent 
Dose 
Route 
Day 
Cycle length 
Carfilzomib1 
56 mg/m2 
IV 
-6, -5, -2, and -1 
 
 
Melphalan2 
 
100 mg/m2 
 
IV 
-4 and -3 
1  Carfilzomib is administered as a continuous IV infusion in 50 mL or 100 mL of 5% 
dextrose in water over 30 minutes after pre-hydration with 500 mL NS iv over 1 hour.  
On day -6, Solu-Medrol 125 mg iv should be administered 1 hour prior to carfilzomib. 
2  Melphalan is administered as a continuous IV infusion in 1000 mL of 0.9% sodium 
chloride over 1 hour. 
 
7.111  Doses will be calculated using the lesser of actual or corrected ideal 
body weight (CIBW) (see appendix IV).  
 
7.12 
Cycle 2 (Day 0) (Stem Cell Transplant) 
  
 
 
Day 0 
Bone marrow or 
peripheral blood stem cell 
infusion 
 
X 
 
7.2 
Dose Escalation:  This study will use a two-stage accelerated design (Simon et al, 1997). 
The first stage will be an accelerated dose escalation with a cohort of one patient.  The 
second stage will resume the standard cohort of three phase I study design. The dose 
levels to which patients will be assigned in sequential cohorts are described below. 
Decisions on when and how to dose escalate are described below. 
 
Dose Level 
Carfilzomib1 
Melphalan 
0* 
27 mg/m2 
100 mg/m2 
1 
36 mg/m2 
100 mg/m2 
2 
45 mg/m2 
100 mg/m2 
3 
56 mg/m2 
100 mg/m2 
             * Starting dose 
1 Subjects with a BSA > 2.2 m2 will receive a dose based on 2.2 m2 BSA. 
 
7.3 
Phase I – Dose Escalation and Determination of MTD  
 
7.31      MTD Determination 
 
 
 
 
MTD is defined as the dose level below the lowest dose that induces dose-
limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 
new patients). A total of 6 patients treated at the MTD will be sufficient to 
identify common toxicities at the MTD.  


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MCCC Addendum 9 
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7.32 
Stage 1 (Accelerate cohort of 1 patient) 
 
7.321   Assign one patient at a dose level and observe for at least 2 cycles (37 
days) to assess toxicity, where toxicity is defined as an adverse event at 
least possibly related to treatment. 
•If this patient has not had a DLT and <2 patients have experienced 
grade ≥3 non-hematologic toxicities during the first 2 cycles over all 
dose levels, then escalate dose to the next higher dose level 
•Repeat Stage 1 if the next higher dose level is not the highest 
level of the treatment 
•Enter Stage 2 if the next higher dose level is the highest level of 
treatment 
•If this patient has had a DLT or ≥2 patients have experienced grade ≥3 
non-hematologic toxicities during the first 2 cycles over all dose levels, 
then expand the current cohort to 3 patients and enter Stage 2 
 
7.322 As of Addendum 4, the phase I study design will be modified to the 
standard cohort of 3 design.  Stage 1 with accelerated dose escalation 
will no longer apply and accrual will continue in Stage 2 with the 
standard cohort of 3 design.   Due to issues with accruing potential 
patients, it is felt that a cohort of 3 design will be more beneficial to the 
patients and to study accrual.  In addition, the study entered Stage 2 of 
the design in error and it is felt that it will be more appropriate to 
continue with standard cohorts of 3 patients. 
 
 
7.33  
Stage 2 (Standard cohort of 3 patients) 
 
7.331 Three patients will be treated at a given dose level combination and 
observed for at least 2 cycles (37 days) to assess toxicity. 
 
7.332 If DLT is not seen in any of the 3 patients treated at a certain dose level, 
up to 3 new patients will be accrued and treated at the next higher dose 
level, or at the same dose level if the current dose level is the highest 
level being tested.  If DLT is seen in at least 2 patients treated at a given 
dose level, then 3 total patients will be treated at the next lower dose 
level. 
 
7.333 If a DLT is seen in 1 of 3 patients treated at a given dose level, up to 3 
additional patients will be enrolled and treated at the same dose level.  If 
DLT is seen in at least one of these additional three patients (≥ 2 of 6), 
the MTD will have been exceeded and further accrual will cease to this 
cohort.  If DLT is not seen in any of the 3 additional patients, 3 new 
patients will be accrued and treated at the next highest dose level. 
 
7.334 If DLT is observed in at least 2 of 6 patients after enrolling 6 patients on 
a specific dose level, then the MTD will have been exceeded and defined 
as the previous dose, unless ≤ 3 patients were treated at the lower dose 
level.  In such cases, a total of 6 patients are treated at the MTD to more 
fully assess the toxicities with the MTD. 


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MCCC Addendum 9 
Protocol Version Date:   August 16, 2018 
 
 
7.34 
Dose De-Escalation 
 
 
If DLT is seen in at least 2 patients at the starting Dose Level 0, then the dose 
level will be closed and the study will need to be amended.  
 
7.35      If a patient fails to complete the initial 2 cycles of therapy (conditioning and 
transplant) for reasons other than toxicity, the patient will be regarded as 
uninformative with respect to the goals of the study and an additional patient will 
be treated at the current dose level. 
 
7.4 
Definition of dose limiting toxicity (DLT for Phase I portion) 
 
 
7.41 
For this protocol, dose-limiting toxicity (DLT) will be defined as an adverse 
event occurring in the first 2 cycles attributed (definitely, probably, or possibly) 
to the study treatment, and meeting one of the following criteria: 
 
Toxicity 
DLT Definition 
Hematologic 
Absolute neutrophil count engraftment* 
delayed beyond day 21 or Platelet 
engraftment* delayed beyond day 30. 
Neurologic 
≥ Grade 3 sensory, motor 
Other 
≥ Grade 4 non-neurologic or non-hematologic 
excluding nausea, vomiting, diarrhea  
* For the purposes of this protocol, engraftment is defined as an absolute neutrophil count 
> 500 on 3 consecutive days and platelets ≥ 20,000/μL, without transfusion, on 3 
consecutive days (see Section 11.16).  
 
 
7.5 
Phase II portion 
 
 
Enrollment to the phase II portion will begin once the MTD has been determined as 
defined in Section 7.31.  If all dose levels are safely tested and an MTD has not been 
determined, enrollment will begin in phase II at the highest dose level tested in phase I 
(Dose Level 4).  A total of 6 phase I patients must be treated at the dose level that will be 
brought forward to the phase II portion. 
 
 
7.6 
 Treatment by a local medical doctor (LMD) is not allowed. 
 
8.0 
Dosage Modification Based on Adverse Events  
 
8.1  
There is no anticipated dose modification (other than the anticipated in the carfilzomib 
dose escalation) for any of the drugs used in the conditioning regimen. However, 
administration of the study drug can be held at the treating physician’s discretion for prior 
life threatening acute side-effect (e.g. allergic or infusion reaction with carfilzomib).  
 


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MCCC Addendum 9 
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9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Investigators will follow the institutional guideline for supportive care in patients 
receiving Hematopoietic stem cell transplant (HCT).  Substitution of the medications 
below based on standard practice is acceptable, for example oral or IV equivalent. 
 
9.2 
Patients may receive concurrent treatment with a bisphosphonate.  
 
9.3 
Patients may continue on low level/stable steroid doses for replacement or inhalation 
therapy. 
 
9.4 
The following medications are not permitted during the trial: 
 
Any other investigational treatment  
 
Any cytotoxic chemotherapy 
 
Any other systemic anti-neoplastic therapies, including, but not limited to, 
immunotherapy or monoclonal antibody therapy 
 
Any external beam radiotherapy 
 
9.5 
Antiemetics may be used at the discretion of the attending physician. 
 
9.6        Solumedrol 125 mg iv can be administered prior to, during, or after administration of  
             carfilzomib for fevers, rigors, rash, dyspnea, or other signs of a hypersensitivity reaction 
 
9.7 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  
 
9.71 
Administration of only leukocyte depleted, irradiated blood products. 
 
9.72 
Transfusion of red blood cells if hemoglobin < 8g/dl or if patient has symptoms 
of anemia. 
 
9.73 
Transfusion of apheresis platelets, if platelet count <10 x 109/liter, or ≤ 20 x 
109/liter and patient is febrile and/or with extensive mucositis, and/or receiving 
low molecular weight heparin.  
 
9.8 
Patients should receive full supportive care while on this study.  This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions.  All blood products and concomitant medications, such 
as antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the 
medical records. 
 
9.9 
Diarrhea:  This can be managed conservatively with loperamide. The recommended dose 
of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed:  
hydration, octreotide, and/or other antidiarrheals. 
 


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MCCC Addendum 9 
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If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed.  
Patients with severe diarrhea, or any diarrhea associated with severe nausea or vomiting,  
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
 
9.9a 
Standard infectious disease prophylaxis 
 
9.9a1 
Anti-bacterial prophylaxis with levofloxacin 500 mg by mouth once daily or by 
IV, beginning on day –1 and continuing until absolute neutrophil count (ANC) 
>0.5x109/liter x 2 days. May be held during therapeutic antibiotics.  Equivalent 
antibacterial prophylaxis may be substituted for drug allergy or MD discretion. 
Penicillin VK 500 mg by mouth twice daily, starting on day -1 through day +365, 
unless held for therapeutic antibiotics. Equivalent antibacterial prophylaxis may 
be substituted for drug allergy or at MD discretion. 
 
9.9a2 
Anti-fungal prophylaxis with fluconazole 400 mg by mouth or IV once daily, 
from the start of conditioning regimen continuing until ANC >0.5x109/liter x 2 
days. Equivalent antifungal prophylaxis may be substituted at the physician 
discretion. 
 
9.9a3 
Prophylaxis of Pneumocystis jiroveci infection with TMP-SMX DS, 1 tablet by 
mouth twice daily from admission until day -1, then resume TMP-SMX SS when 
ANC >1 x109/liter at a dose of one tablet by mouth daily until day +100.  
Equivalent prophylaxis may be substituted for drug allergy or MD discretion. 
 
9.9a4 
Prophylaxis of HSV and HZV with Acyclovir 400 mg by mouth twice daily, or 
by IV from day –6 to day +365.  Equivalent prophylaxis may be substituted for 
drug allergy or MD discretion. 
 
9.9a5 
Empirical broad spectrum antibiotic therapy for patients with fever and 
neutropenia. Introduction of anti-fungal agents, if fever persists or findings 
suggestive of fungal infection. 
 
 


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MCCC Addendum 9 
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10.0 
Adverse Event (AE) Reporting and Monitoring  
 
10.1 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web:  
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm)    
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE version 4.0.  
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.3).  With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4). Expedited reports are to be 
completed within the timeframes and via the mechanisms specified in Sections 
10.4. All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.52 
and 18.0). 
 
10.12 
Each CTCAE term in the current version is a unique representation of a specific event 
used for medical documentation and scientific analysis and is a single MedDRA 
Lowest Level Term (LLT).   
  
 
NOTE:  A severe AE, as defined by the above grading scale, is NOT 
the same as serious AE which is defined in the table in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
 
The determination of whether an AE is expected is based on agent-specific 
information provided in Section 15.0 of the protocol. 
 
 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.0 of the protocol. 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk in the information provided for IRB 
review nor mentioned in the consent form.  
 


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MCCC Addendum 9 
Protocol Version Date:   August 16, 2018 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event.  
 
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) on 
the SAME Arm 
 
NOTE: The combination of an investigational agent with a commercial agent is 
considered investigational. 
 
Routine Reporting 
 
 Routine AE reporting for Phase 1 and Phase 2 clinical studies using an 
investigational agent /intervention in combination with a commercial agent 
is stated in the protocol.  See Section 10.52. 
 
NOTE:  When a commercial agent(s) is (are) used on the same 
treatment arm as the investigational agent/intervention (also, 
investigational drug, biologic, cellular product, or other 
investigational therapy under an IND), the entire combination (arm) is 
then considered an investigational intervention for reporting. 
 
Expedited Reporting 
 
 An AE that occurs on a combination study must be assessed in accordance with 
the guidelines for CTEP investigational agents/interventions in Section 10.4, and 
where indicated, an expedited report must be submitted. 
 
 An AE that occurs prior to administration of the investigational 
agent/intervention must be assessed as specified in the protocol. In general, 
only Grade 4 and 5 AEs that are unexpected with at least possible 
attribution to the commercial agent require an expedited report.  Refer to 
Section 10.4 for specific AE reporting requirements or exceptions. 
 
 Commercial agent expedited reports must be submitted by the Cooperative 
Group to the FDA via MedWatch. 
 


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 An investigational agent/intervention might exacerbate the expected AEs 
associated with a commercial agent.  Therefore, if an expected AE (for the 
commercial agent) occurs with a higher degree of severity, expedited reporting 
is required.  The clinical investigator must determine severity. 
 
10.32 Special Situations for Expedited Reporting  
 
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events1 
 
An expedited report may not be required for specific Grade 1, 2, 3, and 4 Serious 
Adverse Events where the AE is listed in Section 15.0 of the protocol as 
EXPECTED. Any protocol specific reporting procedures MUST BE 
SPECIFIED BELOW and will supersede the standard Expedited Adverse Event 
Reporting Requirements (Note:  These adverse events must still be reported 
through the routine reporting mechanism [i.e., Nadir/adverse events form]: see 
footnote 1):  
  
 
System Organ Class 
(SOC) 
 
Adverse event/ 
Symptoms 
 
CTCAE Grade at 
which the event 
will not be 
reported in an 
expedited  
manner. 
Blood and lymphatic 
system disorders 
Febrile neutropenia 
≤ 4 
Anemia 
≤ 3 
Investigations 
Neutrophil count 
decreased 
≤ 4 
Platelet count 
decreased 
≤ 4 
Lymphocyte count 
decreased 
≤ 4 
White blood cell 
decreased 
≤ 4 
Gastrointestinal 
disorders 
Mucositis oral 
≤ 3 
Diarrhea 
≤ 3 
Nausea 
≤ 3 
Vomiting 
≤ 3 
Metabolism and 
nutrition disorders 
Dehydration 
≤ 3 
1  These exceptions only apply if the adverse event does not result in hospitalization.  If 
the adverse event results in hospitalization, then the standard expedited adverse events 
reporting requirements must be followed. 
 
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 


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10.321 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions (formerly referred to 
as disabilities), congenital abnormities or birth defects, must be reported 
immediately if they occur at any time following treatment with an agent under 
an IND/IDE since they are considered to be a serious AE and must be reported 
to the sponsor as specified in 21 CFR 312.64(b). 
 
10.322 Death 
 
 
Any death occurring within 30 days of the last dose, 
regardless of attribution to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 
 
Any death occurring greater than 30 days with an attribution 
of possible, probable, or definite to an agent/intervention 
under an IND/IDE requires expedited reporting within 24-
hours. 
 
 
Reportable categories of Death  
 
 
Death attributable to a CTCAE term. 
 
 
Death Neonatal:  A disorder characterized by 
cessation of life during the first 28 days of life. 
 
 
Death NOS:  A cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
 
 
Sudden death NOS:  A sudden (defined as instant or 
within one hour of the onset of symptoms) or an 
unobserved cessation of life that cannot be attributed 
to a CTCAE term associated with Grade 5. 
 
 
Death due to progressive disease should be reported 
as Grade 5 “Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) – Other 
(Progressive Disease)” under the system organ class 
(SOC) of the same name.  Evidence that the death 
was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a 
disease process) should be submitted. 


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 
Any death occurring within 30 days of the last dose, 
regardless of attribution to the investigational 
agent/intervention requires expedited reporting within 24 
hours. 
 
 
Any death occurring greater than 30 days after the last does 
of the investigational agent/intervention requires expedited 
reporting within 24 hours only if it is possibly, probably, or 
definitely related to the investigational agent/intervention. 
 
10.323 Secondary Malignancy 
 
 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE be reported. Three options are available to 
describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
10.324 Second Malignancy 
 
 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  
Second malignancies require ONLY routine reporting. 
 
10.325 Pregnancy 
 
If a subject or spouse or partner of a subject becomes pregnant while 
enrolled in this clinical trial, or up to three months following 
administration of carfilzomib, Amgen Global Safety must be notified 
within 24 hours of the Investigator, designee, or site personnel learning 
of the pregnancy (See Amgen Global Safety Contact information in 
Section 10.4).  If the subject is pregnant, carfilzomib must be withheld.   
 




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 Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
Additional instructions: 
1. Notify Amgen Global Safety of all expedited safety reports/serious unexpected suspected 
adverse reactions (SUSARs) and all non-expedited SAEs via the contact information listed 
below.  This applies to all subjects receiving carfilzomib treatment, regardless of whether the 
event is determined to be related or unrelated to carfilzomib.  All report must include the 
SAE Report Cover Page (see forms packet). 
Please note these important SAE reporting timelines: 
 
Expedited Safety Reports/SUSARs: These notifications must be provided to Amgen Global 
Safety in parallel to the Health Authority submissions within seven (7) calendar days for 
any fatal or life-threatening SUSARs and within fifteen (15) calendar days for all other 
SUSARs, but in no case any later than one (1) business day from the submission date.   
 
All other SAEs: These notifications must be provided to Amgen Global Safety no later than 
thirty days (Day 30) from the time the site or Principal Investigator becomes aware of 
the SAE. 
Send Reports to:  
Drug Safety Reporting Fax:   
 (US toll-free fax)  
 
2. Use FDA Medwatch (Form 3500A) available in forms packet for Investigational agents or 
commercial/investigational agents on the same arm.  Submit to Amgen Global Safety (see 
#1). 
 
Mayo Clinic Cancer Center (MCCC) Institutions:  Provide copies, along with the UPIRTSO 
cover sheet, by fax 
 to the MCCC Regulatory Affairs Unit (RAU) Risk 
Information Specialist who will determine and complete IRB reporting. The RAU will 
submit to the MCCC SAE Coordinator and the MCCC IND Coordinator to determine if 
FDA submission is needed.  
 
Non-MCCC Institutions:  Provide copies by fax
 to the MCCC SAE 
Coordinator who will forward to the MCCC IND Coordinator to determine if FDA 
submission is needed. 
 
10.5 
Other Required Reporting 
 
10.51 Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 


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System Organ 
Class (SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Vascular Disorders 
Hypotension 
X 
X 
Investigations 
Blood bilirubin increased 
X 
X 
Creatinine increased 
X 
X 
Nervous System 
Disorders 
Peripheral motor 
neuropathy 
X 
X 
Peripheral sensory 
neuropathy 
X 
X 
 
10.52 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.5: 
 
10.521 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.522 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.523 Grade 5 AEs (Deaths) 
 
10.5231  
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
 
10.5232 
Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
 
10.53    Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in Section 
4.0). 
 
11.0 
Treatment Evaluation – The International Myeloma Working Group (IMWG) uniform 
response criteria (Rajkumar et al, 2011) will be used to assess response to therapy. 
 
11.1 
Multiple Myeloma Patients 
 
11.11  Terms and definitions 
 
 
Baseline values for disease assessment: All disease response measurements 
will be based on the values obtained at the time of diagnosis if there has been 
no relapse prior to transplant. If patients had a disease relapse prior to 
transplant, the baseline values will be those obtained at the time of relapse 
immediately prior to the transplant. If patient had treatment for the relapsed 


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disease prior to transplant, the values will be from prior to this therapy, ie, 
the time of relapse. 
 
Clinical relapse is defined using the definition of clinical relapse in the 
IMWG criteria.   In the IMWG criteria, clinical relapse is defined as 
requiring one or more of the following direct indicators of increasing disease 
and/or end-organ dysfunction that are considered related to the underlying 
plasma cell proliferative disorder: 
1.  Development of new soft tissue plasmacytomas or bone lesions on 
skeletal survey, magnetic resonance imaging, or other imaging 
2.  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 
3.  Hypercalcemia (>11.5 mg/dL; >2.875mM/L) 
4.  Decrease in hemoglobin of more than 2 g/dL (1.25mM) or to less than 10 
g/dL 
5.  Rise in serum creatinine by more than or equal to 2 mg/dL (≥177mM/L) 
6.  Hyperviscosity 
 
NOTE:  If the patient does not meet the IMWG criteria for clinical relapse 
but the patient has increasing M protein leading to a change in clinical 
management, this will also be considered a relapse at the discretion of the 
treating physician. 
 
 
M-protein: synonyms include M-spike, monoclonal protein and myeloma protein, 
paraprotein, M-component. 
 
Serum M-protein level is quantitated using densitometry on SPEP except in cases 
where the SPEP is felt to be unreliable.   
 M-proteins migrating in the -region (usually IgA M-proteins)  
 Cases in which the M-protein is so large and narrow on agarose (some 
specimens >4 g/dL) that they underestimate the actual immunoglobulin level 
(by greater than 1500 mg/dL) due to technical staining properties of the 
agarose gel. 
 Cases in which there are multiple peaks of same M-protein (aggregates or 
dimers) 
 
If SPEP is not available or felt to be unreliable (above examples) for routine M-
protein quantitation, then quantitative immunoglobulin levels derived from 
nephelometry or turbidometry can be accepted.  However, this must be explicitly 
reported at baseline, and only nephelometry can be used for that patient to assess 
response. SPEP derived M-protein values and quantitative nephelometric 
immunoglobulin values cannot be used interchangeably.   
 
Urine M-protein measurement is estimated using 24-h UPEP only.  Random or 24 h 
urine tests measuring kappa and lambda light chain levels are not reliable and are not 
recommended. 


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


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 
Non-secretory myeloma: Patient with multiple myeloma who has NEVER had a 
detectable M-protein in his/her serum and/or urine. 
 
11.12  Clarification of test indications 
 
Listed below are the minimal required tests required to assess response based on the 
characteristics of their disease at on study.   
 
Table 11.12 
Tests  Required To Assess Response (Must Be Done At Each Disease Measurement Visit 
except as indicated1,2) 
On Study Baseline Value 
SPEP4  
24 hr 
UPEP2  
Ig 
FLC 
BM Bx 
Serum M-protein ≥1 g/dl, and urine M-protein≥ 
200 mg/24 hrs 
X 
X 
 
 
Serum M-protein ≥ 1 g/dl, but urine M-protein < 
200 mg/24 hrs 
X 
 
 
 
Serum M-protein <1 g/dl, and urine M-protein≥ 
200 mg/24 hrs 
 
X 
 
 
Serum M-protein < 1 g/dl, urine M-protein < 200 
mg/24 hrs, but involved Ig FLC is ≥10 mg/dL 
 
 
X 
 
Serum M-protein < 1 g/dl, urine M-protein< 200 
mg/24 hrs, involved Ig FLC is <10 mg/dL, bone 
marrow ≥30% plasma cells 
 
 
 
X3 
1  SPEP, UPEP, Immunofixation studies of both serum and urine, and Bone marrow 
biopsy are required to document CR regardless of registration values, and in addition 
FLC measurement and bone marrow immunophenotyping is required to document 
sCR.  SPEP and UPEP are required to document VGPR regardless of registration 
values. 
2  For serum measurable patients, 24 hour urine does not need to be confirmed (i.e. 
repeated after documented response) for any response category 
3  At a minimum, a bone marrow biopsy should be repeated every 3 months until 
documented response.  Bone marrow biopsy results do not need to be repeated after 
documented response. 
4    If serum M-protein is being followed by quantitative immunoglobulin levels derived 
from nephelometry or turbidometry, quantitative immunoglobulins are required.  SPEP 
is only required to document CR or VGPR.  
 
11.13 Confirmed response  
 
In order to be classified as a hematologic response, confirmation of serum M- protein, 
serum immunoglobulin free light chain (when primary determinant of response) and 
urine M- protein (when primary determinant of response) results must be made by 
verification on two consecutive determinations.   
 
Bone marrow aspirate and biopsy are only required to document CR or sCR, 
except for patients with evaluable disease only, where a bone marrow is required 
to document all response categories including progression. However, a second 
confirmatory bone marrow is not required to confirm response in any case. 


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 
Radiographic studies are not required to satisfy these response requirements; 
however, if radiographic studies were performed there should be no evidence of 
progressive or new bone lesions. 
 
Appropriate tests required to document and confirm response are listed in Table 11.12 
 
11.14 Bone progression  
 
Caution must be exercised to avoid rating progression on the basis of variation of 
radiologic technique alone.  Compression fracture does not exclude continued response 
and may not indicate progression.  When progression is based on skeletal disease alone, it 
should be discussed with the Study Chair before removing the patient from the study.  
 
 11.15  Response and Progression 
 
Criteria for response and progression are listed in Table 11.15. Progressive disease for all 
patients as defined in Table 11.15.  
 
Table 11.5 
CATEGORY 
RESPONSE CATEGORY a 
Stringent Complete 
Response (sCR) b 
 CR as defined plus 
 Normal FLC ratio and 
 Absence of clonal PCs by immunohistochemistry or 2- to 4- color 
flow cytometry i 
Complete Response 
(CR) b,j 
 Negative immunofixation of serum and urine c and 
 Disappearance of any soft tissue plasmacytoma and 
 <5% PCs in Bone Marrow and 
 If the only measurable disease is FLC, a normal FLC ratio d  
Very Good Partial 
Response (VGPR)  
 Serum and urine M-protein detectable by immunofixation but not 
on electrophoresis c or 
 ≥90% reduction in serum M-protein and urine M-protein <100 
mg/24 h c 
 If the only measurable disease is FLC, a >90% reduction in the 
difference between involved and uninvolved FLC levels 
Partial Response (PR) 
 If present at baseline, ≥ 50% reduction of serum M-protein and 
reduction in 24-hour urinary M-protein by ≥90% or to <200 
mg/24hrs c 
 If the only measurable disease is FLC, a ≥50% reduction in the 
difference between involved and uninvolved FLC levels 
 If the only measurable disease is BM, a ≥ 50% reduction in BM 
PCs (provided the baseline PCs was ≥ 30%) 
 If present at baseline, ≥ 50% reduction in the size of soft tissue 
plasmacytomas 
Minor Response (MR)  
 If present at baseline, ≥25% but ≤ 49% reduction of serum M 
protein and reduction in 24-hour urine M-protein by 50-89% 
which still exceeds 200mg/24 hours c and 
 If present at baseline, 25-49% reduction in the size of soft tissue 
plasmacytoma and 
 No increase in the size or number of lytic bone lesions 
(development of compression fracture does not exclude response) 


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


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i Presence/absence of clonal cells is based upon the k/l ratio. An abnormal k/l ratio by immunohistochemistry 
requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is 
k/l of 4:1 or 1:2.  
 
j  If a patient has already achieved a complete response prior to registration as a result of the induction therapy or 
stem cell transplant, the patient will be considered a continued complete response if they continue to meet the 
complete response criteria at the next assessment.  Reconfirmation of complete response is not required. 
 
11.16 Criteria for engraftment (for hematopoietic stem cell transplant studies only) 
 
Engraftment is defined as: 
•   The first day of three consecutive days on which the absolute neutrophil count 
(ANC) >500/mm3 
and 
•   The first of three consecutive days with an un-transfused platelet count 
>20,000/mm3. 
 
12.0 
Descriptive Factors  
 
12.1 
Prior Immunomodulatory agents (IMiDs):  Yes vs. no 
 
12.2 
Prior Alkylators: Yes vs. no 
 
12.3 
Prior Proteasome inhibitors:  Yes vs. no 
 
12.4 
Response to last treatment: Yes vs. no 
 
12.5 
Timing of transplant: < 12 months from diagnosis vs. ≥ 12 months from diagnosis  
 
12.6 
Dose Level (to be assigned by Registration Office): 0 vs. 1 vs. 2 vs. 3 vs. 4 
 
12.7 
Parameters followed for hematologic response (pick one):  serum M-spike ≥ 1 g/dL and 
urine M-spike ≥200 mg/24 hours vs. serum M-spike ≥1g/dL only vs. urine M-spike ≥200 
mg/24 hours only vs. serum immunoglobulin free light chain ≥10 mg/dL vs. bone 
marrow plasma cells ≥ 30%.   Distinguish between SPEP measurement versus 
quantitative IgA measurement for serum M-spike.   All measurements are based on those 
at the time of Baseline values for disease assessment as defined in Section 11.11. 
12.8 
Relapse status category as a descriptive factor:  No relapse prior to transplant vs. Disease 
relapse prior to transplant with no treatment for most recent relapse vs. Disease relapse 
prior to transplant with treatment for most recent relapse. 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
13.1 
Patients who are sCR, CR, VGPR, PR, or SD (or usCR, uCR, uVGPR, uPR) will 
continue the conditioning regimen and stem cell transplant per protocol.  
 


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13.2      Observation:  If the patient has achieved sCR, CR, VGPR, PR, or SD, (or usCR, uCR, 
uVGPR, uPR) at the post-transplant evaluation, the patient will be observed at 100 days 
post-transplant and then every 90 days for up to1 year from time of registration.  The 
follow-up visit may be performed by local MD if the patient is unable to return to the 
study site.  If the patient develops progressive disease or receives subsequent treatment 
for myeloma while in observation then the patient will go to the event-monitoring phase 
per Section 18.0. 
 
13.3 
Criteria for Patient Initiation of Event Monitoring 
As of Addendum 8, patient follow-up is no longer required.  
 
Patients will go to event monitoring for the following reasons: 
 
 
Progressive multiple myeloma  
 
Subsequent treatment for multiple myeloma 
 
Patient withdraws consent to continue in the trial 
 
Patient develops an intercurrent illness that precludes further participation, or 
requires a prohibited concomitant treatment 
 
The Investigator withdraws the patient in the patient’s best interests 
 
Patient is lost to follow-up (defined as the inability to contact the patient on 3 
separate occasions over the course of one year.) 
 
Administrative reasons (e.g., the patient is transferred to hospice care) 
 
An adverse event, which in the opinion of the investigator, precludes further trial 
participation  
 
All attempts should be made to complete the End of Study procedures if a patient 
withdraws from the trial early. 
 
13.4 
Criteria for Study Discontinuation 
 
The study may be temporarily or permanently discontinued at any site and at any time.  
Reasons for study discontinuation may include, but are not limited to, the following: 
 
 
Safety concerns 
 
Poor enrollment 
 
Non-compliance with the protocol, Good Clinical Practice guidances or other 
regulatory requirements by the Investigator(s) 
 
Request to discontinue the trial by a regulatory or health authority or an IRB 
 
Manufacturing difficulties/concerns 
 
All Investigators and the requisite regulatory authorities will be notified if the study is 
suspended or terminated for safety reasons.  In the case of such termination, the 
Investigator will notify the IRB. 
 
13.5      Phase I Portion only:  If a patient fails to complete treatment (conditioning and 
transplant) for reasons other than toxicity, the patient will be regarded as not evaluable 
and will be replaced.   


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13.6 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered.  
 
 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.  Event monitoring will be required per Section 18.0 
of the protocol.  
 
If the patient never received treatment, on-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted.  No further data submission 
is necessary. 
 
13.7 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event-monitoring phase of the study.  The 
patient may continue treatment off-protocol at the discretion of the physician as long as 
there are no safety concerns, and the patient was properly registered.  Event monitoring 
will be required per Section 18.0 of the protocol.   
 
13.8 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given.  On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted.  No further data submission is necessary. 


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14.0 
Body Fluid Biospecimens   
 
14.1  
Summary Table of Research Blood and Body Fluid Specimens to be collected for this Protocol 
 
 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or 
Body 
Fluid 
being 
Collected 
Type of 
Collection 
Tube 
(color of 
tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Visit 1: 
Study 
Entry  
Visit 2: 
End of 
cycle 3 
(Day 
100) 
Visit 3: 
At 
suspected 
CR 
Process 
at site? 
(Yes or 
No) 
Temperature 
 Conditions 
for Storage 
/Shipping  
Minimal residual 
disease 
Mandatory 
Bone 
marrow 
aspirate 
EDTA 
(lavender) 
3 mL 
(1) 
X 
X 
X1 
No 
Ambient  
HevyLite Assay® 
Mandatory 
Plasma 
ACD 
(yellow) 
6 ml 
(2) 
X 
X 
X1 
No 
Ice pack 
1. Not required for patients who are unable to return to the study site.




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minimal residual disease positivity at various stages of treatment, among 
patients achieving a conventional complete response. Bone marrow 
aspirates will be evaluated for presence of clonal plasma cells a well as 
the ratio of clonal to non-clonal plasma cells after 3 cycles and whenever 
a CR is suspected and a marrow is done.  
 
MRD detection will be done on BM samples as previously described32.  
Plasma cells are identified by their characteristic CD45/CD38/CD138 
staining pattern with light chain restriction and CD19/CD56 phenotype 
on each case. One ml (milliliter) of BM (bone marrow) is subjected to 
flow cytometry on a Cantos Flow Cytometer.  Samples are collected 
ungated, up to one million events per tube. 
 
14.42 HevyLite Assay®: Immunoparesis may be a valuable biomarker of the 
presence of residual malignant disease. However, immunoparesis of 
uninvolved immunoglobulins (Igs) lacks precision. The novel Hevylite™ 
assay measures levels of each distinct Ig subtype (i.e., IgG, IgG, IgA, 
IgA, IgM, and IgM,) and enables us for the first time to determine if 
suppression of isotype-specific Ig of the opposite LC type is occurring. 
We have found that suppression of isotype specific M protein (i.e., IgG 
in IgG MGUS) is associated with a significantly increased risk of 
progression in MGUS indicating ability to detect malignant 
phenotype.(Katzmann, Clark et al. 2009) In the studies proposed here, 
we will determine if suppression of isotype specific Ig level can help 
identify patients who have persistent MRD. 
 
15.0 
Drug Information 
 
15.1 
Carfilzomib (PR-171, Kyprolis™) 
 
15.11 Background:  Carfilzomib is an analog of epoxomicin and eponemycin; 
a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to 
the N-terminal threonine-containing active sites of the 20S proteasome, 
the proteolytic core particle within the 26S proteasome.  Carfilzomib had 
antiproliferative and proapoptotic activities in vitro in solid and 
hematologic tumor cells.  In animals, carfilzomib inhibited proteasome 
activity in blood and tissue and delayed tumor growth in models of 
multiple myeloma, hematologic, and solid tumors.  
 
15.12 Formulation:  Carfilzomib for Injection is supplied as a white to off-
white lyophilized cake or powder in a 60 mg single-use vial.  Upon 
reconstitution, Carfilzomib for Injection consists of 2 milligram per 
milliliter (mg/mL) carfilzomib, 100 mg/mL sulfobutylether-beta-
cyclodextrin (SBECD), and 1.9 mg/mL citrate buffer (pH3 to 4).  


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15.13 Preparation and storage:  Unopened vials of carfilzomib are stable 
until the date indicated on the package when stored in the original 
package at 2°C to 8°C (36°F to 46°F). Retain carfilzomib in the original 
package to protect from light. The reconstituted solution contains 
carfilzomib at a concentration of 2 mg/mL. Read the complete 
preparation instructions prior to reconstitution. 
 
Reconstitution/Preparation Steps: 
1. Remove vial from refrigerator just prior to use. 
2. Aseptically reconstitute each vial by slowly injecting 29 mL 
Sterile Water for Injection, USP, directing the solution onto the INSIDE 
WALL OF THE VIAL to minimize foaming.  Do not use alternative 
diluents, such as 0.9% Sodium Chloride Injection, USP, for 
reconstitution. 
3. Gently swirl and/or invert the vial slowly for about 1 minute, or until 
complete dissolution of any cake or powder occurs. DO NOT SHAKE to 
avoid foam generation. If foaming occurs, allow solution to rest in vial 
for about 2 to 5 minutes, until foaming subsides. 
4. After reconstitution, carfilzomib is ready for intravenous 
administration.  The reconstituted product should be a clear, colorless 
solution. If any discoloration or particulate matter is observed, do not use 
the reconstituted product. 
5. When administering in an intravenous bag, withdraw the calculated 
dose from the vial and dilute into 50 mL or 100 mL 5% Dextrose 
Injection, USP intravenous bag.  If required, an equivalent volume of 
D5W could be withdrawn prior to dilution of carfilzomib. 
6. Immediately discard the vial containing the unused portion. 
 
Onyx does not have any data to support the use of closed-system drug 
transfer devices other than a standard syringe needle, therefore use of 
closed-system drug transfer devices are to be avoided.  However, 
institutions must comply with internal procedures and guidelines for 
preparation of oncologic drugs when preparing carfilzomib.  Therefore, 
use of these systems may be required by these procedures. 
 
Prepared IV bags are stable in the refrigerator for 24 hours, or at room 
temperature for 4 hours.  Total time from reconstitution to administration 
should not exceed 24 hours. 
 
15.14 Administration:   
Current clinical experience indicates that carfilzomib can be safety 
administered IV over 2 to10 minutes, or at rates of approximately 10 
mL/minute for doses up to 27 mg/m2; higher doses (>27 mg/m2) are most 
often administered as a 30-minute infusion. 
 
The IV administration line should be flushed with 5% dextrose in water 
or normal saline, immediately before and after carfilzomib 
administration. Carfilzomib should not be administered as a bolus. 
 


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The dose is calculated using the less of actual or corrected ideal body 
weight (see Appendix IV).  Patients with a BSA greater than 2.2 m2 will 
receive a dose based upon a BSA of 2.2 m2. 
 
15.15 Pharmacokinetic information: 
 
a)  Absorption – The Cmax and AUC following a single IV dose of 27 
mg/m2 was 4232 ng/mL and 379 ng•hr/mL, respectively. Following 
repeated doses of carfilzomib at 15 and 20 mg/m2, systemic exposure 
(AUC) 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. There are no apparent differences in carfilzomib clearance, 
AUC, and Cmax between subjects with normal and those with varying 
levels of renal functional impairment following single- or repeat-dose 
administration.  
b)  Distribution – The mean Vss 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. 
 
c)  Metabolism – Carfilzomib was rapidly and extensively metabolized. 
The predominant metabolites measured in human plasma and urine, and 
generated in vitro by human hepatocytes, were peptide fragments and the 
diol of carfilzomib, 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. The metabolites have no known biologic activity.  
 
d)  Excretion – Following intravenous administration of doses ≥ 15 
mg/m2, carfilzomib was rapidly cleared from the systemic circulation 
with a half-life of ≤ 1 hour on Day 1 of Cycle 1. The systemic clearance 
ranged from 151 to 263 L/hour, and exceeded hepatic blood flow, 
suggesting that carfilzomib was largely cleared extrahepatically. Within 
24 hours following administration of a single 27 mg/m2 IV dose of 
carfilzomib to subjects with multiple myeloma or solid tumors, 
approximately 30% of the administered dose of carfilzomib was excreted 
in urine as metabolites.   
 
 
15.16 Potential Drug Interactions:  Carfilzomib is primarily metabolized via 
peptidase and epoxide hydrolase activities. The drug-drug interaction 
potential of carfilzomib is expected to be low. In cultured fresh human 
hepatocytes, carfilzomib did not induce human CYP1A2 and CYP3A4. 
In a study conducted in subjects with solid tumors (PX-171-008), single 
and repeat dosing of carfilzomib at 27 mg/m2 did not affect the PK of 
midazolam, a sensitive CYP3A substrate. Together, the in vitro and in 
vivo results indicate a low potential for carfilzomib to inhibit the 
metabolism of CYP3A4/5 substrates and other CYP450 substrates in 
human subjects. Cytochrome P450-mediated mechanisms play a minor 
role in the overall metabolism of carfilzomib; thus, the potential impact 
of other concomitant medications on carfilzomib PK is expected to be 
low. 
 


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Since it is unknown whether carfilzomib is an inducer of CYP2C9 at 
relevant therapeutic concentrations, the current data cannot exclude that 
the efficacy of oral contraceptives may be reduced during carfilzomib 
treatment.  Caution should be observed when carfilzomib is combined 
with medicinal products that are substrates of these enzymes, such as oral 
contraceptives. 
 
Carfilzomib is a substrate of efflux transporter P-glycoprotein (P-gp), but 
it only showed marginal inhibitory effect to P-gp at concentrations as 
high as 3 micromoles and is not a BCRP substrate. Given that 
carfilzomib is administered IV and is extensively metabolized, the PK 
profile of carfilzomib is unlikely to be affected by P-gp inhibitors or 
inducers. 
 
In vitro, carfilzomib does not inhibit OATP1B3, OAT1, OAT3, OCT2, 
or BSEP at concentrations up to 3 µM.   The risk of clinically relevant 
interactions with substrates of OATP1B1 and UGT1A1 is low. 
 
15.17 Known potential toxicities:  Most commonly reported adverse 
reactions (incidence ≥30%) are fatigue, anemia, 
thrombocytopenia, and diarrhea. 
Common known potential toxicities, > 10% - <30%:   
Central nervous system: Headache, dizziness, insomnia, peripheral 
neuropathy 
Gastrointestinal: Vomiting, constipation, abdominal pain, nausea 
Hematologic: Lymphopenia, neutropenia, leukopenia 
Metabolism and Nutrition: Anorexia, hypokalemia,  
hyperglycemia 
Neuromuscular & skeletal: Back pain, arthralgia, muscle spasms, 
pain in extremity 
Renal: Increased creatinine 
Respiratory: Dyspnea, cough, respiratory tract infection, 
pneumonia, nasopharyngitis 
Vascular: Hypertension 
General Disorders:   Asthenia, peripheral edema, and pyrexia  
 
Less common known potential toxicities, 1% - 10%:  
Cardiovascular:  Cardiac failure, tachycardia, palpitations, atrial 
fibrillation  
Central nervous system: Paresthesia,   anxiety, hypoesthesia 
Dermatologic:  Rash, pruritus, erythema, hyperhidrosis 
Endocrine & metabolic:  Elevated uric acid, low albumin levels 
Gastrointestinal:  Dyspepsia 
Hematologic:  Febrile neutropenia, leukopenia, platelet count 
decreased, lymphocyte count decreased 
Hepatic:  ALT increased, AST increased, hyperbilirubinemia, 
increased gamma glutamyltransferase 
Infections:  Urinary tract infections, sepsis, bronchitis, influenza, 
viral infection 


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Metabolism and Nutritional disorders:  Hypocalcemia, 
hypercalcemia, hypophosphatemia, hyponatremia, dehydration, 
hyperkalemia, hypomagnesemia, hyperuricemia 
Neuromuscular & skeletal:  Myalgia, musculoskeletal pain, 
musculoskeletal chest pain, muscular weakness, bone pain 
Ocular:  Blurred vision, cataracts 
Respiratory: Epistaxis, pulmonary edema, oropharyngeal pain, 
dysphonia, wheezing, pulmonary hypertension, rhinitis 
Vascular:  Hypotension, DVT, PE, flushing 
Other:  Pain, increased C-reactive protein, toothache, chills, 
infusion site reaction 
 
Rare known potential toxicities, <1% (Limited to important or 
life-threatening):  
 
Cardiovascular: Cardiac arrest, myocardial infarction, myocardial 
ischemia, pericardial effusion, ejection fraction decreased 
Hepatic: Hepatic failure, cholestasis 
Respiratory: Pneumonitis, acute respiratory distress syndrome, 
acute respiratory failure, interstitial lung disease, lung infection, 
pulmonary hemorrhage 
Vascular:  Thrombotic thrombocytopenic purpura, thrombotic 
microangiopathy 
Other:  Tumor lysis syndrome, posterior reversible encephalopathy 
syndrome, multi-organ failure, cerebrovascular accident, 
intracranial hemorrhage, hypertensive crisis/emergency, 
hemorrhage, drug hypersensitivity 
 
Potential risks (unknown if there is a causal association between 
the event and carfilzomib):  
Herpes zoster infections (The risk of herpes zoster infections can 
be minimized with antiviral prophylaxis). 
 
Detailed safety information for carfilzomib, including 
contraindications, warnings, and precautions, adverse reactions, 
and overdose can be found in the current prescribing information.  
Carfilzomib should be administered under the supervision of a 
physician experienced in the use of anti-neoplastic therapy.  
 
15.18 Drug procurement:  Drug is provided to the study free of charge by 
Onyx Pharmaceuticals, Inc. 
  
 
15.19 Nursing Guidelines:  
 
15.191 Fatigue is the most commonly reported side effect. 
Instruct patient in energy conserving lifestyle and monitor 
for effectiveness. 
 


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15.192 Anemia and thrombocytopenia are also commonly seen. 
Monitor CBC closely and instruct patient to report any 
unusual bruising or bleeding to the health care team. 
 
15.193 GI side effects are commonly seen, but are usually mild 
in nature (nausea, diarrhea). Treat symptomatically and 
monitor for effectiveness.  
 
15.194 Pneumonia and pulmonary hypertension have been seen. 
Instruct patient to report any shortness of breath, cough 
and/or chest pain to the study team.  
 
15.195 Elevated creatinine and isolated cases of renal failure 
(some associated with tumor lysis syndrome) have been 
seen. Make sure patient is well hydrated prior to 
administration and monitor creatinine levels closely. 
Urinary tract infections can also be seen, instruct patient 
to report signs and symptoms to study team. 
 
15.196 Take a detailed history of patient’s concomitant 
medications including OTC and herbal preparations. 
Instruct patients not to start any new medications without 
checking with the study first. 
 
15.197 Cardiac side effects, including peripheral edema, 
hypertension, hypotension, DVT and PE can be seen. 
Instruct patient to report any signs or symptoms to health 
care team. 
 
15.198 Monitor LFT’s and instruct patient to report any hepatic 
symptoms (abdominal pain, jaundice) to study team 
immediately. 
 
15.199aThe IV line should be flushed with D5W or NS immediately 
before and after carfilzomab administration. Do not administer 
as a bolus. 
 
15.199bDosing is calculated using patient’s actual body surface area 
(BSA). Patients with a BSA greater than 2.2 m2 should receive 
dose based upon a BSA of 2.2 m2. 
 
15.199cMonitor electrolytes. Administer replacement doses as ordered 
and follow labs for effectiveness.  
 
15.2 
Melphalan (Alkeran®, LPAM) 
 
15.21 Background: Melphalan is an alkylating agent which is a derivative of 
mechlorethamine that inhibits DNA and RNA synthesis via formation of 


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carbonium ions; cross-links strands of DNA; acts on both resting and 
rapidly dividing tumor cells. 
 
15.22 Formulation: Commercially available for injection as:  
 
Injection, powder for reconstitution: 50 mg [diluent contains ethanol and 
propylene glycol] 
  
15.23 Preparation, storage, and stability: Refer to package insert for 
complete preparation and dispensing instructions. Store intact vials 
at room temperature. Protect from light.  
 
The time between reconstitution/dilution and administration 
of parenteral melphalan must be kept to a minimum 
(manufacturer recommends <60 minutes) because 
reconstituted and diluted solutions are unstable. Dissolve 
powder initially with 10 mL of diluent to a concentration of 5 
mg/mL. Shake vigorously to dissolve. This solution is chemically 
and physically stable for no more than 90 minutes at room 
temperature. Immediately dilute dose in 0.9% Sodium Chloride to 
a concentration of ≤ 0.45 mg/mL. Solution should be administered 
within 60 minutes of dilution.   DO NOT REFRIGERATE 
solution; precipitation occurs. 
  
15.24 Administration:  Refer to the treatment section for specific 
administration instructions. Melphalan is administered as a continuous 
I.V. infusion over one hour in 1000 mL 0.9% Sodium Chloride.  
 
 
15.25 Pharmacokinetic information: 
Distribution: Vd: 0.5-0.6 L/kg throughout total body water, low 
penetration into CSF 
Protein binding: 60% to 90%; primarily to albumin, 20% to α1-
acid glycoprotein 
Metabolism: Hepatic; chemical hydrolysis to 
monohydroxymelphalan and dihydroxymelphalan 
Half-life elimination: Terminal: I.V.: 75 minutes 
Time to peak, serum: ~1-2 hours  
 
 
15.26 Potential Drug Interactions: 
Increased Effect/Toxicity: Risk of nephrotoxicity of cyclosporine 
is increased by melphalan. Concomitant use of I.V. Melphalan 
may cause serious GI toxicity. Cisplatin may increase the 
levels/effects of I.V. melphalan. Melphalan may increase risk of 
vaccinal infection. 
Decreased Effect: Melphalan may decrease the levels/effects of 
digoxin. 
Ethanol/Herb Interactions: Avoid ethanol (due to GI irritation).  
 
15.27 Known potential adverse events: Consult the package insert for 
the most current and complete information. U.S. Boxed Warnings 
include: bone marrow suppression, hypersensitivity, 


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chromosomal changes potentially mutagenic and 
leukemogenic. 
 
Common known potential toxicities, > 10%:   
Gastrointestinal: Vomiting 
Hematologic: Myelosuppression, leukopenia, thrombocytopenia 
Miscellaneous: Secondary malignancy 
 
Less common known potential toxicities, 1% - 10%:  
Miscellaneous: Hypersensitivity 
 
Infrequent, frequency undefined, Postmarketing, and/or case 
reports:  
Agranulocytosis, allergic reactions, alopecia, amenorrhea, 
anaphylaxis, anemia, bladder irritation, bone marrow failure 
(irreversible), diarrhea, hemolytic anemia, hemorrhagic cystitis, 
hemorrhagic necrotic enterocolitis, hepatic veno-occlusive disease, 
hepatitis, interstitial pneumonitis, jaundice, nausea, ovarian 
suppression, pruritus, pulmonary fibrosis, radiation myelopathy, 
rash, secondary carcinoma, secondary leukemia, secondary 
myeloproliferative syndrome, SIADH, skin hypersensitivity, skin 
necrosis, skin ulceration (injection site), skin vesiculation, sterility, 
stomatitis, testicular suppression, transaminases increased, 
vasculitis 
 
15.28 Drug procurement:  Commercial supplies. Pharmacies or clinics shall 
obtain supplies from normal commercial supply chain or wholesaler. 
 
 
15.29 Nursing Guidelines:  
 
15.291  Hematologic toxicity is a major and dose-limiting adverse effect 
and is principally manifested by leukopenia and 
thrombocytopenia. Myelosuppression usually occurs 2-3 weeks 
after therapy and may persist for 6 weeks or more.  Monitor 
CBC frequently. Instruct patient to report any signs/symptoms of 
infection, unusual bruising or bleeding to the health care team.  
 
15.292  Assess for nausea and vomiting and treat symptomatically.  
Severe nausea and vomiting has been reported with high dose 
treatment. Pre-medicate with antiemetics before high dose IV 
treatment.  Occasional diarrhea and stomatitis has been reported 
also. Treat symptomatically. Encourage good oral care.  
 
15.293  Assess for pulmonary toxicity.  Instruct patient to report any 
unusual cough, chest pain, or respiratory difficulties.  
 
15.294  Anaphylaxis is possible with IV administration. Have 
anaphylaxis tray and necessary emergency equipment nearby 
when administering IV. Monitor for signs symptoms of 
hypersensitivity reaction, which include, rash, diaphoresis, 
difficulty breathing, and hypotension. 


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15.295  Drug is an irritant. Avoid extravasation. Establish IV patency 
before and throughout administration. 
   
15.296  Monitor renal function tests.  
 
16.0  
Statistical Considerations and Methodology  
 
16.1 
Overview:  This is a phase I/II study of a novel conditioning regimen 
incorporating carfilzomib and melphalan for multiple myeloma patients 
undergoing autologous stem cell transplantation.  The phase I portion of this study 
is designed to determine the maximum tolerated dose (MTD) of carfilzomib and 
melphalan conditioning in patients with multiple myeloma.  The phase II portion 
of this study will use a one-stage design to assess the efficacy of carfilzomib and 
melphalan conditioning in patients with multiple myeloma.   
 
16.11 
Endpoint: The primary endpoint of the phase I portion of this trial is to 
assess the maximum tolerated dose (MTD).  For the phase II portion of 
this trial, the primary endpoint is the proportion of complete responses.  
A complete response is defined as a CR noted as the objective status on 
two consecutive evaluations.  Complete response will be evaluated using 
all cycles.  Note that a patient may have already achieved a complete 
response prior to registration from induction therapy.  In this case, a 
continued complete response will be considered a complete response for 
the primary endpoint. 
 
16.12 
Sample Size:  This phase I portion of this study is expected to require a 
minimum of 10 (one patient each at dose levels 0-3 plus 6 patients at 
dose level 4) and a maximum of 30 (6 patients at each dose level 0-4) 
evaluable patients.  The 6 patients treated at the MTD in the phase I 
portion will also be included in the phase II portion.  An additional 33 
evaluable patients will be accrued for a maximum of 39 evaluable 
patients in the phase II portion of this study.  We anticipate accruing 5 
additional patients (2 phase I, 3 phase II) to account for ineligibility, 
cancellation, major treatment violation, or other reasons.  Therefore, the 
study is expected to accrue a maximum of 32 patients in phase I, 36 
patients in phase II, and 68 patients overall. 
 
 
As of Addendum 4, the number of dose levels in the phase I portion will 
be reduced.  A total of 5 patients have been accrued as of August 2014.  
We expect a maximum of 9 additional evaluable patients to be accrued in 
phase I.  The new overall maximum sample size is 51 patients (14 
patients total in phase I + 33 patients in phase II + 4 additional patients to 
account for patients who are replaced). 
 
16.13 
Accrual Rate and Study Duration:  The anticipated accrual rate is 2-3 
evaluable multiple myeloma patients per month.  At this rate, it will 
likely take about 2 months (cohort of 1 patient) to 3 months (cohorts of 3 
patients) to enroll, treat, and evaluate each cohort in the phase I portion 
of this study.  The phase I portion is expected to take between 14 and 30 
months.  The phase II portion of this study will accrue in the subsequent 


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1.5 years.  The maximum total study duration is expected to be 
approximately 4.5 years, or until the last patient accrued has been 
observed for at least 6 months.   
 
 
As of Addendum 4, phase I accrual will continue with the standard 
cohort of 3 design.  The phase I portion is expected to take an additional 
6-9 months.  Therefore, the maximum study duration is expected to be 
approximately 3 years after Addendum 3 is implemented. 
 
Phase I Portion  
 
16.2 
Study Design:  This portion of the study will consist of a phase I trial to 
determine the MTD of carfilzomib and melphalan conditioning.   A two-stage 
accelerated design will be utilized (Simon et al, 1997). The first stage is an 
accelerated dose escalation with a cohort of one patient as in Section 7.32. Once 
one DLT has been observed or ≥2 patients have experienced grade 3+ non-
hematologic toxicities during the first 2 cycles over all dose levels, the second 
stage will resume the standard cohort of three design as in Section 7.33.   A total 
of 6 patients will be enrolled and treated at the dose level prior to the one where 
the two DLTs occurred; i.e. at the MTD. 
 
 
As of Addendum 4, the phase I study design will be modified to the standard 
cohort of 3 design.  The first stage with accelerated dose escalation will no longer 
apply and accrual will continue in the second stage with the standard cohort of 3 
design.   Due to issues with accruing potential patients, it is felt that a cohort of 3 
design will be more beneficial to the patients and to study accrual.  In addition, 
the study entered the second stage of the design in error and it is felt that it will 
be more appropriate to continue with standard cohorts of 3 patients. 
 
16.21 MTD Determination:  MTD is defined as the dose level below the lowest 
dose that induces dose-limiting toxicity in at least one-third of patients 
(at least 2 of a maximum of 6 new patients). See section 7.3 for the MTD 
determination algorithm and section 7.4 for DLT definitions. 
 


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16.22 Primary Outcome Analyses: 
 
16.221 Adverse Events Profile:  The number and severity of all adverse 
events will be tabulated and summarized in this patient 
population. The grade 3+ adverse events will also be described 
and summarized in a similar fashion. This will provide an 
indication of the level of tolerance for this treatment combination 
in this patient group.  
 
16.222 Toxicity Profile:  The term toxicity is defined as adverse events 
that are classified as either possibly, probably, or definitely 
related to study treatment.  Non-hematologic toxicities will be 
evaluated via the ordinal CTC standard toxicity grading. 
Hematologic toxicity measures of thrombocytopenia, 
neutropenia, and leukopenia will be assessed using continuous 
variables as the outcome measures (primarily nadir) as well as 
categorization via CTC standard toxicity grading.  Overall 
toxicity incidence as well as toxicity profiles by dose level and 
patient will be explored and summarized. Frequency 
distributions, graphical techniques and other descriptive 
measures will form the basis of these analyses.  
 
Phase II Portion  
 
16.3  
Statistical Design: 
 
16.31 Decision Rule:  In a Mayo Clinic database study that captured data 
prospectively into a continuously updated database, 178 multiple 
myeloma patients received a stem cell transplant within 12 months of 
diagnosis.(Kumar, Lacy et al. 2011)  All of these patients received 
conditioning with single agent melphalan.  The complete response rate to 
stem cell transplant was 35%.  Since patients in this study are expected to 
receive a stem cell transplant within 12 months of diagnosis, an increase 
in complete response rate to greater than 35% with the addition of 
carfilzomib to melphalan in the conditioning regimen for patients with 
multiple myeloma would be of interest.  
 
 
The largest success proportion where the proposed treatment regimen 
would be considered ineffective in this population is 35%, and the 
smallest success proportion that would warrant subsequent studies with 
the proposed regimen in this patient population is 55%.  The following 
one-stage binomial design uses 39 evaluable patients to test the null 
hypothesis that the true success proportion in a given patient population 
is at most 35%.   
 
16.311 
Final Decision Rule:  If 17 or fewer successes are observed in 
the first 39 evaluable patients, we will consider this regimen 
ineffective in this patient population. If 18 or more successes 
are observed in the first 39 evaluable patients, we may 
recommend further testing of this regimen in subsequent 
studies in this population. 


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16.312 
Over Accrual: If more than the target number of patients are 
accrued, the additional patients will not be used to evaluate the 
stopping rule or used in any decision making process.  
Analyses involving over accrued patients are discussed in 
Section 16.44. 
 
16.32 Power and Significance Level:  Assuming that the number of successes 
is binomially distributed, the significance level is .10, i.e. there is a 10% 
chance of finding the drug to be effective when it truly is not.  The 
probability of declaring that this regimen warrants further study (i.e. 
statistical power) under various success proportions can be tabulated as a 
function of the true success proportion as shown in the following table. 
 
If the true success proportion is... 
0.35 
0.40 
0.45 
0.50 
0.55 
Then the probability of declaring 
that the regimen warrants further 
study is… 
0.10 
0.27 
0.50 
0.74 
0.90 
 
16.33 Other considerations:  Adverse events, quality/duration of response, and 
patterns of treatment failure observed in this study, as well as scientific 
discoveries or changes in standard care will be taken into account in any 
decision to terminate the study 
 
16.4 
Analysis Plan 
 
16.41 Primary Outcome Analyses: 
 
16.411 Definition:  The primary endpoint in the phase II portion of this 
trial is the proportion of complete responses.  A complete 
response is defined as a CR noted as the objective status on two 
consecutive evaluations.  Complete response will be evaluated 
using all cycles.  Note that a patient may have already achieved a 
complete response prior to registration as a result of the 
induction therapy.  In this case, a continued complete response 
will be considered a complete response for the primary endpoint.  
All patients meeting the eligibility criteria who have signed a 
consent form and have begun treatment will be evaluable for 
response. 
 
16.412 Estimation:  The proportion of successes will be estimated by the 
number of successes divided by the total number of evaluable 
patients. Exact binomial 95% confidence intervals for the true 
success proportion will be calculated. 
 
16.42 Secondary Outcome Analyses 
 
16.421 The complete response rate at day 100 will be estimated by the 
total number of patients who achieve a complete responses by 
day 100 post-transplant divided by the total number of 
evaluable patients. All evaluable patients will be used for this 


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analysis. Exact binomial 95% confidence intervals for the true 
complete response rate at day 100 will be calculated. 
 
16.422    Time to progression is defined as the time from registration to 
the earliest date with documentation of disease progression   If a 
patient dies without a documentation of disease progression,  
the patient will be considered to have had tumor progression at 
the time of their death unless there is sufficient documented 
evidence to conclude no progression occurred prior to death.  
The distribution of time to progression will be estimated using 
the method of Kaplan-Meier.(Kaplan and Meier 1958)  The 
progression-free rate at 1 year and 2 years will be assessed. 
 
16.425 Adverse Events:  All eligible patients that have initiated 
treatment will be considered evaluable for assessing adverse 
event rate(s).  The maximum grade for each type of adverse 
event will be recorded for each patient, and frequency tables will 
be reviewed to determine patterns.  Additionally, the relationship 
of the adverse event(s) to the study treatment will be taken into 
consideration. 
 
16.43   Correlative Analyses 
 
16.431  Minimal residual disease will be assessed on bone marrow 
aspirate in all patients achieving CR.  The proportion of patients 
who achieve MRD negative status will be estimated by the 
number of patients who are MRD negative divided by the total 
number of evaluable patients who achieve a CR.  Exact binomial 
95% confidence intervals for the true MRD negative rate will be 
calculated. 
 
16.432   The HevyLite assay will be assessed prior to treatment, at the 
end of cycle 3 (day 100), and at the time of suspected CR.  
Patients will be categorized by whether they have an abnormal 
ratio (yes vs. no) and uninvolved immunoglobulin suppressed 
(yes vs. no) at each time point.  The correlation of these 
categories with whether MRD is present (yes vs. no) will be 
evaluated using Fisher’s exact test.   In addition, the relationship 
between these categories and time to progression will be 
evaluated using Kaplan-Meier methods and log-rank statistics.  
Due to the limited sample size, these analyses will be considered 
exploratory. 
 
16.44 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used 
in any decision making processes; however, they will be included in final 
endpoint estimates and confidence intervals. 
 


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16.5 
Data & Safety Monitoring: 
 
16.51 The principal investigator(s) and the study statistician will review the 
study at least twice a year to identify accrual, adverse event, and any 
endpoint problems that might be developing. The Mayo Clinic Cancer 
Center (MCCC) Data Safety Monitoring Board (DSMB) is responsible 
for reviewing accrual and safety data for this trial at least twice a year, 
based on reports provided by the MCCC Statistical Office. 
 
16.52 Adverse Event Stopping Rules (includes all phase II patients, including 
phase I patients treated at the MTD):   The stopping rules specified 
below are based on the knowledge available at study development.  We 
note that the Adverse Event Stopping Rule may be adjusted in the event 
of either (1) the study re-opening to accrual or (2) at any time during the 
conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under 
investigation.  The study team may choose to suspend accrual because of 
unexpected adverse event profiles that have not crossed the specified rule 
below. 
 
Accrual will be temporarily suspended to this study if at any time we 
observe events considered at least possibly related to study treatment (i.e. 
an adverse event with attribute specified as  “possible,” “probable,” or 
“definite”) that satisfy one of the following: 
 
 
if 5 or more patients in the first 15 treated patients experience a grade 
4 or higher non-hematologic adverse event at least possibly related to 
treatment. 
 
 
if after the first 15 patients have been treated, 40% of all patients 
experience a grade 4 or higher non-hematologic adverse event at 
least possibly related to treatment.  
 
We note that we will review grade 4 and 5 adverse events deemed 
“unrelated” or “unlikely to be related”, to verify their attribution and to 
monitor the emergence of a previously unrecognized treatment-related 
adverse event. 
 
16.6   Results Reporting on ClinicalTrials.gov: At study activation, this study will have 
been registered within the “ClincialTrails.gov” website. The Primary and 
Secondary Endpoints along with other required information for this study will be 
reported on ClinicalTrials.gov. For purposes of timing of the Results Reporting, 
the initial estimated completion date for the Primary Endpoint of this study is 4.5 
years after the study opens to accrual. The definition of “Primary Endpoint 
Completion Date” (PECD) for this study is at the time the last patient registered 
has been followed for at least 6 months. 
 
16.7 
Inclusion of Women and Minorities 
 
16.71 This study will be available to all eligible patients, regardless of race, 
gender, or ethnic origin. 


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16.72 There is no information currently available regarding differential effects 
of this regimen in subsets defined by race, gender, or ethnicity, and there 
is no reason to expect such differences to exist. Therefore, although the 
planned analysis will, as always, look for differences in treatment effect 
based on racial and gender groupings, the sample size is not increased in 
order to provide additional power for subset analyses. 
 
16.73 The geographical region served by MCCC has a population which 
includes approximately 3% minorities.  Based on prior MCCC 
studies involving similar disease sites, we expect about 3-5% of 
patients will be classified as minorities by race and about 33% of 
patients will be women. Expected sizes of racial by gender subsets 
are shown in the following table: 
 
Accrual Estimates by Gender/Ethnicity/Race  
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
1 
0 
1 
Not Hispanic or Latino 
17 
33 
0 
50 
Ethnic Category: Total of all subjects* 
17 
34 
0 
51 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
Black or African American 
1 
1 
0 
2 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
White 
16 
33 
0 
49 
Racial Category: Total of all subjects* 
17 
34 
0 
51 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rico, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 


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Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa.  Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 


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17.0  
Pathology Considerations/Tissue Biospecimens:  None. 
 
18.0 
Records and Data Collection Procedures   
 
18.1 
Submission Timetable 
 
Initial Material(s)  
Case Report Form (CRF) 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
On-Study Form 
 
 
 
 
2 weeks after registration 
Baseline Adverse Event Form 
Pretreatment Measurement Form 
(Registration Values) 
Pretreatment Measurement Form Baseline 
Values for Disease Assessment 
Pretreatment Measurement Form Baseline 
Values at Time of Diagnosis 
SPEP, UPEP, FLC , Serum and Urine 
Immunofixation, Bone Marrow biopsy and 
aspirate, X-Ray skeletal survey, PCLI, 
Cytogenetic, FISH on study reports 
Research Blood Submission Form (see 
Section 14.0) 
Research Bone Marrow Aspirate Submission 
Form (see Section 14.0) 
End of Active Treatment/Cancel Notification 
Form 
Submit 2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
 




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19.0  
Budget 
 
19.1 
Costs charged to patient:  Melphalan, Stem cell transplant, Routine physical exams and 
blood and urine tests, Bone marrow aspirate and biopsy, X-ray skeletal survey, Chest x-
ray, Pulmonary function tests, ECHO, Pregnancy tests for women of childbearing 
potential. 
 
 
19.2 
Tests to be research funded: Minimal residual disease testing and HevyLite Assay®. 
 
19.3 
Other budget concerns: Protocol administration, data management and statistical analysis 
efforts will be by funded by Onyx Pharmaceuticals.  Carfilzomib will be provided free of 
charge from Onyx Pharmaceuticals. 
 


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20.0 
References 
 
Alsina, M., S. Trudel, et al. (2007). "Phase 1 Single Agent Antitumor Activity of Twice Weekly 
Consecutive Day Dosing of the Proteasome Inhibitor Carfilzomib (PR-171) in Hematologic 
Malignancies." ASH Annual Meeting Abstracts 110(11): 411-. 
Arastu-Kapur, S., K. Shenk, et al. (2008). "Non-Proteasomal Targets of Proteasome Inhibitors 
Bortezomib and Carfilzomib." ASH Annual Meeting Abstracts 112(11): 2657-. 
Attal, M., J. L. Harousseau, et al. (1996). "A prospective, randomized trial of autologous bone 
marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du 
Myelome." N Engl J Med 335(2): 91-97. 
Badros, A. Z., R. Vij, et al. (2009). "Phase I Study of Carfilzomib in Patients (Pts) with Relapsed 
and Refractory Multiple Myeloma (MM) and Varying Degrees of Renal Insufficiency." ASH 
Annual Meeting Abstracts 114(22): 3877-. 
Bross, P. F., R. Kane, et al. (2004). "Approval summary for bortezomib for injection in the 
treatment of multiple myeloma." Clinical cancer research : an official journal of the American 
Association for Cancer Research 10(12 Pt 1): 3954-3964. 
Child, J. A., G. J. Morgan, et al. (2003). "High-dose chemotherapy with hematopoietic stem-cell 
rescue for multiple myeloma." N Engl J Med 348(19): 1875-1883. 
Demo, S. D., C. J. Kirk, et al. (2007). "Antitumor activity of PR-171, a novel irreversible 
inhibitor of the proteasome." Cancer Res 67(13): 6383-6391. 
Gertz, M. A., M. Q. Lacy, et al. (2005). "Clinical implications of t(11;14)(q13;q32), 
t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy." Blood 
106(8): 2837-2840. 
Jagannath, S., R. Vij, et al. (2010). "Long-Term Treatment and Tolerability of the Novel 
Proteasome Inhibitor Carfilzomib (CFZ) In Patients with Relapsed and/or Refractory 
Multiple Myeloma (R/R MM)." ASH Annual Meeting Abstracts 116(21): 1953-. 
Kaplan, E. and P. Meier (1958). "Nonparametric estimation from incomplete observations." J Am 
Stat Assoc 53: 457-481. 
Katzmann, J., R. Clark, et al. (2009). "Isotype-Specific Heavy/Light Chain (HLC) Suppression as 
a Predictor of Myeloma Development in Monoclonal Gammopathy of Undetermined 
Significance (MGUS)." ASH Annual Meeting Abstracts 114(22): 1788-. 
Khan, M. L. and A. K. Stewart (2011). "Carfilzomib: a novel second-generation proteasome 
inhibitor." Future oncology 7(5): 607-612. 
Kirk, C. J., J. Jiang, et al. (2008). "The Selective Proteasome Inhibitor Carfilzomib Is Well 
Tolerated in Experimental Animals with Dose Intensive Administration." ASH Annual 
Meeting Abstracts 112(11): 2765-. 
Kuhn, D. J., Q. Chen, et al. (2007). "Potent activity of carfilzomib, a novel, irreversible inhibitor 
of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma." 
Blood 110(9): 3281-3290. 
Kumar, S. (2009). "Stem cell transplantation for multiple myeloma." Curr Opin Oncol 21(2): 
162-170. 
Kumar, S. K., M. Q. Lacy, et al. (2011). "Early versus delayed autologous transplantation after 
immunomodulatory agents-based induction therapy in patients with newly diagnosed multiple 
myeloma." Cancer: n/a-n/a. 
Lonial, S., J. Kaufman, et al. (2010). "A phase I/II trial combining high-dose melphalan and 
autologous transplant with bortezomib for multiple myeloma: a dose- and schedule-finding 
study." Clin Cancer Res 16(20): 5079-5086. 
Mateo, G., M. A. Montalban, et al. (2008). "Prognostic value of immunophenotyping in multiple 
myeloma: a study by the PETHEMA/GEM cooperative study groups on patients uniformly 
treated with high-dose therapy." J Clin Oncol 26(16): 2737-2744. 


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Paiva, B., M.-B. Vidriales, et al. (2009). "Multiparameter flow cytometry quantification of bone 
marrow plasma cells at diagnosis provides more prognostic information than morphological 
assessment in myeloma patients." Haematologica 94(11): 1599-1602. 
Parlati, F., S. J. Lee, et al. (2009). "Carfilzomib can induce tumor cell death through selective 
inhibition of the chymotrypsin-like activity of the proteasome." Blood 114(16): 3439-3447. 
Roussel, M., P. Moreau, et al. (2010). "Bortezomib and high-dose melphalan as conditioning 
regimen before autologous stem cell transplantation in patients with de novo multiple 
myeloma: a phase 2 study of the Intergroupe Francophone du Myelome (IFM)." Blood 
115(1): 32-37. 
Sarasquete, M. E., R. Garcia-Sanz, et al. (2005). "Minimal residual disease monitorization in 
multiple myeloma patients achieving complete response after autologous stem cell 
transplantation: a comparitive study between ASO real time quantitative PCR and flow 
cytometry." Haematologica 90. 
Siegel, D., L. Wang, et al. (2009). "PX-171-004, An Ongoing Open-Label, Phase II Study of 
Single-Agent Carfilzomib (CFZ) in Patients with Relapsed or Refractory Myeloma (MM); 
Updated Results From the Bortezomib-Treated Cohort." ASH Annual Meeting Abstracts 
114(22): 303-. 
Simon RM, Friedlin B, Rubinstein LV, Arbuck S, Collins J, Christian M 1997 Accelerated 
titration designs for phase I clinical trials in oncology. Journal of the National Cancer 
Institute 89:1138-1147 
Wang, L., D. Siegel, et al. (2009). "Updated Results of Bortezomib-I Patients in PX-171-004, An 
Ongoing Open-Label, Phase II Study of Single-Agent Carfilzomib (CFZ) in Patients with 
Relapsed or Refractory Myeloma (MM)." ASH Annual Meeting Abstracts 114(22): 302. 
 


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


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Appendix II 
 
NYHA Classification 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 1 
 
Class I:  
NO Symptoms with ordinary activity  
Class II:  
Symptoms with ordinary activity  
Class III:  Symptoms with minimal activity 
Class IV:  Symptoms at rest 
 


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Appendix III 
Multiple Myeloma Diagnostic Criteria 
 
Page 1 of 1 
 
Standard criteria for a diagnosis of multiple myeloma are as follows (Kyle et al British Journal of 
Haematology. 121(5):749-57, 2003)  
 
Multiple Myeloma 
Monoclonal protein present in serum ≥ 3 g/dl 
and/or 
Bone marrow clonal plasma cells ≥ 10% 
 
Myeloma-related organ or tissue impairment (ROTI) 
Calcium 1 mg/dL (0.25 mmol/L) above the upper limit of normal 
Creatinine > 2 mg/dL (173 mmol/L) 
Lytic bone lesions or osteoporosis 
 
Asymptomatic myeloma 
Multiple myeloma and absence of ROTI 
 
Symptomatic myeloma 
Multiple myeloma and presence of any ROTI that can be attributed to myeloma. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix IV 
Chemotherapy Dosing Information 
 
Principle:  Use the lesser of actual or corrected ideal body weight (CIBW) for all 
chemotherapy dosing. 
 
For patients who are overweight, a corrected ideal body weight should be calculated and used to calculate 
chemotherapy doses. Ideal body weight (IBW) can be calculated as follows:  
1. Males: IBW = 50 kg + (2.3 x number of inches over 5 feet)  
2. Females: IBW = 45.5 kg + (2.3 x number of inches over 5 feet)  
 
The corrected ideal body weight can then be calculated by the following formula:  
1. Corrected IBW = IBW +0.25 (actual body weight - IBW)  
 
 
The lesser of actual or corrected ideal body weight is then used in the Gehan and George BSA formula to 
calculate carfilzomib and melphalan dosing 
 
The Gehan and George formula 
BSA (m²) = 0.0235 x Height(cm)0.42246 x Weight(kg)0.51456 
Gehan EA, George SL, Estimation of human body surface area from height and weight.   Cancer Chemother Rep 
1970 54:225-35.