Conditions: Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 28
Healthy volunteers: no

Brief summary:
This phase II trial studies how well sonidegib and lenalidomide after stem cell transplant works in treating patients with multiple myeloma. Sonidegib and lenalidomide may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and may delay multiple myeloma from coming back after a stem cell transplant.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the complete response (CR) rate with lenalidomide and sonidegib (LDE225) maintenance following an upfront single autologous stem cell transplant (SCT).

SECONDARY OBJECTIVES:

I. To assess the toxicity of lenalidomide and LDE225 when used as maintenance therapy in patients post autologous SCT.

II. To determine the progression-free survival rate at 1 and 2 years post autologous SCT.

III. To evaluate progression-free survival and overall survival.

TERTIARY OBJECTIVES:

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

OUTLINE:

Patients receive sonidegib orally (PO) once daily (QD) on days 1-28 and lenalidomide PO QD on days 1-21. Treatment repeats every 28 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve stringent complete response (sCR), CR, very good partial response (VGPR), partial response (PR), minor response (MR), or stable disease (SD) (or unconfirmed \[u\]sCR, uCR, uVGPR, uPR, uMR) continue treatment in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 90 days for up to 3 years.

Arms:
arm 1: Patients receive sonidegib PO QD on days 1-28 and lenalidomide PO QD on days 1-21. Treatment repeats every 28 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients who achieve sCR, CR, VGPR, PR, MR, or SD (or usCR, uCR, uVGPR, uPR, uMR) continue treatment in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Lenalidomide intervention 3: Sonidegib
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Given PO

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/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation   
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
 Consent Form  
Appendix I – Prohibited concomitant medications 
Appendix II - ECOG Performance Status 
Appendix III – NYHA Classification 
Appendix IV – Patient Diary 


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Schema 
 
 
 
 
 
 
 
 
 
 
   
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.  Every 90 days for up to 3 years from the time of registration, or until progression or subsequent 
treatment for myeloma 
2. Patients will be seen prior to each cycle for the first 6 cycles, after that they can be seen every  
3 months (3 cycles)  
 
Generic name:   LDE225 
Brand name(s): 
Mayo Abbreviation:  LDE225   
Availability:  Novartis 
Generic name:    Lenalidomide  
Brand name(s): Revlimid® 
Mayo Abbreviation:  REVLIMID 
  
Availability:   Commercial via Revlimid REMS 
Registration 
Treatment2 
Lenalidomide Days 1-21 
LDE225 Days 1-28 
 
28-day cycles, repeat for up to 18 cycles 
Event-Monitoring 
 
 
Unacceptable adverse events  
                     Event Monitoring 
Patient refusal 
PD at any time 
Subsequent treatment for myeloma  
Observation1 


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1.0 
Background 
 
1.1 
Role of autologous stem cell transplantation in myeloma:  High dose therapy and stem 
cell transplantation (SCT) remain the standard of care for patients with multiple 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.  
 
1.2 
Depth of response and outcome: Several lines of evidence suggest that the depth of 
response achieved with various treatments, especially in the context of SCT, is a 
powerful determinant of the response duration. In multiple studies it has been noted that 
achievement of CR post SCT predicts the duration of response and in some studies the 
overall survival of these patients.(Rajkumar, Fonseca et al. 2000; Harousseau, Palumbo et 
al. 2010) However, in nearly half of the patients with a clinical CR residual myeloma 
cells can be detected using more sensitive methods such as multicolor flow cytometry or 
PCR based techniques. In the setting of MM, we know that MRD is an important 
predictor of outcome in patients undergoing aggressive therapy.   Rawstron et al used a 
sensitive flow cytometry assay that quantitated normal and neoplastic plasma cells (PCs) 
to monitor the bone marrow (BM) of 45 patients undergoing autologous stem cell 
transplant (ASCT).(Rawstron, Davies et al. 2002) Among the 42% of patients in whom 
monoclonal PCs were detectable 3 months after ASCT, the median PFS was 20 months 
compared to 35 months for those with undetectable PCs. Even among those with negative 
immunofixation studies, considered the hallmark of “CR”, a third had detectable PCs and 
had a poorer outcome. Bakkus et al examined the utility of detecting MRD using a 
quantitative allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) assay 
at 3–6 months post-transplant in 67 patients.(Bakkus, Bouko et al. 2004) Using specific 
cutoffs for the quantitative PCR results, the authors identified patients with residual 
disease and a short time to relapse. Lipinski et al retrospectively analyzed the tumor load 
in peripheral blood (PB) and BM samples of 13 patients at time of remission after ASCT 
and at the time of progression using ASO-qPCR(Lipinski, Cremer et al. 2001). 
Progression was detected early by this method compared to monoclonal protein 
estimation demonstrating sensitivity of the technique. Galimberti et al examined the 
prognostic value of PCR based monitoring of MRD in 20 patients after ASCT by non-
myeloablative allogeneic transplant (NMT).(Galimberti, Benedetti et al. 2005) After 
ASCT, only 3 patients (15%) achieved PCR-negativity, versus 12 (60%) after NMT. 76% 
of patients with no MRD were still alive at 2 years versus 34% of PCR positive patients. 
 


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 1.3 
Maintenance strategies after autologous stem cell transplantation: The concept of 
maintenance therapy has been tested mostly in the setting of high dose therapy and 
autologous stem cell transplantation. Patients invariably relapse after initial treatment 
strategies including SCT and various trials have attempted to maintain the SCT response 
through maintenance approaches. Initial trials prior to the availability of the new drugs 
have examined steroids or interferon, and a small randomized clinical trial of interferon- 
(3 x 106 units/m2) subcutaneously 3 times weekly, following initial ASCT, suggested a 
modest improvement in EFS.(Cunningham, Powles et al. 1998) The IFM99-02 trial 
randomized patients with standard-risk MM (Beta2-microglobulin [B2M] <3, no deletion 
13), : to receive no maintenance, pamidronate, or pamidronate plus thalidomide after 
tandem SCT.(Attal, Harousseau et al. 2006) Thalidomide was associated with higher 
response rates, improved EFS (52% vs. 36% with no maintenance) and improved overall 
survival (4-year estimated survival from diagnosis with thalidomide (87%) compared 
with no maintenance (77%). At least 5 different randomized trials have examined the role 
of thalidomide as a maintenance therapy post-SCT.(Lokhorst, van der Holt et al. 2009; 
Spencer, Prince et al. 2009; Stewart, Trudel et al. 2010) A meta-analysis of these trials 
support  improved progression-free survival, but remains equivocal in terms of overall 
survival improvement. In addition a, high discontinuation rate has been noted in all these 
studies due to toxicity. In particular the Canadian study showed worsening of QoL 
parameters among patients getting thalidomide maintenance.(Stewart, Trudel et al. 2010)  
 
  
A phase 3 study from the IFM enrolled 614 patients < 65 years, with non-progressive 
disease, within 6 months after upfront ASCT.(Attal, Lauwers et al. 2010) Patients 
received 2 cycles of consolidation with lenalidomide 25 mg daily for 3 of 4 weeks 
followed by a randomization to lenalidomide 10-15 mg/day until relapse or to placebo 
(n=307 in each arm). Patients were stratified according to Beta-2M, del13, and VGPR to 
initial therapy. There was an improvement in the PFS with maintenance therapy, with a 
median PFS of 42 months for lenalidomide vs. 24 months for the placebo. The 
improvement in the PFS was seen in all the subgroups based on stratification. With the 
current follow-up, overall survival (OS) remains identical in the two groups. In a very 
similar trial, McCarthy and colleagues randomized patients 70 years or younger, who 
attained a stable disease or better with their induction therapy and underwent ASCT 
within one year of diagnosis, to lenalidomide (5-15 mg/day) or placebo until 
relapse.(McCarthy, Owzar et al. 2010) Patients were stratified based on Beta-2M and use 
of thalidomide or lenalidomide therapy during induction. Patients were enrolled prior to 
the ASCT, with 19% of the 568 enrolled dropping out before randomization. As 
expected, grade 3 and 4 adverse events were significantly higher lenalidomide arm during 
in the maintenance arm compared to the placebo, with hematological toxicities being the 
common events. The median time to progression was 42 months with lenalidomide 
compared to 21.8 months with the placebo, results very similar to the French study. More 
recent updates suggest an improvement in the overall survival for the lenalidomide arm in 
the CALGB study. There are differences, however, between the two trials in terms of the 
design as well as duration of therapy. Patients in the IFM trial received uniform induction 
therapy unlike the CALGB trial. Patients in the IFM study received 2 cycles of 
consolidation with lenalidomide before starting maintenance. In addition, the IFM trial 
limited maintenance to approximately 24 months based on concerns regarding second 
malignancies and did not allow cross over. However, the CALGB trial allowed cross over 


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from placebo arm to lenalidomide maintenance based on interim analysis and also 
allowed maintenance until progression. 
 
  
So the bulk of evidence points to the importance of exploring continued treatment 
approaches in the majority of patients with myeloma post-SCT, preferable in the context 
of clinical trials. In vitro studies suggest that the major obstacle to eradicating the tumor 
clone of myeloma is the result of the protective tumor microenvironment that exists in the 
marrow. Clearly novel approaches need to be examined in the context of SCT for 
eradication of residual disease. This is even more relevant today, with the deep responses 
we are able to obtain with new agents pre-SCT, thus enabling the use of experimental 
approaches in the context of minimal residual disease.  
 
1.4 
Hedgehog signaling in myeloma: In multiple myeloma, the abnormal proliferation of 
plasma cells is very much dependent on the bone marrow microenvironment.(Podar, 
Richardson et al. 2007) Hedgehog (Hh) signaling is a highly conserved pathway that 
plays an important role in development in both vertebrates and invertebrates (Ingham and 
McMahon 2001). Aberrant functioning of the Hh pathway has been reported in several 
tumors including prostate and lung cancers. To summarize the Hh pathway, Hh ligands 
secreted by the stromal cells, namely indian (Ihh), sonic (Shh) and desert (Dhh) bind to 
their receptor, patched (PTCH) on tumor cells. This binding alleviates the inhibition of 
PTCH on its downstream target, smoothened (Smo), thereby activating it. This activation 
leads to activation of the cubitus interruptus-like transcription factor involved in glioma 
formation (Gli) which promotes the transcription of its target genes leading to tumor 
development and progression (Xie and Abbruzzese 2003). In the myeloma setting it has 
been found that Hh pathway is essential for maintaining a subset of tumor causing stem 
cells. Blocking the Hh pathway by inhibiting Smo activation by treatment with 
cyclopamine, an inhibitor of Smo, did minimize the clonal expansion of the subset of 
tumor causing stem cells by enabling them to differentiate terminally (Peacock, Wang et 
al. 2007). When MM cell cultures were treated with cyclopamine and cell viability was 
examined, it was found that the MM cells were less viable in the presence of cyclopamine 
than in the absence of it (Dierks, Grbic et al. 2007). More recently, Blotta et al 
demonstrated that plasma cells from MGUS patients express higher levels of Ihh/Shh, 
Smo and Ptch1 receptors, as well as Gli1 and Gli2 transcription factors, but lower levels 
of the repressor genes Ptch2 and Gli3 compared with normal plasma cells.(Blotta, 
Jakubikova et al. 2012) Similarly, plasma cells from patients with MM showed up-
regulation of Ptch1, Gli1 and Gli2 and down-regulation of Ptch2 and Gli3, again 
supporting a role of this pathway in myeloma pathogenesis. In contrast, these changes 
were less obvious in cell lines and plasma cell leukemia likely reflecting the lack of 
microenvironment dependence in these situations. The investigators were also able to 
show activation of both ligand dependent (canonical) as well as independent (non-
canonical) mechanisms for the up regulation of Hh pathway seen in MM. Finally, these 
studies confirmed prior observations regarding the stromal cells being a major source of 
Shh that can drive proliferation of myeloma cells as well as afford protection against anti-
myeloma drugs.  
  
 
1.5 
LDE225: LDE225 is a potent, selective and orally bioavailable Smo antagonist. LDE225 
is a high-affinity ligand for human and mouse Smo, as shown by its ability to displace 
radiolabeled Smo agonists, with an IC50 of 11 nM for human Smo and 12 nM for mouse 


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Smo. In multiple cell-based assays, LDE225 is a potent antagonist of Hh-dependent 
pathway activation. It inhibits Hh-mediated Gli1 activation in mouse TM3 and human 
HEPM cells with an IC50 of 7 nM and 13 nM, respectively. LDE225 potently inhibits 
proliferation and Gli1 expression of freshly isolated mouse MB tumor cells in vitro with 
an IC50 of 7 nM. Treatment with LDE225 results in tumor regression in vivo in several 
genetically defined animal models. Efficacy in these tumor models is dose-related and 
correlates with inhibition of Hh pathway signaling, as measured by decreased Gli1 
mRNA. Treatment with LDE225 also shows in vivo efficacy in models of pancreatic 
cancer and SCLC. In vivo studies in the myeloma setting have shown significant efficacy 
of LDE225, particularly in combination with bortezomib.(Blotta, Jakubikova et al. 2012) 
 
 
LDE225 was well tolerated in mice with no significant body weight loss at all doses (up 
to 160 mg/kg QD) investigated. In vivo PK/PD analysis in MB models showed a good 
correlation between the given dose, the measured blood and tissue levels, the effects on 
the Hh pathway as measured by Gli1 mRNA expression and the anti-tumor activity. It 
appeared that almost complete and sustained Gli1 mRNA inhibition (above 
approximately 95%) is required to yield tumor regression in the animal models studied. 
LDE225 was well absorbed with Tmax occurring within 0.5 to 24 hours post-dose. The 
clearance was low to moderate and the volume of distribution was always greater than the 
total body water in all species investigated. The majority of adverse effects of LDE225 
observed in toxicity studies in rats and dogs can be attributed to the pharmacologic 
mechanism of action on developmental pathways. The most striking of these 
pharmacologic effects were on growing bones and teeth (growing incisors in rodents). 
The bone effects included thinning or closure of the bone growth plates in the sternum 
and femur. Effects on the reproductive systems were seen in rats and dogs. GI toxicity 
was likely dose limiting in the animal studies. In the GLP juvenile rat study minimal to 
slight degeneration of nerve fibers was found in the sciatic nerve and, less commonly, in 
the thoracic spinal cord, but not in the cervical or lumbar spinal cord or optic nerve. 
Effects on nerves were not seen in any of the toxicity studies on more mature rats or 
dogs. 
 
We have examined the activity of LDE in combination with lenalidomide in myeloma, 
especially in the context of bone marrow derived stromal cells or tumor 
microenvironment. In in vitro experiments, LDE225 treatment of myeloma cell lines 
resulted in a modest inhibition of cell proliferation at increasing doses (Figure 1).   




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Figure 2: MM1.s myeloma cell line was incubated with the indicated concentrations of 
LDE225 and lenalidomide for 72 hours and cell viability was measured by thymidine 
incorporation. Y-axis represents the thymidine uptake as counts per min. standardized to 
the control. 
 
1.6 
Clinical experience with LDE225: LDE225 is currently undergoing evaluation in three 
Phase I clinical trials (CLDE225X2101, CLDE225X1101 and CLDE225X2104) and one 
Phase II trial (CLDE225A2201) to assess the safety, tolerability, PK, PD and potential 
efficacy of continuous daily oral administration in patients with malignant solid tumors. 
As of October, 2011, data were available on 103 patients with cancer who have been 
treated with LDE225 at dose levels of 100, 200, 400, 800, 1000, 1500, and 3000 mg once 
daily (QD) and 250, 400 and 750 mg twice daily (BID). Based on the available data, the 
recommended phase II of LDE225 in adults is 800 mg once daily. DLTs that are 
characterized by CTC grade 3 or 4 increases in plasma creatine phosphokinase (CK) 
observed at once daily doses ≥ 800 mg and twice daily doses ≥250 mg. The majority of 
the DLT events occurred during the initial 4-6 weeks of treatment with LDE225. None of 
the patients experienced impairment of renal function as a result of this toxicity. The 
DLTs resolved following discontinuation of LDE225 therapy. Across all the doses 
studied, the commonly (>10%) reported CTCAE grade 1 or 2 adverse events that are 
suspected to be treatment-related include: nausea, vomiting, dysgeusia, decreased 
appetite, myalgia, muscle spasms, blood CK increased, alopecia, asthenia and fatigue. 
 
1.7 
Study Rationale: These findings form the basis of evaluation of HH inhibition as a 
strategy to enhance the activity of lenalidomide in the post-transplant maintenance 
setting. The minimal residual state post SCT provides the most optimal situation for 
evaluation of a drug that is likely to work by inhibiting the interaction between tumor 
cells that escaped the high dose therapy with the help of protection by the 
microenvironment.  
 
 
 


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2.0 
Goals    
 
 
2.1 
Primary 
 
2.11 
To assess the CR rate with lenalidomide and LDE225 maintenance following an 
upfront single autologous SCT 
 
2.2 
Secondary 
 
2.21 
To assess the toxicity of lenalidomide and LDE225 when used as maintenance 
therapy in patients post autologous SCT. 
 
2.22 
To determine the progression-free survival rate at 1 and 2 years post autologous 
SCT 
 
2.23   To evaluate progression-free survival and overall survival 
 
2.3 
Correlative Research 
 
2.31 
To determine the proportion of patients achieving a minimal residual disease 
(MRD) negative status 
 
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: 
• 
Absolute neutrophil count ≥1500/µL 
• 
Platelet count ≥ 80,000/µL 
• 
Hemoglobin ≥ 9.0 g/dL 
• 
Serum total bilirubin ≤ 1.5 x ULN(upper limit of normal) 
• 
AST and ALT ≤ 2.5 x ULN or ≤ 5 x ULN if liver involvement 
• 
Plasma creatine phosphokinase (CK) < 1.5 x ULN 
• 
Serum creatinine ≤ 1.5 x ULN or 24-hour clearance ≥ 50ml/min  
 
 
3.13 
Diagnosis of symptomatic MM 
3.14 
Patients should have received single autologous stem cell transplantation 60-120 
days prior to enrollment to the trial. 
 
3.15 
Patients should have received the autologous SCT within 12 months of their 
diagnosis of myeloma to be eligible for the study. 
 
3.16 
ECOG performance status (PS) 0, 1 or 2 (Appendix I). 
 


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3.17 
Recovered from toxicity of previous chemotherapy (excludes grade 1 
neurotoxicity and hematological toxicity) 
 
3.18 
Voluntary written informed consent before performance of any study-related 
procedure not part of normal medical care, with the understanding that the 
subject may withdraw consent at any time without prejudice to future medical 
care 
 
3.19a 
Willingness to return to the Mayo Clinic enrolling institution for follow-up 
 
3.19b  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 (involved FLC) ≥10 mg/dL AND 
abnormal serum immunoglobulin kappa to lambda free light chain ratio. 
 
NOTE: For patients with no relapse prior to transplant, measurable disease at the 
time of diagnosis. 
 
 
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.  
 
3.19c 
Patients may have a history of current or previous deep vein thrombosis or 
pulmonary embolism but must be willing to initiate prophylaxis with low 
molecular weight heparin. 
 
3.19d Females of childbearing potential (FCBP)† must have a negative serum or urine 
pregnancy test with a sensitivity of at least 50 mIU/mL within 10 – 14 days prior 
to and again within 24 hours of starting lenalidomide and LDE225 and must 
either commit to continued abstinence from heterosexual intercourse or begin 
TWO acceptable methods of birth control, one highly effective method and one 
additional effective method AT THE SAME TIME, at least 28 days before she 
starts taking lenalidomide and LDE225.  FCBP must also agree to ongoing 
pregnancy testing.  Men must agree to use a latex condom during sexual contact 
with a FCBP even if they have had a successful vasectomy.  All patients must be 
counseled at a minimum of every 28 days about pregnancy precautions and risks 
of fetal exposure.   
 
 
 


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† A female of childbearing potential is any woman, regardless of sexual 
orientation or whether they have undergone tubal ligation, who meets the 
following criteria: 1) has not undergone a hysterectomy or bilateral 
oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 
consecutive months. 
 
3.19e 
Sexually active males must be willing to use a condom (even if they have 
undergone a prior vasectomy) while having intercourse, while taking 
lenalidomide and for 4 weeks after stopping treatment. 
 
3.19f 
Patient enrolling to this study must agree to register to the mandatory 
REVLIMID REMS™) program, and be willing and able to comply with the 
requirements of (REVLIMID REMS™) 
 
3.19g Patients must be willing to provide biological samples as required by the study 
(Section 14). 
 
3.2 
Exclusion Criteria 
 
3.21  
Prior allogeneic bone marrow/peripheral blood stem cell transplant 
 
3.22 
Patients with evidence of disease progression post SCT at the time of 
consideration for the study enrollment will not be included. 
 
3.23 
Impaired cardiac function or clinically significant heart disease, including any 
one of the following: 
• 
Angina pectoris within 3 months 
• 
Acute myocardial infarction within 3 months 
• 
QTcF > 450 msec for males and > 470 msec for females on the screening 
ECG 
• 
A past medical history of clinically significant ECG abnormalities or a 
family history of prolonged QT-interval syndrome 
• 
Other clinically significant heart disease (e.g. congestive heart failure, 
uncontrolled hypertension, history of labile hypertension, or history of poor 
compliance with an antihypertensive regimen) 
 
3.24 
Seroreactivity for HIV, HTLV I or II, HBV, HCV 
 
3.25 
Other active malignancy requiring therapy.  EXCEPTIONS:  Non-melanotic 
skin cancer or carcinoma-in-situ of the cervix.  
 
3.26 
Any of the following: 
• 
Pregnant or nursing (lactating) women, where pregnancy is defined as the 
state of a female after conception and until the termination of gestation, 
confirmed by a positive hCG laboratory test (> 5 mIU/mL). 


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• 
Patients who are not willing to apply highly effective contraception during 
the study and through the duration as defined below after the final dose of 
study treatment. 
• 
Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, must use highly 
effective contraception during the study and through 6 months after 
the final dose of study treatment. Highly effective contraception is 
defined as either: 
1. Total abstinence: When this is in line with the preferred and 
usual lifestyle of the patient. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception.  
2. Sterilization: Patient has had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least six 
weeks before taking study treatment. In case of oophorectomy 
alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment  
3. Male partner sterilization (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate). [For 
female study patients, the vasectomised male partner should be 
the sole partner for that patient]  
4. Use a combination of the following (both a+b):  
a. Placement of a non-hormonal intrauterine device (IUD) or 
non-hormonal intrauterine system (IUS) 
b. Barrier method of contraception: Condom or Occlusive cap 
(diaphragm or cervical vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository.  
Note: Hormonal contraception methods (e.g. oral, injected, implanted) are 
not allowed as it cannot be ruled out that the study drug decreases the 
effectiveness of hormonal contraception 
Note: Woman are considered post-menopausal and not child bearing 
potential if they have had 12 months of natural (spontaneous) amenorrhea 
with an appropriate clinical profile (e.g. age appropriate, history of 
vasomotor symptoms) or six months of spontaneous amenorrhea with 
serum FSH levels > 40 mIU/mL and estradiol < 20 pg/mL or have had 
surgical bilateral oophorectomy (with or without hysterectomy) at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential     
• 
Male patient must use highly effective (double barrier) methods of 
contraception (e.g., spermicidal gel plus condom) for the entire duration of 
the study, and continuing using contraception and refrain from fathering a 
child for 6 months following the study drug. A condom is required to be 
used also by vasectomized men as well as during intercourse with a male 
partner in order to prevent delivery of the study treatment via seminal fluid 


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• 
Sexually active males who are unwilling to use a condom during 
intercourse while taking drug and for 6 months after stopping 
investigational medications and agree not to father a child in this period.. 
 
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 for treatment of 
multiple myeloma.   
 
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 
 
3.30  
Major surgery within 4 weeks prior to registration. 
 
3.31 
Patients with concurrent uncontrolled medical conditions that may interfere with 
their participation in the study or potentially affect the interpretation of the study 
data. 
 
3.32 
Patients unable to take oral drugs or with lack of physical integrity of the upper 
gastrointestinal tract or known malabsorption syndromes. 
 
3.33 
Patients who have previously been treated with systemic LDE225 or with other 
hedgehog pathway inhibitors. 
 
3.34 
Patients who have neuromuscular disorders (e.g. inflammatory  myopathies, 
muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) 
or are on concomitant treatment with drugs that are recognized to cause 
rhabdomyolysis, such as HMG CoA inhibitors (statins), clofibrate and 
gemfibrozil, and that cannot be discontinued at least 2 weeks prior to starting 
LDE225 treatment.  NOTE:  If it is essential that the patient stays on a statin to 
control hyperlididemia, only pravastatin may be used with extra caution.  
 
3.35 
Patients who have taken part in an experimental drug study ≤ 4 weeks prior to 
registration. 
 
3.36 
Patients who are receiving treatment with medications known to be moderate and 
strong inhibitors or inducers of CYP3A4/5 or drugs metabolized by CYP2B6 or 
CYP2C9 that have narrow therapeutic index, and that cannot be discontinued 
before starting treatment with LDE225.  
 
3.37  
Patients unwilling or unable to comply with the protocol. 
 
3.38 
Requirement for anticoagulation with warfarin 
 


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4.0 
Test Schedule  
 
 
Active Monitoring1 
 
Days Prior to 
Registration 
Prior to 
each 
cycle11 © 
Day 15, 
Cycles 1 
and 213 
 
End of 
Cycle 18 
Observation 
every 90 
days  5 
 
≤30 
days 
≤14 
days 
Complete medical history 
X 
 
 
 
 
 
Adverse Event monitoring 
 
X 
Xd 
 
X 
X 
Physical exam, including weight and vital signs 
 
X 
Xb 
 
X 
X 
Height 
 
X 
 
 
 
 
Performance status (ECOG scale)  
 
X 
X 
 
X 
X 
CBC with differential 
 
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, plasma creatinine 
phosphokinase (CK), ALT 
 
 
X 
 
X 
 
 
 
X 
 
X 
sTSH 
 
X 
X4 
 
X 
 
LDH, Beta2-microglobulin, C-reactive protein 
X 
 
 
 
 
 
Electrophoresis of serum and urine 
 
X 
X12 
 
X12 
X12 
Affected serum immunoglobulin 
 
X 
X7 
 
X7 
X7 
Immunofixation serum and urine 
X 
 
 X2 
 
X2 
X2 
Immunoglobulin serum free light chains 
 
X 
X6 
 
X6 
X6 
Metastatic skeletal survey 
X 
 
X4 
 
X4 
X4 
Bone marrow aspirate and biopsy, myeloma 
FISH, metaphase cytogenetics, and flow 
cytometry  
X 
 
X10 
 
X8 
X10, 8 
Research blood sample as per 521-93, optionalR   
 
X 
X10 
 
X 
X10 
Research bone marrow aspirate (see Section 
14.0)R 
 
X 
X9 
 
X 
X9 
Chest x-ray, ECG 
X 
 
 
 
 
 
Serum pregnancy test 
 
X3 
 
 
 
 
 
1) All scheduled visits will have a window of ± 7 days, unless otherwise stated 
2) Immunofixation (IF) needed only in the absence of M-protein to document sCR or CR. 
3) For women of childbearing potential only.  Must be done ≤7 days prior to registration. 
4) Every 6 cycles 
5) For up to 3 years from the time of registration, or until progression or subsequent treatment for 
myeloma, whichever occurs first 
6) Immunoglobulin free light chain required only if used to assess disease response.  
7) 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.   Affected 
immunoglobulin is required after baseline only if it used for disease monitoring instead of SPEP (for 
e.g. IgA myeloma) 
8)  No FISH or cytogenetics required unless clinically indicated 
9) At the time of suspected CR 


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10) Only required to document CR or sCR. 
11) Does not need to be repeated at Cycle 1 Day 1. Baseline values can be used for Cycle 1. 
12) Urine Electrophoresis required only if used to assess disease response. 
13) Can be completed at local MD 
R Research funded (see Section 19.0).  Will be charged to study and not to patient’s account. 
b) After 6 cycles of follow up this will be done every 3 months (3 cycles) 
c) Routine blood work and urine tests can be done at home or by mail in kit if patient is not being seen 
at Mayo clinic prior to each cycle. 
d) Nurse will call patient for adverse event monitoring prior to each cycle if patient is not being seen at 
Mayo Clinic that cycle. 
 
5.0 
Grouping Factor:  
 
None 
 
6.0  
Registration/Randomization Procedures 
6.1 
Registration Procedures 
 
 
To register a patient, access the Mayo Clinic Cancer Center (MCCC) web page and enter 
the remote registration/randomization application. The remote registration/randomization 
application is available 24 hours a day, 7 days a week. Back up and/or system support 
contact information is available on the Web site. If unable to access the Web site, call the 
MCCC Registration Office a
 between the hours of 8 a.m. and 4:30 p.m. 
Central Time (Monday through Friday).The instructions for remote registration are 
available on the MCCC web page 
 and detail the 
process for completing and confirming patient registration. Prior to initiation of protocol 
treatment, this process must be completed in its entirety and a MCCC subject ID number 
must be available as noted in the instructions. It is the responsibility of the individual 
registering the patient to confirm the process has been successfully completed prior to 
release of the study agent. Patient registration via the remote system can be confirmed in 
any of the following ways: 1) Contact the MCCC Registration Office 
. If 
the patient was fully registered, the Registration Office staff can access the information 
from the centralized database and confirm the registration. 2) Refer to “Instructions for 
Remote Registration” in section “Finding/Displaying Information about a registered 
subject”. 
 
6.2 
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 
 


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6.3 
Prior to accepting the registration/randomization, the remote 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 
 
6.4 
Treatment on this protocol must commence at a Mayo Clinic institution under the 
supervision of a member of the hematology group. 
 
6.5 
Treatment cannot begin prior to registration and must begin ≤14 days after registration. 
 
6.6 
Pretreatment tests/procedures must be completed within the guidelines specified on the 
test schedule. 
 
6.7 
All required baseline symptoms must be documented and graded. 
 
6.8 
A mandatory correlative research component is part of this study, the patient will   
be automatically registered onto this component (see Sections 3.19g, 14.1). 
 
7.0 
Protocol Treatment 
 
 
Treatment should start before 180 days from the day of transplant. 
 
 
7.1 
Treatment Schedule  
 
 
 
Cycle 1 
 
Agent 
Dose 
Route 
Day 
Cycle length 
Lenalidomide 
10 mg 
PO 
1-21 
28 days 
LDE225 
400 mg 
PO 
1-28 
 
7.2  
The study will be temporarily closed to accrual after the first six patients have been 
accrued.  Patients will be evaluated for toxicity after they have completed 3 months of 
therapy.  If the level of toxicity in the first 6 patients is acceptable per Section 16.351, 
then the study will reopen for accrual. 
 
 
7.3 
For this protocol, the patient must return to the Mayo Clinic every 28 days for the first 6 
cycles. After this if patients do not have ongoing toxicity issues, they may return to the 
Mayo Clinic every 3 months (3 cycles). 
 
 
 
 


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8.0 
Dosage Modification Based on Adverse Events  
 
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained.  Thereafter, these modifications should be regarded as guidelines to 
produce mild-to-moderate, but not debilitating, side effects.  If multiple adverse events are seen, 
administer dose based on greatest reduction required for any single adverse event observed.  
Reductions or increases apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose. 
 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
 
8.1  
Dose Levels (Based on Adverse Events in Table 8.2),  
Dose Level 
Lenalidomide 
0* 
10 mg PO QD Days 1-21  
-1 
5 mg PO QD Days 1-21 
-2 
5 mg PO QD Days 1-7, 15-21 
-3 
Discontinue 
 
Dose Level 
LDE225 
0* 
400 mg PO QD Days 1-28 
-1 
200 mg PO QD Days 1-28 
-2 
200 mg PO QD Days 1-21 
-3 
Discontinue 
 
*Dose level 0 refers to the starting dose.  All cycles are 28 days in length. 
 
If patients cannot tolerate dose level – 2 of BOTH drugs they will go to event monitoring. 
 
8.11  
Instruction for initiation of a new cycle of therapy  
A new cycle of treatment may begin on the scheduled Day 1 of a new cycle if: 
• 
The ANC is ≥ 1000/μL 
• 
The platelet count is ≥ 50,000/μ L 
• 
Any other drug-related adverse event that may have occurred has resolved to 
≤ grade 1 or baseline severity. 
If these conditions are not met on Day 1 of a new cycle, the subject will be 
evaluated weekly and a new cycle of therapy will be held until the toxicity 
has resolved as described above.   
If any drug dosing was halted during the previous cycle and was restarted 
with a one-level dose reduction without requiring an interruption for the 


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remainder of the cycle, then that reduced dose level will be initiated on Day 1 
of the new cycle.  
If any drug dosing was omitted for the remainder of the previous cycle or if 
the new cycle is held due to known hematologic toxicity newly encountered 
on the scheduled Day 1, then the new cycle will be started with a one-level 
dose reduction.  If a new cycle of therapy cannot be restarted within 4 weeks 
of the scheduled day 1, the patient will be removed from protocol therapy 
and will go to event monitoring. 
 
8.2  
Dose modifications based on adverse events during a cycle 
 
 
Table 0-1 
Recommended Dose Modifications and Dose Delays for suspected treatment-related 
toxicities  
 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* 
unless otherwise specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
BASED ON INTERVAL ADVERSE EVENT ** 
Blood and 
lymphatic 
system 
disorders 
Febrile neutropenia 
Grade 3 or 4  
LDE225 
Omit dose until resolved, then decrease 
dose by 1 step 
Investigations 
Platelet count decreased 
≥ Grade 3 (platelet count 
< 50,000/mm³) 
LDE225 
 
Omit dose until resolved to ≤ grade 1, 
then: 
• If resolved in ≤ 7 days, then maintain 
dose level 
• If resolved in > 7 days, then decrease 
dose by 1 step 
Neutrophil count 
decreased ≥ grade 3 
(ANC < 1,000/mm3) 
LDE225 
Omit dose until resolved to ≤ grade 1, 
then: 
• If resolved in ≤ 7 days, then maintain 
dose level 
• If resolved in > 7 days, then decrease 
dose by 1 step 


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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* 
unless otherwise specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
CPK increased 
 
 
Grade 1 or 2 CPK 
increased and 
asymptomatic myalgia 
(no new-onset myalgia 
or worsening of pre-
existing myalgia) 
 
 
Grade 1 or 2 CPK 
increased and 
symptomatic myalgia 
(new-onset myalgia or 
worsening of pre-
existing myalgia) 
 
Grade 3 or 4 CPK 
increased (with or 
without myalgia) 
 
LDE225 
• For CTCAE grade 1 CPK increased, 
continue treatment on same dose and 
continue monitoring as per schedule 
of assessments 
• For CTCAE grade 2 CPK increased, 
consider performing a muscle 
biopsy; continue on same dose level 
of LDE225.  CPK should be 
measured weekly until resolution to 
≤ grade 1. 
 
• For CTCAE grade 1 CPK with 
myalgia ≥ CTCAE grade 1, continue 
treatment at same dose and measure 
CPK weekly until CPK returns to 
normal or baseline value or myalgia 
resolves 
• For CTCAE grade 2 CPK with 
myalgia ≥ CTCAE grade 1, continue 
treatment at same dose level of 
LDE225.  CPK should be measured 
weekly until CPK is ≤ CTCAE 
grade 1 
• Omit LDE225 dose, check blood 
myoglobin and monitor renal 
function. Measure CPK weekly until 
resolution to grade ≤ 1  
• Consider performing 
electromyography, MRI scan of 
symptomatic muscle group(s) and 
muscle biopsy  
• If renal function is not impaired and 
resolution to ≤ CTCAE grade 1 
occurs within 21 days, consider 
resuming treatment at a reduced 
dose; CPK should be measured 
weekly for 2 months after re-


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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* 
unless otherwise specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
administration of LDE225 
• Patients who experience renal 
impairment (serum creatinine > 2x 
ULN) should be permanently 
discontinued from treatment.  
Patient goes to event monitoring per 
section 18.0 
 
Creatinine increased 
 
Grade 2 (1.5-3 x ULN) 
 
 
 
 
 
 
Grade 3 (>3.0 – 6.0 x 
ULN) 
 
Grade 4 (>6.0 x ULN) 
 
 
Omit dose until resolved to ≤ grade 1, 
then: 
• 
If resolved in ≤ 7 days, then 
maintain dose level 
• If resolved in > 7 days, then 
decrease dose by 1 step (consider 
checking serum CPK, if not already 
done) 
Omit dose until resolved to ≤ grade 1, 
then decrease dose by 1 step 
 
Omit dose and discontinue patient from 
treatment.  Patient goes to event 
monitoring per section 18.0 
 
Blood bilirubin 
increased 
 
Grade 2 (1.5- 3 x ULN) 
 
 
 
 
 
 
Grade 3 (>3.0 – 10.0 x 
ULN) 
 
 
Omit dose until resolved to ≤ grade 1, 
then: 
• If resolved in ≤ 7 days, then 
maintain dose level 
• If resolved in > 7 days, then 
decrease dose by 1 step (consider 
checking serum CPK, if not already 
done) 
 
Omit dose until resolved to ≤ grade 1, 
then decrease dose by 1 step 


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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* 
unless otherwise specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
 
 
Grade 4 (>10.0 x ULN) 
 
Omit dose and discontinue patient from 
treatment.  Patient goes to event 
monitoring per section 18.0 
 
 
 
Aspartate 
aminotransferase 
increased or alanine 
aminotransferase 
increased 
 
Grade 3 (>5.0 – 20.0 x 
ULN) 
 
 
Grade 4 (>20.0 x ULN) 
 
Omit dose until resolved to ≤ grade 1 or 
baseline, then: 
• If resolved in ≤ 7 days, then 
maintain dose level 
• 
If resolved in > 7 days, then 
decrease dose by 1 step  
 
Omit dose until resolved to ≤ grade 1 or 
baseline, then decrease dose by 1 step 
 
 
Electrocardiogram QT 
corrected interval 
prolonged ≥ grade 3  
 
First Occurrence: 
• Omit dose 
• Perform an analysis of serum 
potassium and magnesium, and  if 
below lower limit of normal, correct 
with supplements to within normal 
limits. Concomitant medication 
usage must be reviewed. 
• Perform a repeat ECG within one 
hour of the first QTc of > 500 ms 
• If QTc remains > 500 ms, repeat 
ECG as clinically indicated but at 
least once a day until the QTc 
returns to < 480 ms. 
• Once QTcF prolongation has 
resolved, study treatment may be 
restarted at a reduced dose level 
 
Second Occurrence: 
Discontinue patient from further study 
treatment.  Patient goes to event 


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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* 
unless otherwise specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
monitoring per section 18.0. 
Musculoskeleta
l and 
connective 
tissue disorders 
Myalgia 
 
Grade 2 
 
 
 
Grade 3 
LDE225 
Measure CPK weekly until myalgia 
resolves to ≤ grade 1.  If CPK is 
elevated, follow guidance for CPK 
elevation as described above. Continue 
treatment with LDE225 
 
For new-onset CTCAE grade 3 myalgia, 
interrupt LDE225. Check CPK 
measurement at the time of dose 
interruption.  Provide symptomatic 
treatment. Measure CPK weekly until 
the myalgia resolves to ≤ grade 1 and 
resume therapy at a reduced dose.  
Measure CPK weekly for 2 months after 
re-administration. 
Respiratory, 
thoracic and 
mediastinal 
disorders 
Dyspnea ≥ grade 3 
 
Omit dose and discontinue the patient 
from treatment.  Patient goes to event 
monitoring per section 18.0 
 
Pulmonary edema ≥ 
grade 3 
 
Omit dose and discontinue the patient 
from treatment.  Patient goes to event 
monitoring per section 18.0 
Cardiac 
disorders 
Palpitations ≥ grade 2 
 
 
 
Myocarditis grade > = 2 
 
Omit dose and discontinue the patient 
from treatment.  Patient goes to event 
monitoring per section 18.0 
 
Omit dose and discontinue the patient 
from treatment.  Patient goes to event 
monitoring per section 18.0 
Other non-
hematologic 
adverse events 
Grade 3 
 
 
Grade 4 
 
 
Omit dose until resolved to ≤ grade 1, 
then decrease dose by 1 step 
 
Omit dose and discontinue patient from 
treatment.  Patient goes to event 
monitoring per section 18.0. 


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Rescue medication 
The use of rescue medication/ procedures, such as any surgery or radiation therapy during the 
study is not permitted.  The patient will be discontinued if such procedures are required.   
 
 


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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
BASED ON INTERVAL ADVERSE EVENT 
Blood and 
lymphatic 
system disorders 
Febrile neutropenia 
associated with fever 
(temperature ≥ 38.5º C) 
 
Lenalidomide 
• 
Omit lenalidomide dose. 
• 
Follow CBC weekly. 
• 
If neutropenia has resolved to ≤ 
grade 2 prior to Day 21 and fever 
has resolved, restart lenalidomide 
at next lower dose level and 
continue the cycle through Day 
21.  If febrile neutropenia is the 
only toxicity for which a dose 
reduction is required. G-CSF may 
be used and the lenalidomide 
dose maintained. 
Investigations 
Grade 3 neutrophil 
decreased and sustained 
for 7 days or 
Grade 4 neutropenia 
 
 
Lenalidomide 
• 
Omit lenalidomide dose. 
• 
Follow CBC weekly. 
• 
If neutropenia has resolved to ≤ 
grade 2 prior to Day 21, restart 
lenalidomide at next lower dose 
level and continue the cycle 
through Day 21.  Restart next 
cycle at the lower dose level. If 
neutropenia is the only toxicity 
for which a dose reduction is 
required. G-CSF may be used and 
the lenalidomide dose 
maintained. 
Platelet count decreased 
≥ Grade 3 (platelet count 
< 50,000/mm³) 
 
Lenalidomide 
• 
Omit lenalidomide dose. 
• 
Follow CBC weekly  
• 
Hold anticoagulation until 
platelets > 50,000 
• 
If platelet count resolves to ≤ 
grade 2 prior to Day 21, restart 
lenalidomide at next lower dose 
level and continue the cycle 
through Day 21. 
 


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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
Skin and 
subcutaneous 
tissue disorders 
Rash maculo papular  
Grade 2 or 3. 
 
Lenalidomide 
 
• 
Omit lenalidomide dose.  Follow 
weekly. 
• 
If the toxicity resolves to ≤ grade 
1 prior to Day 21, restart 
lenalidomide at next lower dose 
level and continue the cycle 
through Day 21. Restart next 
cycle at the lower dose level. 
Any rash  
Grade 4 
Lenalidomide 
 
Discontinue lenalidomide.  Remove 
patient from study.  Go to event 
monitoring. 
 
 
Nervous system 
disorders 
Peripheral sensory 
Neuropathy 
 
Grade 3 
 
 
 
Lenalidomide 
• 
Omit lenalidomide dose.  Follow 
at least weekly. 
• 
If the toxicity resolves to ≤ grade 
1 prior to Day 21, restart 
lenalidomide at next lower dose 
level and continue the cycle 
through Day 21. Restart next 
cycle at the lower dose level. 
Grade 4 
Lenalidomide 
• 
Discontinue lenalidomide.  
• 
Remove patient from study. 
• 
Go to event monitoring. 
Immune system 
disorders 
Allergic reaction  
Grade 2-3 
 
 
 
 
Lenalidomide Omit dose. Follow at least weekly. 
If the toxicity resolves to ≤ grade 1 prior 
to Day 15 restart at next lower dose level 
and continue the cycle until Day 21. 
Restart next cycle at the lower dose level. 
Grade 4 
Lenalidomide Discontinue lenalidomide study drug.  Go 
to event monitoring. 
Vascular 
disorders 
Thromboembolic event 
≥ Grade 3 
Lenalidomide Omit dose and start anticoagulation; 
restart at investigator’s discretion 
(maintain dose level). 
Hyperthyroidism or 
Hypothyroidism 
Lenalidomide 
• 
Omit lenalidomide for remainder 
of cycle, evaluate etiology, and 
initiate appropriate therapy.  
See Instructions for Initiation of a New 
Cycle and reduce the dose of 
lenalidomide by 1 dose level. 


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  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0* unless 
otherwise specified   
CTCAE 
System/Organ/
Class (SOC) 
 
ADVERSE EVENT 
 
AGENT 
 
ACTION 
Other non-hematologic 
toxicity ≥ Grade 3 
 
 
Lenalidomide 
Omit (interrupt) lenalidomide dose.  
Follow at least weekly. If the toxicity 
resolves to ≤ grade 2 prior to Day 21, 
restart lenalidomide at next lower dose 
level and continue the cycle through Day 
21. Restart next cycle at the lower dose 
level. 
 
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic applications.ctc.htm 
**  Use the following to describe actions in the Action column: 
• Omit = The current dose(s) for the specified drug(s) during a cycle is skipped. The patient does not 
make up the omitted dose(s) at a later time 
• Hold/Delay = The current dose(s) of all drugs during a cycle is delayed. The patient does make up 
the delayed dose(s) when the patient meets the protocol criteria to restart drugs. 
• Discontinue = The specified drug(s) are totally stopped.  
 
NOTE: If the toxicity can be attributed to either lenalidomide or LDE225, both drugs must be 
omitted, and once toxicity has resolved to the level allowing restarting the drugs, lenalidomide 
should be reintroduced first at the same dose level and if no toxicity is observed for the rest of the 
cycle, LDE can be reintroduced at one lower dose level. If the toxicity recurs, lenalidomide stopped 
and restarted at one lower dose level once toxicity resolves to the required grade. In this situation, 
LDE225 can be restarted at the same level. 
 
NOTE:  If the patient experiences a significant adverse event requiring a dose reduction at the start 
of the next cycle, then the dose will remain lowered for that entire subsequent cycle.  If that cycle is 
completed with no further adverse events >Grade 2, then the dose may be increased, at the 
investigator’s discretion, one level at a time, in the following cycles.  
 
NOTE:  Adverse events requiring a dose-reduction step for any or all drugs beyond the two dose-
reduction steps (levels –1 and –2) will be at the discretion of the treating physician, if the decision  
is made for the patient to be kept on study.  These dose reductions must be clearly recorded in 
reported clinical data.  
 
NOTE:  If one of the drugs have to be discontinued, the patient can continue on the other drug. 
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Patients may receive concurrent treatment with a bisphosphonate.  
 
9.2 
Patients may continue on low level/stable steroid doses for replacement or inhalation 
therapy. 
 
9.3 
The following medications are not permitted during the trial: 


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• 
Any other investigational treatment  
• 
Any cytotoxic chemotherapy 
• 
Any other systemic anti-neoplastic therapy including, but not limited to, 
immunotherapy, hormonal therapy or monoclonal antibody therapy. 
• 
Any external beam radiotherapy 
 
9.4 
Antiemetics may be used at the discretion of the attending physician. 
 
9.5 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations.  The use of growth factors should 
follow published guidelines of the ASCO 2006 Update of  Recommendation for the Use 
of White Blood Cell Growth Factors: An Evidence-based Clinical Practice Guideline 
Journal of Clinic Oncology, Vol. 24, No 19 (July 1), 2006” pp. 3187-3205  
 
9.6 
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. 
 
9.7 
Diarrhea:  This could be managed conservatively with loperamide.  The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea 
free (maximum 16 mg/day). 
 
In the event of grade 3 or 4 diarrhea, the following supportive measures are allowed:  
hydration, octreotide, and antidiarrheals.   
 
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed.  
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting  
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
 
9.8  
Prophylactic full dose aspirin (325 mg once daily) is mandatory to protect against 
thrombosis. If patients are intolerant to aspirin, substitution with low molecular weight 
heparin (LMWH) is recommended.  
 
9.9 
Patients who are planning on embarking on a new strenuous exercise regimen after 
initiation of study treatment. NB: Muscular activities, such as strenuous exercise, that can 
result in significant increases in plasma CK levels should be avoided while on LDE225 
treatment. 
 
 
 


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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 site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm)    
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE version 4.0.  
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.5).  With this information, determine whether the event must be 
reported as an expedited report (see Section 10.31). 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 10.6 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).  Grade is an essential element of the Guidelines and, in 
general, relates to severity for the purposes of regulatory reporting to NCI. 
 
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 and the study specific 
consent form. 
 
• 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.0 of the protocol and the study specific consent form. 
 
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.  
  
 
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: 


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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:  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. 
 
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 10.6. 
 
• Routine AE reporting for Phase 3 clinical studies using an investigational 
agent/intervention and a commercial agent in combination must be 
reported as defined by the general guidelines provided by sponsors, 
Groups, Cancer Centers, or Principal Investigators. See Section 10.6. 
 
Expedited Reporting 
 
• An AE that occurs on a combination study must be assessed in accordance with 
the guidelines for 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 to the FDA via 
MedWatch. 
 
• An investigational agent/intervention might exacerbate the expected AEs 
associated with a commercial agent.  Therefore, if an expected AE (for the 






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1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
 
Effective Date:  May 5, 2011 
 
 
Additional Instructions: 
1. An increased incidence of an expected adverse event (AE) is based on the patients 
treated for this study at their site.  A list of known/expected AEs is reported in the 
package insert or the literature, including AEs resulting from a drug overdose. 
 
2. Submit form to the FDA, MedWatch, 5
 
   
 
10.43 Special Situations for Expedited Reporting 
 
Exceptions to Expedited Reporting: EXPECTED Serious Adverse Events 
 
An expedited report may not be required for specific Grade 1, 2 and 3 Serious Adverse 
Events where the AE is EXPECTED. Any protocol specific reporting procedures MUST 
BE SPECIFIED BELOW and will supersede the standard Expedited Adverse Event 
Reporting Requirements  
 
System Organ Class (SOC) 
 
Adverse event/Symptoms 
 
CTCAE Grade at which the 
event will not be 
expeditedly reported. 
Blood and lymphatic system 
disorders 
Anemia 
Grade 3 or 4 
Investigations 
White blood cell decreased 
Grade 3 or 4 
Lymphocyte count decreased 
Grade 3 or 4 
Neutrophil count decreased 
Grade 3 or 4 
Platelet count decreased 
Grade 3 or 4 
Specific protocol exceptions to expedited reporting should be reported expeditiously by 
investigators ONLY if they exceed the expected grade of the event. 
 
10.5 
Other Required Reporting 
 
10.51 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 


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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). 
 
10.52  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 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. 
 
 
10.53 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 
Myeloctyic Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 


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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. 
 
 
 
10.54 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. 
 
10.55 Special reporting requirements for Novartis 
The principal investigator has the obligation to report all serious adverse events to the 
FDA, IRB, and Novartis Pharmaceuticals Clinical Safety and Epidemiology Department 
(CS&E) 
Reporting procedures 
The investigator must complete the FDA MedWatch 3500a form and Novartis SAE 
coversheet in English, assess the relationship to study treatment and send the initial 
completed MedWatch form and Novartis SAE coversheet by fax 1.888.299.4565 within 
24 hours to the local Novartis Clinical Safety & Epidemiology (CS&E) Department.  The 
investigator must then ensure that the form and coversheet are accurately and fully 
completed with follow-up information and fax those to Novartis CS&E Department 
within 2 to 3 calendar days for deaths or life-threatening events and 5 calendar days for 
other serious adverse events. The original and the duplicate copies of the FDA 
MedWatch form, Novartis SAE coversheet, and the fax confirmation sheet must be kept 
with the case report forms at the study site.  
Follow-up information should describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not, and whether the patient 
continued or discontinued study participation. The MedWatch form, Novartis SAE 
coversheet, and fax confirmation sheet must be retained. Pregnancy follow-up should 
describe the outcome of the pregnancy, including any voluntary or spontaneous 
termination, details of the birth, and the presence or absence of any congenital 
abnormalities or birth defects. 
 
 
10.6 
Required Routine Reporting  
Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
 
 
System Organ 
Class (SOC)  
 
Adverse event/Symptoms 
 
Baseline 
Each 
evaluation 
Investigations 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
General disorders 
Edema limbs 
X 
 


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and administration 
site conditions 
 
 
Fatigue 
X 
X 
Gastrointestinal 
Disorders 
# of Stools per day 
X 
 
Diarrhea 
 
X 
Constipation 
 
X 
Vomiting 
X 
X 
Pain 
Myalgia 
X 
X 
Infections and 
infestations 
Sepsis 
X 
X 
Blood and 
lymphatic system 
disorders 
Febrile neutropenia 
X 
X 
Skin and 
subcutaneous 
tissue disorders 
Rash maculo-papular 
X 
X 
Nervous system 
disorders 
Peripheral sensory neuropathy 
X 
X 
Vascular 
Thromboembolic Event 
X 
X 
 
10.61 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 10.6: 
10.611 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.612 Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
 
10.613 Grade 5 AEs (Deaths) 
 
10.6131  
Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
 
 
 
10.6132 
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. 
 
10.62 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). 
 
 


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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  Determination of Baseline values for disease assessment 
 
• 
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 
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. 
 
11.12  Terms and definitions 
 
• 
M-protein: synonyms include M-spike, monoclonal protein and myeloma 
protein, paraprotein, M-component. 
 
Serum M-protein level is quantitated using densitometry on SPEP except in 
cases where the SPEP is felt to be unreliable.   
• M-proteins migrating in the β-region (usually IgA M-proteins)  
 
 


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• 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. 
 
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 
 
 
 


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The serum free light chain (FLC) assay is of particular use in monitoring 
response to therapy in patients who have oligo-secretory or non-secretory disease 
and should be used in assessing response only if the baseline serum and/or 
urine M proteins are not “measurable” as above, and the baseline level of 
the involved FLC is “measurable.”  When using this assay, it is important to 
note that the FLC levels vary considerably with changes in renal function and in 
patients with renal insufficiency, the levels of both the kappa and lambda may 
remain elevated, but the ratio normalizes with achievement of CR.  Thus, both 
the level of the involved and the uninvolved FLC isotype (i.e., the 
involved/uninvolved ratio or involved-uninvolved difference) should be 
considered in assessing response.  Patients included on the study on the basis of 
FLC alone (i.e., no measurable serum/urine M-protein) should be the only 
ones who are evaluated using FLC response criteria.  The others should follow 
usual criteria and ignore FLC results with the exception of defining stringent 
complete response. 
 
• 
Evaluable disease: Patients who do not have a “measurable” serum M-
protein, serum free light chain, or urine M-protein. 
 
• 
Oligosecretory myeloma: Patient with multiple myeloma who has NEVER 
had “measurable” serum M-protein or urine M-protein, but has had a 
detectable M-protein in his/her serum and/or urine and/or measurable serum 
free light chain.  
 
• 
Non-secretory myeloma: Patient with multiple myeloma who has NEVER 
had a detectable M-protein in his/her serum and/or urine. 
 
11.2  
Clarification of test indications 
 
Listed below are the minimal required tests required to assess response based on 
the characteristics of their disease at on study.   
 
Table 11.2 
Tests  Required To Assess Response (Must Be Done At Each Disease Measurement Visit 
except as indicated1,2) 
On Study Baseline Value 
SPEP4  
24 hr 
UPEP2  
Ig 
FLC 
BM Bx 
Serum M-protein ≥1 g/dl, and urine M-protein≥ 
200 mg/24 hrs 
X 
X 
 
 
Serum M-protein ≥ 1 g/dl, but urine M-protein < 
200 mg/24 hrs 
X 
 
 
 
Serum M-protein <1 g/dl, and urine M-protein≥ 
200 mg/24 hrs 
 
X 
 
 
Serum M-protein < 1 g/dl, urine M-protein < 200 
mg/24 hrs, but involved Ig FLC is ≥10 mg/dL 
 
 
X 
 
 
 


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Serum M-protein < 1 g/dl, urine M-protein< 200 
mg/24 hrs, involved Ig FLC is <10 mg/dL, bone 
marrow ≥30% plasma cells 
 
 
 
X3 
1  SPEP, UPEP, Immunofixation studies of both serum and urine, and Bone 
marrow biopsy are required to document CR regardless of registration values, 
and in addition FLC measurement and bone marrow immunophenotyping is 
required to document sCR.  SPEP and UPEP are required to document VGPR 
regardless of registration values. 
2  For serum measurable patients, 24 hour urine does not need to be confirmed 
(i.e. repeated after documented response) for any response category 
3  At a minimum, a bone marrow biopsy should be repeated every 3 months until 
documented response.  Bone marrow biopsy results do not need to be repeated 
after documented response. 
4    If serum M-protein is being followed by quantitative immunoglobulin levels 
derived from nephelometry or turbidometry, quantitative immunoglobulins are 
required.  SPEP is only required to document CR or VGPR.  
 
11.3 
Confirmed response  
 
In order to be classified as a hematologic response, confirmation of serum M- 
protein, serum immunoglobulin free light chain (when primary determinant of 
response) and urine M- protein (when primary determinant of response) results 
must be made by verification on two consecutive determinations.   
• 
Bone marrow aspirate and biopsy are only required to document CR or 
sCR, except for patients with evaluable disease only, where a bone 
marrow is required to document all response categories including 
progression. However, a second confirmatory bone marrow is not 
required to confirm response in any case. 
• 
Radiographic studies are not required to satisfy these response 
requirements; however, if radiographic studies were performed there 
should be no evidence of progressive or new bone lesions. 
 
Appropriate tests required to document and confirm response are listed in Table 
11.2 
 
11.4 
Bone progression  
 
Caution must be exercised to avoid rating progression on the basis of variation of 
radiologic technique alone.  Compression fracture does not exclude continued 
response and may not indicate progression.  When progression is based on 
skeletal disease alone, it should be discussed with the Study Chair before 
removing the patient from the study.  
 
 11.5 
 Response and Progression 
 
Criteria for response and progression are listed in Table 11.5. Progressive disease 
for all patients as defined in Table 11.5.  


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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 involved 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 involved FLC levels 
• If the only measurable disease is BM, a ≥ 50% reduction in BM 
PC's (provided the baseline PC's 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) 
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 mg/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 


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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. 
 
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. 


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12.0 
Descriptive Factors  
 
12.1 
Prior treatment(s) types and number 
 
12.1.1 Immunomodulatory agents (IMiDs) 
12.1.2 Alkylators 
12.1.3 Proteasome inhibitors 
 
12.2 
Response to last treatment prior to SCT: Yes vs. no 
 
12.3 
Parameters followed for hematologic response (pick one):  serum M-protein ≥ 1 g/dL and 
urine M-protein ≥200 mg/24 hours vs. serum M-protein ≥1g/dL only vs. urine M-protein 
≥200 mg/24 hours only vs. serum immunoglobulin free light chain (involved FLC)  ≥10 
mg/dL vs. Distinguish between SPEP measurement versus quantitative IgA measurement 
for serum M-protein.   All measurements are based on those at the time of Baseline 
values for disease assessment as defined in Section 11.11. 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
13.1 
Patients who are sCR, CR, VGPR, PR, MR, or SD (or usCR, uCR, uVGPR, uPR, uMR) 
will continue treatment per protocol. 
 
13.2      Observation:  At the completion of 18 cycles of treatment, the patient will be observed 
every 90 days for up to 3 years from the time of registration.  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: 
 
• 
Progressive multiple myeloma 
•     Subsequent treatment for multiple myeloma 
• 
Patient refuses further treatment on 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) 
• 
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.  The patient will go to the event-monitoring phase per 
Section 18.0. 
 


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13.4 
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. The patient will 
go directly to the event-monitoring phase of the study (or off study, if applicable).  
 
• 
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. 
 
13.5 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go directly to the event-monitoring phase of the study. Event 
monitoring will be required per Section 18.0 of the protocol.   
 
13.6 
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. 
 
13.7 
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. 


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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 18 
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 
X 
No 
Ambient  
Flow cytometry for 
early myeloma cell 
(myeloma stem cell) 
Mandatory 
Bone 
marrow 
aspirate 
EDTA 
(lavender) 
3 mL 
(1) 
X 
X 
X 
No 
Cool Pak 
Gene expression 
profiling 
 
Optional 
Bone 
marrow 
aspirate 
EDTA 
(lavender) 
3 mL 
(2) 
X 
X 
X 
No 
Cool Pak  


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14.2  
Collection and Processing  
 
14.21 Minimal residual disease evaluation: This will be performed on bone marrow 
aspirate following a wash no lyse method on fresh samples. 
 
14.22 Gene expression profiling: This will be performed on CD138 sorted plasma cells 
from the bone marrow aspirate. 
 
14.3 
Shipping and Handling 
 
14.31 Minimal Residual Disease 
 
Draw 1-2 mLs of bone marrow aspirate into one 2 mL lavender top EDTA tube. 
It is important to thoroughly mix the blood with the anticoagulant agent by gently 
inverting the tube not less than five times. Carefully unstop the EDTA tube and 
using the pipette provided transfer 1 mL of aspirate into the provided 1 mL Cyto-
Check tube. Gently invert vial by hand 3 times to mix. Immediately ship ambient 
via overnight delivery to to the address below.  A kit will be shipped to the 
participating site. 
 
Please plan to obtain samples for bone marrow aspirates on Monday through 
Thursday only.  
 
14.32 Gene expression profiling 
 
No special instructions 
 
 
14.33 Shipping Specimens: Samples can be shipped on ice. They should be shipped 
overnight taking care to avoid Friday collection and shipping. 
 
Please notify Mayo Clinic by email
 or phone, 
 
5 to ensure that samples are received. 
 
 
Mayo Clinic 
 
200 First Street SW 
Rochester, MN 55905 
 
14.4 
Background and Methodology 
 
 
14.41 Minimal residual disease evaluation: Currently 30-40% of patients achieve a CR 
with initial therapy. In most cases, patients classified as CR in reality have 
minimal residual disease (MRD) since (i) many such patients relapse, and (ii) 
residual clonal disease is detectable in most by more sensitive techniques such as 
multiparameter flowcytometry and PCR based techniques.(Sarasquete, Garcia-
Sanz et al. 2005; Mateo, Montalban et al. 2008; Paiva, Vidriales et al. 2009). We 
will determine minimal residual disease positivity at various stages of treatment, 
among patients achieving a conventional complete response. Bone marrow  
 
 


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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 Gene expression profiling. CD138-sorted MM tumors cells, and CD138 negative 
tumor microenvironment cell compartment, obtained from clinical bone marrow 
sampling, will be banked before and after 12 cycles of therapy as well as at the 
time of documented CR (CD138- only); high-resolution array-based gene 
expression studies of paired (before/after) samples will be undertaken Samples 
will be analyzed using high-density oligonucleotide microarrays containing 
probes for 50,000 transcripts and variants including 14,500 known genes (U133 
Plus 2- array; Affymetrix, Santa Clara, CA) using standard methods. 
 
14.421  Sample Preparation, Fragmentation, Array Hybridization, and Scanning: 
The puriﬁed cDNA is used as the template for in vitro transcription 
reaction for synthesizing biotinylated complementary RNA (cRNA) 
using an RNA transcript labeling reagent (Affymetrix). The quality of 
the fragmented biotin–labeled cRNA in each experiment is evaluated 
before hybridizing by both gel electrophoresis and hybridizing (fraction 
of the sample) onto test-3 microarray and analyzing as a measure of 
quality control. Appropriate amounts of labeled cRNA and control 
oligonucleotide B2 are added along with control cRNA (BioB, BioC, 
BioD), herring sperm DNA, and bovine serum albumin to the 
hybridization buffer. The hybridization mixture is heated at 99°C for 5 
minutes followed by incubation at 45°C for 5 minutes before applying 
the sample onto the GeneChip. Hybridization is performed at 45°C for 16 
hours with mixing, following which the solutions are removed, and 
arrays washed and stained with streptavidin-phycoerythrin (Molecular 
Probes, Portland, OR). After washes, probe arrays are scanned using the 
gene chip system confocal scanner. All samples will run individually 
with no pooling. 
 
14.422  Data Analysis and Interpretation: The arrays will be scanned using a 
Genechip 300 scanner and GeneChip 5.0 software (Affymetrix) will used 
to quantitatively analyze the scanned image. Algorithms in the software 
use probe cell ﬂuorescence intensities to calculate an average intensity 
for each set of probe pairs representing a gene, which directly correlates 
with the amount of mRNA.  The plasma cell gene expression from 
different patient groups as described before will be compared using 
Genespring. The selection criteria for all genes reported as differentially 
expressed will be as follows: (1) in absolute analysis, a detection call of 
present; (2) a change either increased or decreased; (3) signal of greater 
than 1,000; and (4) greater than 2-fold differences in expression in all 


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pair wise comparisons. Only genes with transcript levels that satisﬁed all 
4 criteria will be considered as signiﬁcantly differentially expressed. 
Average differences in mean expression (as measured by ﬂuorescence 
intensity) of transcripts that met all of these criteria are compared across 
groups using the 2-sided Student’s t test. P values for differences 
between means of P less than .05 are considered statistically signiﬁcant. 
 
15.0 
Drug Information 
 
15.1 
Lenalidomide (Revlimid, CC-5013, CDC-501)   
 
Please consult the most current Investigator’s Brochure and package insert for 
complete drug information. 
 
15.11 Background: Lenalidomide has a wide range of effects, including the inhibition 
of hematopoietic tumor cell proliferation, the enhancement of T cells and natural 
killer (NK) cell activity, the modulation of stem cell differentiation, the inhibition 
of angiogenesis, and the inhibition of inflammation. 
 
15.12 Formulation: For clinical study, lenalidomide is provided as 1.25-, 2.5-, 5-, 10-, 
15-, 20-, and 25-mg capsules for oral administration. Each capsule contains 
lenalidomide as the active ingredient and the following inactive ingredients: 
anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, and 
magnesium stearate. 
 
Placebo capsules for the 1.25-, 2.5-, 5-, 10-, 15-, 20-, and 25-mg lenalidomide 
capsules are available for use in blinded studies. Each placebo capsule visually 
matches the drug product. 
 
The lenalidomide and placebo capsules are supplied in push-through blister foil 
or tamper-evident, child-resistant, opaque, high-density polyethylene (HDPE) 
containers with HDPE caps. 
 
A lenalidomide formulation for constitution to oral suspension is available for 
subjects who cannot swallow capsules and for subjects who participate in clinical 
studies; however, it is not commercially available. It is provided in an 
individually sealed 10 mL polyethylene terephthalate glycol (PETG) vial with a 
chlorobutyl stopper sealed with an aluminum crimp seal and a flip-off cap. Each 
vial contains 80 mg of lenalidomide powder with no inactive ingredients. The 
lenalidomide powder in each vial is constituted with 8 mL of suspending vehicle 
(Flavor Blend flavored) to create a lenalidomide suspension with a final 
concentration of 10 mg/mL. 
 
15.13 Preparation and storage: Lenalidomide should be stored at room 
temperature, between 59 and 86ºF (15-30ºC).  Store drug away from direct 
sunlight.   
 
15.14 Administration:  Capsules are administered by mouth daily with water. Patients 
should not break, chew or open the capsules. 
 


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The suspension formulation is administered by mouth. 
 
 
15.15 Pharmacokinetic information: 
a) Absorption – Lenalidomide is rapidly absorbed following oral administration 
to subjects with multiple myeloma or MDS, with maximum plasma 
concentrations occurring between 0.5 and 1.5 hours post-dose. Co-administration 
with a high-fat and high-calorie meal in healthy subjects reduced the extent of 
absorption, resulting in an approximately 20% decrease in AUC and 50% 
decrease in Cmax in plasma.  
 
In the pivotal MM and MDS registration trials where the efficacy and safety were 
established for lenalidomide, the drug was administered without regard to food 
intake. Thus, lenalidomide can be administered with or without food. 
 
Multiple dosing (up to 100 mg BID) did not cause marked drug accumulation.   
 
The bioavailability of the lenalidomide oral suspension (10 mg/mL, active 
pharmaceutical ingredient in Flavor Blend flavored suspending vehicle) was also 
evaluated in healthy subjects. The study demonstrated that the lenalidomide oral 
suspension is bioequivalent to the approved 25-mg capsule formulation at the 25-
mg dose. A high-fat meal reduced the rate and extent of lenalidomide suspension 
absorption, resulting in an approximate 20% decrease in AUC, 57% decrease in 
Cmax, and 1.9-hour delay in tmax. 
 
 
b) Distribution – In vitro (14C)-lenalidomide binding to plasma proteins is 
approximately 30%. 
 
c) Metabolism – Lenalidomide undergoes limited metabolism. Unchanged 
lenalidomide is the predominant circulating component in humans. Two 
identified metabolites are hydroxy-lenalidomide and N-acetyl-lenalidomide; each 
constitutes less than 5% of parent levels in circulation. 
 
d) Excretion – Elimination is primarily renal.  Approximately 65% to 85% 
of lenalidomide is eliminated unchanged through urinary excretion in 
subjects with normal renal function. The half-life of elimination is 
approximately 3 to 4 hours (2 to 3 hours in patients 5 to 21 years) at the 
clinically relevant doses (5 to 50 mg/day). Steady-state levels are achieved 
within 4 days.  
 
15.16 Potential Drug Interactions:  In vitro studies demonstrate that lenalidomide is 
not a substrate of CYP enzymes. In addition, lenalidomide shows little inhibitory 
or induction potential towards the CYP enzymes in vitro. Hence, 
coadministration of CYP substrates, inhibitors, or inducers with lenalidomide is 
not likely to result in clinically relevant drug-drug interactions in humans.  
 
In vitro, lenalidomide is not a substrate of BCRP, MRP1, MRP2, MRP3, OAT1, 
OAT3, OATP1B1, OCT1, OCT2, MATE1, OCTN1, or OCTN2. Thus, it is 
unlikely that substrates or inhibitors of these transporters would affect 
lenalidomide disposition in humans. 
 


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Lenalidomide is not an inhibitor of BSEP, BCRP, MRP2, OAT1, OAT3, 
OATP1B1, OATP1B3, or OCT2. Thus, lenalidomide is not anticipated to cause 
any significant drug-drug interactions due to inhibition of these transporters. 
 
Lenalidomide is not an inhibitor of UGT1A1 and is not anticipated to cause any 
significant drug-drug interactions due to UGT1A1 inhibition. 
 
In vitro, lenalidomide is a weak substrate, but not an inhibitor of P-glycoprotein 
(P-gp). 
 
Erythropoietic agents or other agents that may increase the risk of thrombosis, 
such as hormone replacement therapy and oral contraceptives, should be used 
with caution in patients with multiple myeloma receiving lenalidomide with 
dexamethasone. 
 
 
Periodic monitoring of digoxin plasma levels is recommended due to increased 
Cmax and AUC with concomitant lenalidomide therapy.  Close monitoring of PT 
and INR is recommended in multiple myeloma patients taking concomitant 
warfarin. 
 
 
15.17 Known potential toxicities:   
 
Pregnancy Warning: Lenalidomide, a thalidomide analogue, caused limb 
abnormalities in a developmental monkey study similar to birth defects caused by 
thalidomide in humans. If lenalidomide is used during pregnancy, a teratogenic 
effect of lenalidomide in humans cannot be ruled out.  .  Pregnancy must be 
excluded before start of treatment. Prevent pregnancy during treatment by the use 
of two reliable methods of contraception. 
 
Very Common AEs (≥ 10%): anemia, febrile neutropenia, granulocytopenia, 
leukopenia, lymphopenia, neutropenia, thrombocytopenia, cataracts, blurred 
vision, abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, 
asthenia, chills, edema including peripheral, fatigue, pyrexia, abnormal liver 
function tests, bronchitis, gastroenteritis, influenza, nasopharyngitis, sinusitis , 
pneumonia, rhinitis, upper respiratory tract infection, urinary tract infection 
weight decreased, decreased appetite, hyperglycemia, hypocalcemia, 
hypokalemia, arthralgia, back pain, bone pain, muscle spasms, musculoskeletal 
pain, myalgia, pain in extremity, dizziness, dysgeusia, headache, hypoesthesia, 
neuropathy peripheral, neuropathy, paresthesia,tremor, depression, insomnia, 
renal failure, cough, dyspnea, epistaxis, pharyngitis, pulmonary embolism, dry 
skin, pruritus, rash, and deep vein thrombosis. 
 
Common (≥ 1% and < 10%):, hemolytic anemia, pancytopenia, acute myocardial 
infarction, atrial fibrillation, cardiac failure, congestive heart failure, myocardial 
ischemia, tachycardia, vertigo, upper abdominal pain, dry mouth, toothache, 
chest pain, fall,  cholestasis, arthritis infective, bacteremia, cellulitis, erysipelas, 
herpes simplex, herpes zoster, lower respiratory infection, lung infection, 
meningitis, ophthalmic herpes zoster, respiratory infection, sepsis, contusion, 
alanine aminotransferase increased, c-reactive protein increased, gamma-glutamy 


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ltransferase increased, dehydration, diabetes mellitus, gout,  hypercalcemia, 
hyperuricemia, hypophosphatemia, hypomagnesemia, hyponatremia, iron 
overload, muscular weakness, acute myeloid leukemia, basal cell carcinoma, T-
cell type acute leukemia, Myelodysplastic syndrome, squamous cell carcinoma of 
skin, tumor flare, tumor lysis syndrome, cerebrovascular accident, lethargy, 
peripheral sensory neuropathy, syncope, mood altered, respiratory distress, 
erythema, hyperhidrosis, night sweats, hematoma, hypertension, hypotension, 
thrombosis, and vasculitis. 
 
Uncommon, limited to important or life-threatening (< 1%): appendicitis, 
bursitis infective, clostridium difficile, colitis, infective exacerbation of chronic 
obstructive airways disease, pyelonephritis,  hypersensitivity, Graft vs. Host 
Disease, viral reactivation (such as hepatitis B virus or herpes zoster), DRESS. 
 
The following additional adverse reactions have been reported in Celgene-
sponsored clinical studies and are considered by the company to be at least 
possibly related to the administration of lenalidomide: pneumonitis, transient 
abnormal liver laboratory tests, hyperthyroidism, hypothyroidism, viral 
reactivation (such as hepatitis B virus or herpes virus), acute graft-versus-host 
disease following allogeneic hematopoietic transplant, solid organ rejection, 
TLS, TFR, and allergic conditions (including angioedema, SJS, TEN, and 
DRESS. These reactions are reported voluntarily from a population of uncertain 
size, so it is not possible to reliably estimate their frequency. 
  
Lenalidomide may have minor or moderate influence on the ability to drive and 
use machines. Fatigue, dizziness, somnolence, vertigo and blurred vision have 
been reported with the use of lenalidomide. Therefore, caution is recommended 
when driving or operating machines. 
 
Please refer to the Investigator’s Brochure for a more comprehensive list of 
treatment-emergent adverse events. 
 
15.18 Drug procurement:  Lenalidomide (Revlimid®) will be provided directly to 
research subjects for the duration of their participation in this trial in accordance 
with the REVLIMID REMS™  program.  Per standard requirements all 
physicians who prescribe lenalidomide for research subjects enrolled into this 
trial, and all research subjects enrolled into this trial, must be registered in and 
must comply with all requirements of the Celgene  REVLIMID REMS™  
program.  Prescriptions must be filled within 7 days.  Only enough lenalidomide 
for one cycle of therapy will be supplied to the patient each cycle. 
 
 
Any unused lenalidomide should be returned for disposition in accordance with 
the REVLIMID REMS™   program. 
 
15.19 Nursing Guidelines:  
 
15.191 Myelosuppression is dose-dependent and reversible with treatment 
interruption and/or dose reduction. Monitor CBC w/diff regularly. 
Instruct patient to report any unusual bruising or bleeding 


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(thrombocytopenia); signs and symptoms of infection (neutropenia); and 
energy conserving lifestyle (anemia). 
 
15.192 Lenalidomide can have thrombotic adverse events (i.e DVT and PE). 
Instruct patient to report any limb swelling or pain, and to seek medical 
attention for shortness of breath or chest pain. 
 
15.193 Because of the potential for birth defects patients should be instructed in 
effective methods of birth control. Female patients should use 2 forms of 
birth control during treatment and for 4 weeks after discontinuing 
therapy. Males must be instructed to use a latex condom during any 
sexual contact with a woman of child bearing potential (even if they have 
had a vasectomy), because it is unknown if lenalidomide is present in 
semen. 
 
15.194 Patents may experience pruritus, rash and dry skin. Because of the rare 
risk of Steven’s Johnson Syndrome, patients should immediately report 
any rash to their provider. 
 
15.195 Drug may cause hyperglycemia. Patients with diabetes or impaired fasting 
glucose may need to have their glucose levels monitored more closely. 
 
15.196 Gastrointestinal side effects (diarrhea, constipation, nausea, dyspepsia, 
anorexia, etc) are commonly seen. Manage patent symptomatically and 
monitor for effectiveness. 
 
15.197 Patients may experience myalgias, arthralgias, parasthesias, and 
other generalized pain. Administer analgesics as ordered and 
monitor for their effectiveness. Rarely infective bursitis and arthritis 
have been reported. Instruction patients to report any joint pain or redness 
to study team immediately 
 
15.198 Upper respiratory symptoms (nasopharyngitis, cough, epistaxis, etc.) can 
be seen. Manage symptomatically and monitor for effectiveness. 
 
15.199 Agent may cause fatigue, dizziness, vertigo or blurred vision. Instruct 
patients to use caution when driving or operating machines.  
 
15.200 Monitor LFT’s and report any elevations to the study team. 
Instruct patient to report abdominal pain and/or jaundice to the 
study team. 
 
15.201 All prescribers and patients must be enrolled into the REVLIMID 
REMS program. Only enough lenalidomide for one cycle of 
therapy will be supplied to the patient each cycle. 
 


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15.202 Rarely secondary malignancies have been seen after lenolidamide 
therapy, including MDS, squamous/basal cell carcinomas of the 
skin, T-cell type acute leukemia. 
 
15.203 Monitor Renal function, renal failure has been reported. 
 
 
15.2 
LDE225 Sonidegib (LDE225, Odomzo®)   
 
15.21 Background:  Sonidegib (LDE225) is a potent antagonist of Hedgehog (Hh)- 
and Smoothened (Smo)-dependent signaling. Smo is a G protein-coupled 
receptor (GPCR)-like molecule that positively regulates the Hh signal 
transduction pathway.  Hh pathway activation at or upstream of Smo is linked to 
the pathogenesis of several types of cancer .   
 
 
In particular, activating mutations in Hh pathway genes have been identified in 
patients with medulloblastoma (MB), basal cell carcinoma (BCC), and 
rhabdomyosarcoma. Aberrant upregulation of the Hh pathway without known 
mutation is linked to the pathogenesis of many other cancer types including 
pancreatic breast, esophageal, gastric, colorectal, glioblastoma, ovarian, sarcoma, 
acute and chronic leukemias, multiple myeloma, lymphoma and small-cell lung 
cancer (SCLC). Antagonists of Smo are hypothesized to block the growth of 
tumors that are dependent on Hh pathway activation. Furthermore, preclinical 
and emerging clinical data suggests Hh signaling may play an important role in 
many hematological cancers, such as acute and chronic leukemia, multiple 
myeloma and lymphomas. 
 
 
  
15.22 Formulation: Hard gelatin capsules contain LDE225 drug substance at dose 
strength of 200 mg,  with the following excipients: crospovidone, lactose 
monohydrate, magnesium stearate, poloxamer 188, silica colloidal 
anhydrous/colloidal silicon dioxide and sodium laurilsulfate/sodium lauryl 
sulfate. The capsule uses a size 00   pink (“Swedish Orange”) opaque capsule 
shell with either no imprint or with “NVR” imprinted in black ink on the cap and 
“SONIDEGIB 200MG” in black ink on the body. The capsule shell contains 
gelatin, red iron oxide and titanium dioxide.  
 
Immediate-release film-coated tablets contain 200 mg sonidegib drug substance 
(based on free base content), with the following excipients for the tablet core: 
cellulose, microcrystalline cellulose, crospovidone, hypromellose, magnesium 
stearate, colloidal silicon dioxide, silicon dioxide, sodium lauryl sulfate, sodium 
starch glycolate and talc. The film-coating contains black, red, and yellow iron 
oxides, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. The 
tablets are reddish to pale red in color with an ovaloid shape, a beveled edge, and 
“CC” engraved on one side and “NVR” on the other side. 
 
An oral suspension has been established at the dose strength of 50 mg sonidegib 
per mL (based on free base content) for adult and pediatric use in the 
medulloblastoma indication (refer to Study CLDE225A2114 for relative 


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bioavailability relative to the capsule in healthy volunteers and Study 
CLDE225C2301 for patient experience). The oral suspension is prepared in-situ 
at the clinical sites, yielding a white homogenous suspension. The clinical sites 
are supplied with sonidegib powder for oral suspension, which is packaged in 
amber glass bottles with a white child-resistant cap. The white to practically 
white powder contains sonidegib drug substance with the following commonly 
used compendial grade excipients: colloidal silicon dioxide, magnesium stearate, 
microcrystalline cellulose, sucralose (or E955) and Tutti Frutti dry flavor. 
Additionally, 80 ml of a Solvent for oral suspension (a clear solution of medium-
chain triglycerides) is supplied packaged in amber glass bottles with a white 
child-resistant cap. (Each bottle contains a 20 ml overfill to permit the complete 
withdrawal of the 60 ml nominal volume from the bottle). Oral dosing syringes 
are provided to enable accurate preparation and dispensing of the reconstituted 
suspension. The packaging materials employed are commonly used in 
commercial products. 
 
 
15.23 Preparation and storage: The Capsules are packaged in high density 
polyethylene (HDPE) bottles with an induction seal and child-resistant 
closure, with desiccant. Please refer to the clinical label for the current 
shelf-life, in-use period and storage conditions.  
 
Novartis provides a kit composed of an amber bottle with sonidegib 
powder for oral suspension, an amber glass bottle with solvent for oral 
suspension, and a dosing syringe to prepare the oral suspension.  The 
instructions for use describe reconstitution of the powder at the study site 
by site personnel.  Patients receive reconstituted oral suspension in 
multiple-use bottles, and dosing syringes for daily administration.  A 
second instruction for use describes drug dosing at home.  As the shelf-life 
and storage conditions of both the sonidegib powder and the solvent for 
oral suspension will be continually assessed based on accelerated and long 
term stability data, please refer to the clinical label for current shelf-life, 
in-use and storage conditions. 
 
Sonidegib is considered a teratogenic agent. Great care must be taken 
when handling dosage forms of sonidegib, especially while pregnant. Due 
to the physical properties of sonidegib drug substance and dosage forms, 
sonidegib can neither be inhaled nor absorbed through the skin. Therefore 
hands should be washed thoroughly with soap and water upon direct 
exposure to sonidegib. 
 
  
15.24 Administration:  LDE225 capsules should be taken once daily, at approximately 
the same time each day. 
 LDE225 should be taken as follows: 
Patients should be instructed to take their once-a day dose at approximately the 
same time each day 2 hours after a light breakfast (eg. juice, toast and jam). Food 
intake should be avoided for at least 1 hour after study drug administration.  


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Patients should follow the administration instructions on the clinical label and the 
instructions for use that accompany the sonidegib suspension. 
 
• 
On days where PK samples need to be collected prior to taking study drug, 
that day’s dose should be taken in the clinic (study site) 
• 
Each daily dose of LDE225 should be taken with a glass of water and 
consumed over as short a time as possible (e.g. 1 capsule every 2 minutes) 
• 
Patients should be instructed to swallow capsules whole and to not chew or 
open them 
• 
Each daily dose of LDE225 (including days which involve PK blood 
sampling) should be taken 2 hours after a light breakfast (e.g., consisting of 
juice, toast and jam). If breakfast was completed at 08:00 a.m., then study 
drug administration should occur at 10:00 a.m. Food intake should be 
avoided for at least 1 hour after study drug administration 
• 
Patients must avoid grapefruit, pomegranate, star fruit and Seville (sour) 
oranges during the entire study. The juices and products containing these 
fruits may also be avoided. 
• 
If vomiting occurs during the course of the treatment, then no re-dosing of 
the patient is allowed before the next scheduled dose 
• 
If the patient forgets to take his/her daily morning dose, then he/she should 
take LDE225 within 6 hours after the missed dose. If more than 6 hours have 
passed, then that day’s dose should be omitted and the patient should 
continue treatment with the next scheduled dose 
• 
Patients should inform the investigational site staff of any missed or delayed 
dose 
 
 
15.25 Pharmacokinetic information: 
 
  
  
Absorption and Distribution – Median time to Tmax occurs at 2-4 hours 
(range 1-48 hrs).  Tmax appeared to be independent of dose.  Steady state 
for sonidegib is anticipated to be reached after 8-12 weeks of dosing in 
most patients.  The 2nd generation tablet variants provided bioavailability 
similar to the capsule formulation. The oral suspension provided higher 
bioavailability compared with the capsule formulation, with a 600 mg oral 
suspension dose yielding a similar AUC0-14d to that of 800 mg capsule 
dose. A large positive food effect was observed, with 8-fold Cmax and 7-
fold AUC, compared with fasting conditions.  In anticipation of a food 
effect, food consumption will continue to be restricted around the time of 
dosing for clinical studies. Sonidegib is highly bound (>97%) to human 
plasma proteins. 
Metabolism: The metabolite profile in plasma shows unchanged sonidegib 
as the major circulating component (36%).  The main circulating 
metabolite (M48) is pharmacologically inactive as an inhibitor of 
Smoothened receptor. Sonidegib is primarily metabolized by CYP3A4 in 
the liver. 
 
Excretion – Excretion is almost exclusively through feces (88.7% of dose 
and as unchanged), with no detectable levels in the urine. The median half 
-life is approximately 28 days. 
 
 


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15.26 Potential Drug Interactions:  LDE225 is shown to potently inhibit 
CYP2B6 and CYP2C9. Because of the potential risk for drug-drug 
interactions, using concomitant medications known to be metabolized by 
these enzymes with low therapeutic index (CYP2B6: buproprion, 
efavirenz, cyclophosphamide, ifosfamide, thiotepa, procarbazine; 
CYP2C9: celecoxib, diclofenac, tolbutamide, warfarin, tamoxifen, 
phenytoin) should be carefully monitored or excluded, in accordance with 
protocol-specific guidelines. 
 
Precaution should be taken when LDE225 is administered with any known 
potent CYP3A4 inhibitors and inducers, as these have the potential to 
influence the biotransformation and clearance of LDE225. See 3.37 tables 
for more information. 
 
LDE225 is an inhibitor of breast cancer resistance protein (BCRP) in vitro. 
Therefore substrates, especially those with a narrow therapeutic range, 
should be used with caution.  BCRP substrates include zidovudine, 
pantoprazole, cimetidine, sulfasalazine, nitrofuratoin, mitoxantrone, 
methotrexate, topotecan, imatinib, and irinotecan or “statins”. 
 
15.27 Known potential toxicities:  Based on its mechanism of action and the 
results of the pre-clinical toxicology studies, the major potential toxicities 
of LDE225 in humans are anticipated to be the following: thinning or early 
closure of growth plates, in growing children; disruption of gametogenesis 
and impairment of the development of reproductive organs with resultant 
infertility; and gastrointestinal irritation with potential mucosal damage. 
LDE225 is a teratogen, as are other Smo inhibitors, in view of the role of 
Hh signaling in embryo-fetal development. In addition, the emerging 
clinical data has revealed dose-limiting toxicities characterized by elevated 
plasma CK associated with muscle pain and/or muscle spasms,  
rhabdomyolysis being a serious adverse event. 
 
The following adverse reactions occur at a frequency of   ≥10%: 
 
Metabolism and nutrition disorders: decreased appetite, weight decreased 
 
Nervous system disorder: Dysgeusia, headache, insomnia, dizziness 
 
Gastrointestinal disorders: Nausea, diarrhea, abdominal pain, vomiting 
 
Skin and subcutaneous tissue disorders: Alopecia, pruritus 
 
Musculoskeletal and connective tissue disorders: Muscle spasms, 
musculoskeletal pain, myalgia, asthenia 
 
Reproductive system and breast disorders: amenorrhea 
 
General disorders: Fatigue, pain, cough, UTI, lethargy, pain in extremity, 
pyrexia, dyspnea, lipase increased 
 
 
The following adverse reactions occur at a frequency of 1-10%: 
 
Metabolism and nutrition disorders: Dehydration 
 
Gastrointestinal disorders: Dyspepsia, constipation, gastroesophageal 
reflux disorder 
 
Skin and subcutaneous tissue disorder: Rash, abnormal hair growth 
 
Musculoskeletal and connective tissue disorders: myopathy (muscular 
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Other reported serious adverse reactions include febrile neutropenia, 
anemia, blood glucose increased, gastritis, myositis, myoglobin blood 
increased, hypersensitivity, and acute renal failure.  Adverse events 
occurred based on lab abnormalities: hemoglobin decreased, lymphocyte 
count decreased, serum creatinine increased, serum creatine 
phosphokinase (CK) increased, blood glucose increased, lipase increased, 
alanine amino transaminase (ALT) increased, aspartate amino 
transaminase (AST) increased, amylase increased. 
  
Routine safety monitoring will include physical examinations (including 
vital signs), hematology, serum chemistries, coagulation tests, urinalyses, 
cardiac monitoring, as well as bone monitoring in pediatric patients. In 
particular, the main dose-limiting toxicities observed in the clinic relate to 
muscle toxicity that is characterized with plasma CK elevation, increased 
plasma myoglobin, muscle spasms, myalgia and muscular weakness. 
Therefore, close monitoring of plasma CK levels during the first 8 weeks 
of LDE225 therapy is recommended.  
 
15.28 Drug procurement:  Drug will be provided free of charge to study participants 
by Novartis. 
 
15.29 Nursing Implications: 
 
15.291 Agent is considered teratogenic. Warn patients that they should not 
become pregnant or father a child while on this agent.  Adequate birth 
control measures should be exercised. Caution should be used for health 
care workers that are administering the agent especially if pregnant. If 
direct exposure to LDE225 powder occurs, the hands should be washed 
thoroughly with soap and water. 
15.292 Assess patient’s concomitant medications. Care should be exercised 
when administering with agents that utilize the CYP2B6, CYP2C9, and 
CYP3A4 pathways as there is the potential for drug-to drug interactions, 
especially those with a low therapeutic index (see section 15.16). 
15.293 Given the very early investigational nature of this agent, not all side 
effects can be known at this time. Assess patients regularly and report 
side effects to the study team. 
15.294 Based on preclinical studies, there is the possible risk of infertility, warn 
patients of this possibility. 
15.295 Gastrointestinal side effects (nausea, decreased appetiete, vomiting, 
diarrhea and constipation) have all been repoerted. Manage 
symptomatically and monitor for effectiveness. 
15.296 Muscle spasms and myalgias have been seen. Treat symptomatically and 
monitor for effectiveness. 
15.297 Monitor LFT’s. 
15.298 Alopecia has been reported. Warn patients of this possibility.  
15.199a   Instruct patient to take medication at the same time each day, 2 hours 
after a light breakfast and to avoid food intake for 1 hour after taking 
medication. 


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15.199b  Fever can be seen. Treat symptomatically with antipyretics and monitor 
for effectiveness. 
15.199c  Monitor CBC w/diff. Instruct patient to report any fever, signs or 
symptoms of infection, unusual bruising or bleeding to the study.  
 
 
 
 
 
 
 
 
 
 
 
16.0  
Statistical Considerations and Methodology  
 
16.1  
Overview:  
 
This is a Phase II study designed to assess the proportion of complete responses as well 
as the toxicity associated with Lenalidomide and LDE225 used as maintenance therapy 
following autologous stem cell transplantation. 
 
16.11  Primary Endpoint:  
 
The primary endpoint of this trial is the rate of complete response. Throughout 
Section 16.0, complete response will be considered synonymous with “success”, 
unless specified otherwise.  All patients meeting the eligibility criteria who have 
signed a consent form and have begun treatment will be evaluable for complete 
response, with the exception of patients who are determined to be a major 
treatment violation. 
 
16.2  
Statistical Design: 
 
16.21 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) The 
complete response rate to stem cell transplant was 35%.  Since patients in this 
study will receive a stem cell transplant within 12 months of diagnosis, an 
increase in complete response rate to greater than 35% with the addition of 
maintenance therapy with lenalidomide and LDE225 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%.   
 
 
 


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16.211 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 and terminate this study. Otherwise, if the number of 
successes is at least 18, this will be considered evidence of promising 
activity, and the treatment may be recommended for further testing in 
subsequent studies. 
 
16.212 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 16.34. 
 
16.22  Sample Size:  
 
The single stage study design to be used is fully described in section 16.21.  A 
maximum of 39 evaluable patients will be accrued onto this phase II study unless 
undue toxicity is encountered.  We anticipate accruing an additional 4 patients to 
account for ineligibility, cancellation, major treatment violation, or other reasons.  
Maximum projected accrual is 43 patients. 
 
16.23  Accrual Rate and Study Duration:  
 
The anticipated accrual rate is approximately 2-3 patients per month.  Therefore, 
the accrual period for this phase II study is expected to be about 1.5 years.  The 
final analysis can begin approximately 2 years after the trial begins, i.e. as soon 
as the final patient accrued to this trial has been followed for at least 6 months.  
 
 
16.24 Power and Significance Level: Assuming that the number of responses is 
binomially distributed, with a significance level of 10%, the probability of 
declaring that the regimen warrants further studies (i.e., statistical power) under 
various success proportions can be tabulated as a function of the true success 
proportion as shown in the table below. 
 
If the true success proportion is… 
0.35 0.40 0.45 0.50 0.55 
Then the probability of declaring that the regimen is 
promising and warrants further study is… 
0.10 0.27 0.50 0.74 0.90 
 
16.25 Other Considerations: Toxicity, 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. 
 
16.3 
Analysis Plan:  The analysis for this trial will commence at planned timepoints (see 16.2) 
and at the time the patients have become evaluable for the primary endpoint. Such a 
decision will be made by the Statistician and Study Chair, in accord with CCS Standard 
Operating Procedures, availability of data for secondary endpoints (eg, laboratory 
correlates), and the level of data maturity. It is anticipated that the earliest date in which 
the results will be made available via manuscript, abstract, or presentation format is when 
last patient has been followed for at least 6 months. 
 
 
 


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16.31 Primary Endpoint:   
 
16.311 Definition: The primary endpoint of this trial is the rate of complete 
response. A complete response is defined as a CR noted as the objective 
status on 2 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 or stem cell transplant.  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, 
with the exception of patients who are determined to be a major 
treatment violation. 
 
16.312 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. 
 
16.32 Definitions and Analyses of Secondary Endpoint: 
 
16.321 Overall survival: Survival time is defined as the time from SCT to death 
due to any cause.  The distribution of survival time will be estimated 
using the method of Kaplan-Meier (Kaplan and Meier, 1958).  All 
evaluable patients will be included in this analysis.  In addition, overall 
survival time from the time of registration will also be evaluated. 
 
16.322 Progression-free survival: The progression-free survival time is defined 
as the time from SCT to progression or death due to any cause.  The 
distribution of progression-free survival will be estimated using the 
method of Kaplan-Meier (Kaplan and Meier 1958).  The progression-free 
survival rates at 1 year and 2 years post SCT will be assessed.  In 
addition, progression-free survival from the time of registration will also 
be evaluated. 
 
16.323 Adverse Events: The maximum grade for each type of adverse event, 
regardless of causality, will be recorded and reported for each patient, 
and frequency tables will be reviewed to determine adverse event 
patterns.  Adverse events will continue to be recorded and reported 
through the observation period, or up to 30 days after the last day of 
study drug treatment for patients who do not proceed to observation. 
 
16.33 Correlative Analyses 
 
16.331 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. 
 


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16.34 Over Accrual: If more than the target number of patients are accrued, the 
additional patients will not be used to evaluate the stopping rule or used in any 
decision making processes; however, they will be included in final point 
estimates and confidence intervals. 
 
16.35 Data & Safety Monitoring 
 
16.351 Safety Analysis:  The trial will initially open to only 6 evaluable patients 
that will be included in a safety analysis.  The study will temporarily 
close while these patients are evaluated for toxicity during the first 3 
months of treatment.   
 
 
Safety Analysis Stopping Rule:  If 0 or 1 patients experience a DLT, the 
study will be reopened to accrual.  If 2 or more patients experience a 
DLT, the study team will review all adverse events and determine 
whether study will be closed or reopened with adjustments to the starting 
dose levels as outlined in Table 8.1. 
 
For this protocol, dose-limiting toxicity (DLT) will be defined as an 
adverse event attributed (definitely, probably, or possibly) to the study 
treatment during the first 3 cycles of treatment and meeting the following 
criteria: 
 
Toxicity (CTCAE v4.0) DLT Definition 
 
Toxicity (CTCAE v3.0) 
DLT Definition* 
Hematologic 
Grade 4 ANC for ≥7 days or PLT <25,000 for ≥7 
days 
Infection 
Grade 4 
Febrile Neutropenia 
Defined as fever ≥ 38.5oC (38 > 1 hour) with grade 
≥ 3 neutropenia 
CK elevation 
>  Grade 3 CK elevation 
Other Non-hematologic 
≥ grade 3 as per NCI Common Terminology 
Criteria for Adverse Events v4.0**.  
 
*Any toxicities that caused dose delay of > 2 weeks of the intended next dose will 
also be considered dose-limiting. 
**Grade 3 nausea, vomiting, or diarrhea with maximal supportive treatment(s) will 
be considered dose-limiting.  Fatigue and mouth sores that are considered Grade 3 
with an attribution of definitely, probably, or possibly related to treatment will be 
reviewed by the study team to determine if they were due to other causes (i.e. 
disease progression or infection) or treatment.   If it is determined that the fatigue 
or mouth sores were due to other causes they would not be considered a DLT and 
if they were due to treatment they would be considered a DLT. 
 
 
 


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16.352 The principal investigator(s) and the study statistician will review the 
study at least every quarter 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. 
 
16.353 Adverse Event Stopping Rule: The stopping rule specified below is 
based on the knowledge available at study development.  We note that 
the 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 treatments under investigation.  The study team may 
choose to suspend accrual because of unexpected adverse event profiles 
that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended to this study if at any time we observe 
events considered at least possibly related to study treatment (i.e. an adverse 
event with attribute specified as “possible,” “probable,” or “definite”) that satisfy 
either of the following: 
 
• 
if 4 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, 25% 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. 
 
 
16.4 
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 2 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. 
 
16.5 
Inclusion of Women and Minorities 
 
16.51 This study will be available to all eligible patients, regardless of race, gender, or 
ethnic origin. 
 
16.52 There is no information currently available regarding differential effects of this 
regimen in subsets defined by race or gender, and there is no reason to expect 
such differences to exist.  Therefore, although the planned analysis will, as 


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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. 
 
16.53 The geographical region served by Mayo, has a population which includes 
approximately 3% minorities. Based on prior Mayo studies involving similar 
disease sites, we expect about 3-5% of patients will be classified as minorities by 
race and about 33% of patients will be women.  Expected sizes of racial by 
gender subsets are shown in the following table: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
 0 
 1 
 1 
Not Hispanic or Latino 
 14 
 28 
 42 
Ethnic Category: Total of all subjects 
 14 
 29 
 43 
Racial Category 
American Indian or Alaskan Native 
 0 
 0  
 0 
Asian 
 0 
 0 
 0 
Black or African American 
 1 
 1 
 2 
Native Hawaiian or other Pacific Islander 
 0 
 0 
 0 
White 
 13 
 28 
 41 
Racial Category: Total of all subjects 
 14 
 29 
 43 
 
Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa. Terms such as “Haitian” or “Negro” can be used in addition to 
“Black or African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 
17.0  
Pathology Considerations/Tissue Biospecimens   N/A 
 
 
 


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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) 
Myeloma pretreatment measurement form 
baseline values for disease assessment 
(see Section 11.11) 
Myeloma Pretreatment Measurement Form 
Baseline Values at Time of Diagnosis 
On-study lab reports1:  
SPEP, UPEP, Serum FLC , Serum and Urine 
Immunofixation, Serum Immunoglobulins, 
Bone Marrow biopsy and aspirate, X-Ray 
skeletal survey, Cytogenetic, FISH. 
Bone Marrow Aspirate Submission Form 
Lab reports for baseline values for disease 
assessment1 as defined in Section 11.11: 
SPEP, UPEP, Serum FLC and 
Immunoglobulins 
End of Active Treatment/Cancel Notification 
Form 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
 1.Submit copy of lab reports to the MCCC Operations Office, Attention:  
 
 200 First Street SW, Rochester, MN 55905.  
  
 
Test Schedule Material(s) -  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of treatment 
Observation 
Evaluation/Treatment Form 
X2 
X 
 
Evaluation/Observation Form 
 
 
X1 
Nadir/Adverse Event Form 
X 
X 
X 


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CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation 
during treatment 
At end of treatment 
Observation 
Treatment Measurement Form 
X 
X 
X 
SPEP, UPEP, FLC , Serum and Urine 
Immunofixation, Bone Marrow biopsy and 
aspirate, X-Ray skeletal survey 
X3 
X3 
X3 
End of Active Treatment/Cancel Notification 
Form 
 
X 
 
Notification Form – Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization Form 
At each occurrence 
(see Section 10.0) 
 
 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
 
Bone Marrow Aspirate Submission Form 
X  
(See Section 14.0) 
X 
X 
(See Section 14.0) 
1. Complete at each evaluation during Observation (see Section 4.0). 
2. Complete at each evaluation during Active Treatment (see Section 4.0). 
3. Submission of these reports is only required for documentation of CR or progression. For 
documentation of CR, submit all of these reports at the first confirmation of CR. For 
documentation of progression, submit one report for one of the measures where progression was 
seen to MCCC Operations Office, Attention: 
 200 First 
Street SW, Rochester, MN 55905 . 
 
Follow-up Material(s) -  
CRF 
Event Monitoring Phase1 
q. 3 months until 
PD or 
subsequent 
treatment for 
myeloma2 
At PD or 
subsequent 
treatment 
for 
myeloma2 
q. 6  mos. 
after PD or 
subsequent 
treatment 
for myeloma 
Death 
New Primary 
Event Monitoring Form 
X 
X 
X 
X 
At each occurrence 
1. If a patient is still alive 5 years after registration, no further follow-up is required. 
2. For documentation of progression, submit one report for one of the measures where progression was 
seen (SPEP or UPEP or FLC or X-Ray) to MCCC Operations Office, Attention: 
 
 200 First Street SW, Rochester, MN 55905.  
 
 
19.0  
Budget 
 
 
19.1 
Costs charged to patient:  routine clinical care, study drug lenalidomide 
 


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19.2 
Tests to be research funded: study drug LDE225 
 
19.3  
Other budget concerns: 
 
20.0 
References 
REFERENCES 
 
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Sarasquete, M. E., R. Garcia-Sanz, et al. (2005). "Minimal residual disease monitorization in multiple 
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90. 
Spencer, A., H. M. Prince, et al. (2009). "Consolidation therapy with low-dose thalidomide and 
prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous 
stem-cell transplantation procedure." J Clin Oncol 27(11): 1788-1793. 
Stewart, A. K., S. Trudel, et al. (2010). "A Randomized Phase III Trial of Thalidomide and Prednisone as 
Maintenance Therapy Following Autologous Stem Cell Transplantation (ASCT) In Patients with 
Multiple Myeloma (MM): The NCIC CTG MY.10 Trial." ASH Annual Meeting Abstracts 
116(21): 39-. 
Xie, K. and J. L. Abbruzzese (2003). "Developmental biology informs cancer: the emerging role of the 
hedgehog signaling pathway in upper gastrointestinal cancers." Cancer Cell 4(4): 245-247. 
 Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, Blade  J, Richardson P, 
Orlowski R, Siegel D, Jagannath S, Facon T, Avet-Loiseau H, Lonial S, Palumbo A, Zonder J, 
Ludwig H, Vesole D, Sezer O, Munshi NC, San Miguel J; International Myeloma Workshop 
Consensus Panel 1. Consensus recommendations for the uniform reporting of clinical trials: 
report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011 May 
5;117(18):4691-5. 
 


 
Appendix I 
 
MC128B 
Page 1 of 2 
 
Protocol version date:  25Jul2018 
 
Prohibited concomitant medications 
 
Strong CYP3A inhibitors and inducers 
No clinical studies have been performed to confirm if LDE225 is a sensitive CYP3A4 substrate, hence 
concomitant use of strong CYP3A4 inhibitors and inducers is not permitted. Patients receiving 
concomitant medications known to strongly inhibit and/or induce CYP3A4/5 that are deemed medically 
necessary should be excluded from the study. A partial list of drugs that are inducers, and inhibitors of 
CYP3A4/5 is included in the table below. The above list  of medications has been generated by Novartis 
Oncology Clinical Pharmacology (OncCP)  (DDI database document: last update August 2010) that is 
compiled by using information listed under “draft guidance for industry, drug interaction studies, CDER 
2006”, Indiana University School of Medicine drug interaction tables at 
http://medicine.iupui.edu/clinpharm/DDIs/ClinicalTable, and “drug interaction from University of 
Washington. Patients should be instructed not to take grapefruit, St John Wort or Seville (sour) orange 
juice while receiving LDE225 treatment throughout the study due to potential CYP3A4/5 inhibition. The 
other drugs without an asterisk should be carefully used as concomitant therapy. 
 
 
Table  
 
Medications that are CYP3A4/5 inducers or inhibitors 
Medications 
 
Inhibitors 
HIV antivirals: indinavir, nelfinavir, ritonavir*, saquinavir 
 
Antibiotics: azithromycin, ciprofloxacin, chloramphenicol, clarithromycin, erythromycin*, 
fluconazole&, itraconazole*, ketoconazole*,  voriconazole*, telithromycine, posaconazole, 
norfloxacin 
 
Calcium channel blockers: diltiazem&, verapamil& 
 
Antidepressants: , fluvoxamine, nefazodone* 
 
Miscellaneous: amiodarone, cimetidine, delavirdine, diethyl-dithiocarbamate (chlorzoxazone), 
interleukin-10*, mifepristone, mibefradil , grape fruit juice&, isoniazid&, apepritant& 
Inducers 
HIV antivirals: efavirenz, nevirapine 
 
Anticonvulsants: barbiturates**, carbamazepine**, Oxcarbazepine**, phenytoin**, 
phenobarbital** 
 
Systemic glucocorticoids: dexamethasone&, glucocorticoids, hydrocortisone, prednisolone, 
prednisone 
 
Antibiotics: rifabutin**, rifampicin**,rifapentine** 
 
Antidiabetics: pioglitazone, troglitazone 
 
Miscellaneous: modafinil, hormone replacement therapy, oral contraceptives, St John’s wort** 
*- Known strong inhibitors of CYP3A4 are estimated to cause a≥ 5 fold increase in the AUC values or a 
≥80% decrease in clearance of a CYP3A4 substrate;  
& -a moderate inhibitor is estimated to cause a ≥2-but < 5 fold increase in the AUC values or a 50-80% decrease 
in the clearance of a sensitive substrate when the inhibitor is given at the highest approved dose.  
** -Known strong inducers of CYP3A4/5 (AUC decrease by 50-80%) 
Medications that are CYP2B6 and CYP2C9 substrates (narrow therapeutic index) 
LDE225 is a potent inhibitor of drugs metabolized by the cytochromes CYP2B6 and CYP2C9 in vitro. 
Because of the potential risk for drug-drug interactions, using concomitant medications known to be 
metabolized by these enzymes that have low therapeutic index (see table below) is not permitted in the 
study. The other drugs without an asterisk should be carefully used as concomitant therapy. 


 
2  
Appendix I 
Page 2 of 2 
MC128B 
Protocol version date:  25Jul2018 
 
Table   
 
Drugs metabolized by CYP2B6 and CYP2C9 
CYPs 
Drugs metabolized by CYPs 
CYP2B6 
Bupropion 
, cyclophosphamide, efavirenz, ifosfamide,  methadone 
CYP2C9 
NSAIDs: diclofenac, ibuprofen, lornoxicam, meloxicam, naproxen, piroxicam, suprofen 
 
Oral hypoglycemic agents:  tolbutamide, glipizide 
 
Angiotensin II blockers: losartan, irbesartan 
 
Sulfonylureas: glyburide/glibenclamide, glipizide, glimepiride, tolbutamide 
 
Miscellaneous: amitriptyline, celecoxib, fluoxetine, pravastatin&, glyburide, nateglinide, phenytoin, 
rosiglitazone, tamoxifen, torsemide, warfarin*, quinidine* 
* -narrow therapeutic index: drugs whose exposure-response indicates that increases in their exposure levels by 
the concomitant use of potent inhibitors may lead to serious safety concerns (e.g. Torsade de Pointes) are not 
allowed 
&- statins – If it is essential that the patient takes a statin to control hyperlididemia [see Section 5.1.7.5], then only 
pravastatin may be used with extra caution. Pravastatin has the lowest potential of cause rhabdomyolysis 
compared with other statins  (3 cases/ 6 millions of prescription from 1994 to 2002) (Evans et al. 2002) and the 
lowest risk for drug-drug interactions with LDE225, as it is primarily transformed in the liver cytosol by sulfonation, 
not by CYP2C9 or CYP3A4. (Evans et al. 2002) 
 
 
Warfarin and coumadin derivatives 
Therapeutic doses of warfarin sodium (Coumadin®) or any other coumadin-derivative anticoagulants are 
not permitted since LDE225 is a competitive inhibitor of CYP2C9 based on the in vitro data. An 
alternative, therapeutic anticoagulation may be accomplished using low-molecular weight heparin. 
 Drugs that may increase risk of rhabdomyolysis when used concomitantly with LDE225  
Selected drugs that may increase risk of myopathy and rhabdomyolysis when used concomitantly with 
LDE225 should be avoided. Such drugs should be discontinued for at least 2 weeks prior to initiation of 
LDE225 and it must be ensured the plasma CK is within the normal range at baseline. The list compiled 
below is based on reported association of the individual drugs with muscle toxicity and in addition to the 
potential risk of clinically relevant PK drug-drug interaction with LDE225 through inhibitory effects on 
CYP3A4 
 (enzyme metabolized  LDE225) or the inhibitory effect on CYP2C9 by LDE225 of drugs that may 
induced rhabdomyolysis. 
• 
Azoles antifungals:   Itraconazole, ketoconazole,  fluconazole,  voriconazole 
• 
Macrolides:   azithromycin,  clarithromycin,  erythromycin,  telitromycin 
• 
Fibrates: gemfibrozil 
• 
3-hydroxy-3 methyl-glutaryl (HMG) Coa reductase inhibitors ( Statins): Atovastatin, 
Fluvastatin, Fluvastatin XL, Lovastatin, Pravastatin*,  Rosuvastatin-  and Simvastatin 
• 
Antiretrovirals: Indonavir and ritonavir 
Others: phenobarbital, barbiturates,  phenytoin and isoniazid 
 
* If it is essential that the patient stays on a statin to control hyperlididemia [see Section 5.1.7.5], only 
pravastatin may be used with extra caution; CK should be monitored weekly during the first 8 weeks on 
concomitant treatment with LDE225 and then bi-weekly thereafter for 8 weeks and then every four weeks 


 
Appendix II 
 
MC128B 
 
Protocol version date:  25Jul2018 
 
 
ECOG Performance Status Scale 
 
 
SCORE  
DESCRIPTION  
0  
Fully active, able to carry on all pre-disease performance without 
restriction.  
1  
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, office 
work.  
2  
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.  
3  
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours.  
4  
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair.  
5  
Dead.  
 
 


MC128B 
Appendix III 
 
Page 1 of 1 
 
Protocol version date:  25Jul2018 
 
NYHA Classification 
 
Class I:  
NO Symptoms with ordinary activity  
Class II:  
Symptoms with ordinary activity  
Class III:  Symptoms with minimal activity 
Class IV:  Symptoms at rest 
 
 




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Appendix IV 
 
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