Conditions: POEMS Syndrome
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
This trial investigates the use of Daratumumab (DARA), an antibody directed at the human cluster of differentiation 38 (CD38) molecule, for the treatment of patients with Polyneuropathy, Organomegaly, Endocrinopathy, m Protein Component, Skin Changes (POEMS) syndrome. This trial will enroll ten subjects, who will complete 12 four-week cycles of DARA, in combination with the immunomodulatory drug (IMiD) lenalidomide. Objectives of this study include improvement in neuropathy and performance status, as well as improvement in laboratory values and survival.

Detailed description:
This trial investigates the use of DARA, an antibody directed at the human CD38 molecule, for the treatment of patients with POEMS syndrome. This trial will enroll ten subjects, who will complete 12 four-week cycles of DARA, in combination with the IMiD lenalidomide. Objectives of this study include improvement in neuropathy and performance status, as well as improvement in laboratory values and survival.

Patients will receive DARA in the outpatient setting, with infusions being administered in Infusion 4. Safety and response assessments will occur prior to Cycles 1 through 6, and at the end of DARA treatment. Once DARA is completed, response assessments are completed every 6 months for the first year, then annually until disease progression. Subjects will also be followed for overall survival.

Arms:
arm 1: Up to 12 four-week cycles of Daratumumab (DARA), in combination with the immunomodulatory drug (IMiD) lenalidomide.

DARA is injected. Dosage calculated by weight.On Cycles 1 and 2, DARA is given on Days 1, 8,15 and 22. On Cycles 3-6,DARA is given on Days 1 and 15. On Cycles 7-12, DARA is given on Day 1.

Lenalidomide is taken by mouth. 15 mg on Days 1-21 of each cycle.

Interventions: intervention 1: Daratumumab Injection
Intervention descriptions: intervention 1: DARA is a human monoclonal antibody that specifically recognizes the CD38 molecule that is expressed at a high level in a variety of hematological malignancies, including myeloma cells.

DARA injection will be given with oral lenalidomide for up to 12 four week cycles.

Protocol document:
Prot_SAP_000.pdf: 
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IRB# 207442 
A PHASE II TRIAL FOR THE TREATMENT OF POEMS SYNDROME WITH DARATUMUMAB 
Principal Investigator 
Frits van Rhee, MD PhD 
Myeloma Center 
Sponsor:  University of Arkansas for Medical Sciences 
Funding:   Janssen Scientific Affairs, LLC 
NCT04396496


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TABLE OF CONTENTS 
1.0 
Objectives ......................................................................................................................................................... 5 
1.1 
Primary Objectives ........................................................................................................................................ 5 
1.2 
Secondary Objectives .................................................................................................................................... 5 
 
Background and Rationale ................................................................................................................................ 6 
2.1 
Clinical Description of POEMS Syndrome ..................................................................................................... 6 
2.2 
Treatment of POEMS Syndrome ................................................................................................................. 11 
2.3 
Monitoring Response of POEMS Syndrome ............................................................................................... 14 
2.4 
Daratumumab ............................................................................................................................................. 15 
2.5 
Nonclinical Studies with Daratumumab ..................................................................................................... 15 
2.6 
Clinical Studies with Daratumumab ............................................................................................................ 16 
2.7 
Safety Profile of Daratumumab .................................................................................................................. 21 
2.8 
Daratumumab Pharmacokinetics ............................................................................................................... 23 
 
Study PopulatIon............................................................................................................................................. 24 
3.1 
Number of Subjects .................................................................................................................................... 24 
3.2 
Inclusion Criteria ......................................................................................................................................... 24 
3.3 
Exclusion Criteria ........................................................................................................................................ 24 
3.4 
Design and Methods ................................................................................................................................... 26 
 
Treatment Plan ............................................................................................................................................... 26 
4.1 
Treatment Overview ................................................................................................................................... 26 
4.2 
Investigational Agent .................................................................................................................................. 27 
4.3 
Dosing Schedule .......................................................................................................................................... 31 
4.4 
Drug Accountability .................................................................................................................................... 31 
4.5 
Radiation ..................................................................................................................................................... 31 
 
Dosage Modifications ..................................................................................................................................... 32 
 
Schedule of Evaluations .................................................................................................................................. 32 
6.1 
Laboratory Tests and Evaluations ............................................................................................................... 32 
6.2 
Screening Procedures ................................................................................................................................. 35 
6.3 
Treatment Procedures ................................................................................................................................ 35 
6.4 
End of Dara Treatment Procedures ............................................................................................................ 35 
6.5 
Progression Free Survival/Overall Survival Follow Up Procedures ............................................................. 36 
 
Definitions of Safety Events ............................................................................................................................ 36 
7.1 
Definitions ................................................................................................................................................... 36 
 


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7.2 
Monitoring, Recording, and Reporting of Safety Events ............................................................................ 41 
7.3 
Subject Confidentiality ................................................................................................................................ 45 
7.4 
Investigator Responsibilities ....................................................................................................................... 45 
7.5 
Protocol Amendments ................................................................................................................................ 46 
7.6 
Suspension of Study .................................................................................................................................... 46 
7.7 
Protocol Deviations ..................................................................................................................................... 46 
 
Ethical and Regulatory Considerations ........................................................................................................... 46 
8.1 
Informed Consent ....................................................................................................................................... 46 
8.2 
Institutional Review .................................................................................................................................... 47 
8.3 
Case Report Forms ...................................................................................................................................... 47 
8.4 
Subject Confidentiality ................................................................................................................................ 48 
8.5 
Record Retention ........................................................................................................................................ 48 
 
Statistical Considerations ................................................................................................................................ 48 
9.1 
Definition of Success ................................................................................................................................... 48 
9.2 
Accrual and Study Duration ........................................................................................................................ 49 
9.3 
Sample Size and Power ............................................................................................................................... 49 
9.4 
Toxicity ........................................................................................................................................................ 49 
9.5 
Secondary Endpoints .................................................................................................................................. 49 
 
Ancillary Studies .............................................................................................................................................. 49 
10.1 
Participation, Confidentiality, and Future Studies ...................................................................................... 49 
10.2 
Molecular Studies of CD138-purified Plasma Cells and Bone Marrow Biopsies ........................................ 50 
10.3 
Mass Cytometry/Proteomics Profiling Studies of Peripheral Blood ........................................................... 50 
 
References ...................................................................................................................................................... 51 
 
Appendix I – Diagnostic Criteria for POEMS SYNDROME ............................................................................... 64 
 
Appendix II – Overall Neuropathy Limitations Scale ...................................................................................... 65 
 
Appendix III – IMWG Response Criteria and Survival Outcome Definitions................................................... 66 
 
Appendix IV - Performance Status Scale and Adverse Event Grading ............................................................ 72 
 
Appendix V - Criteria for Removal from Treatment and Study ...................................................................... 73 
 
Appendix V - Institutional Daratumumab Protocol ........................................................................................ 74 
17.1 
Background ................................................................................................................................................. 74 
17.2 
Usual Dosage .............................................................................................................................................. 74 
17.3 
Standard Dilution and Titration Parameters .............................................................................................. 74 
17.4 
Rapid Infusion ............................................................................................................................................. 74 
17.5 
Pre- and Post-Infusion Medications ........................................................................................................... 75 


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17.6 
Recommended Monitoring ......................................................................................................................... 75 
17.7 
Common Side Effects .................................................................................................................................. 75 
17.8 
Management of Adverse Reactions ............................................................................................................ 76 
 
Appendix VI – List of Abbreviations ................................................................................................................ 77 
 
 
 


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PROTOCOL SUMMARY 
This trial investigates the use of Daratumumab (DARA), an antibody directed at the human CD38 
molecule, for the treatment of patients with POEMS syndrome. This trial will enroll ten subjects, who 
will complete 12 four-week cycles of DARA, in combination with the immunomodulatory drug (IMiD) 
lenalidomide. Objectives of this study include improvement in neuropathy and performance status, as 
well as improvement in laboratory values and survival. Details of the study are outlined herein. 
1.0 OBJECTIVES 
1.1 Primary Objectives 
POEMS syndrome is paraneoplastic to typically a low-grade clonal plasma cell (PC) disorder or 
isolated plasmacytoma. The preferred therapy of autologous peripheral blood stem cell transplant 
(PBSCT) poses risks in terms of morbidity and mortality. The study will test the efficacy of DARA 
and lenalidomide avoiding autologous PBSCT. Patients with POEMS syndrome often have a poor 
performance status and are significantly debilitated by their progressive polysensorimotor 
neuropathy. The primary endpoints will address these critical parameters by measuring: 
a) Improvement in Overall Neuropathy Limitations Scale (ONLS) 
b) Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status 
This study will also evaluate the safety of DARA when used in combination of lenalidomide for 
subjects with POEMS syndrome. 
1.2 Secondary Objectives 
Reduction in size of the PC clone often accompanies response. The clonal PC burden will be 
assessed using the International Myeloma Working Group (IMWG) criteria. Vascular endothelial 
growth factor (VEGF) is a critical cytokine thought to be crucial to the pathogenesis of POEMS 
syndrome.  VEGF levels will be followed as an additional secondary endpoint.  The duration of 
improvement in ONLS, progression-free survival (PFS) and overall survival (OS) will be further 
secondary endpoints.  In summary secondary endpoints are: 
a) PC response using IMWG criteria 
b) Reduction in VEGF levels 
c) Duration of improvement in ONLS 
d) PFS 
e) OS 


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 BACKGROUND AND RATIONALE 
2.1 Clinical Description of POEMS Syndrome 
POEMS syndrome is a paraneoplastic syndrome secondary to a PC dyscrasia. It is a rare disorder 
with a reported prevalence of approximately 0.3 per 100,000.1  The peak incidence of the POEMS 
syndrome is in the 5th and 6th decades of life, unlike multiple myeloma (MM), which has a peak 
incidence in the 7th and 8th decades. The acronym POEMS stands for Polyneuropathy, 
Organomegaly, Endocrinopathy, Monoclonal Protein, and Skin Changes. Other clinical features 
can be present as well including extravascular volume overload (peripheral edema, pleural 
effusions, ascites), sclerotic bone lesions, thrombocytosis, Castleman Disease (CD) and elevated 
levels of vascular endothelial growth factor. The constellation of progressive polysensorimotor 
neuropathy and any of the following should prompt evaluation for POEMS syndrome: monoclonal 
protein (especially lambda light chain); thrombocytosis; anasarca; or papilledema. The diagnosis 
of POEMS syndrome is made based on a composite of clinical and laboratory features (Appendix 
I).2 The diagnosis of POEMS syndrome is confirmed when both of the mandatory major criteria, 
one of the three other major criteria, and one of the six minor criteria are present. 
 
POLYNEUROPATHY 
The neuropathy is the dominant characteristic of the syndrome. The quality and extent of the 
neuropathy, which is peripheral, ascending, symmetrical, and affecting both sensation and motor 
function should be elicited.3 It starts as a sensory neuropathy and motor symptoms typically 
dominate over time. Patients are areflexic and typically have a steppage gait and a positive 
Romberg sign. 
Nerve conduction studies in patients with POEMS syndrome show slowing of nerve conduction that 
is more predominant in the intermediate than distal nerve segments as compared to chronic 
inflammatory demyelinating polyneuropathy (CIDP), and there is more severe attenuation of 
compound muscle action potentials in the lower than upper limbs.1,4-7 In contrast to CIDP, 
conduction block is rare. The conduction findings could suggest that demyelination is predominant 
in the nerve trunk rather than the distal nerve terminals and axonal loss is predominant in the lower 
limb nerves.1 Axonal loss is greater in POEMS syndrome than it is in CIDP.7 
 
 
 


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MONOCLONAL PC DISORDER AND HEMATOLOGIC FINDINGS 
The size of the M-protein on electrophoresis is typically small (median 1.1 g/dL) and is rarely more 
than 3.0 g/dL. The M-protein is usually IgG or IgA and almost always of the lambda type.8,9 
Laboratory findings are notable for an absence of cytopenias. In fact, nearly half of patients will 
have thrombocytosis or erythrocytosis.8 In the series of Li and colleagues, 26% of patients had 
anemia, which the authors attributed to impaired renal function.10 Their series was enriched with 
CD cases (25%), which may have also contributed to this unprecedentedly high rate of anemia. 
Bone marrow (BM) usually contains < 5% PCs, and again when clonal cells are found they are 
almost always monoclonal lambda.  Little is known about the PCs in POEMS syndrome except that 
more than 95% of the time they are lambda light chain restricted with restricted immunoglobulin 
light chain variable gene usage (IGLV1).11-13 Translocations and deletion of chromosome 13 have 
been described, but hyperdiploidy is not seen.14,15 The BM biopsy reveals megakaryocyte 
hyperplasia and megakaryocyte clustering in 54% and 93% of cases, respectively.16 One-third of 
patients do not have clonal PCs on their iliac crest biopsy.  These are the patients who present with 
a solitary or “multiple solitary plasmacytomas.” The other two-thirds of patients have clonal PCs in 
their BM, and 91% of these cases are clonal lambda. Immunohistochemical staining is more 
sensitive than 6-color flow since the former provides information on BM architecture, which is key 
in making the diagnosis in nearly half of cases. In a study by Dispenzieri et al. of 67 pretreatment 
BMs biopsies from patients with POEMS syndrome, lymphoid aggregates were found in 49% of 
cases.17 Of these, there was PC rimming in all but one, and in 75% and 4% the rimming was clonal 
lambda and kappa, respectively.  This finding was not seen in BMs from normal controls or from 
patients with monoclonal gammopathy of undetermined significance (MGUS), MM, or amyloidosis. 
Overall, only 8/67 (12%) of POEMS cases had normal iliac crest BM biopsies, i.e. no detectable 
clonal PCs, no PC rimmed lymphoid aggregates, and no megakaryocyte hyperplasia. 
 
BONE LESIONS 
Osteosclerotic lesions occur in approximately 95% of patients and can be confused with benign 
bone islands, aneurysmal bone cysts, non-ossifying fibromas, and fibrous dysplasia.9,18-20 Some 
lesions are densely sclerotic, while others are lytic with a sclerotic rim, while still others have a 
mixed soap-bubble appearance.  Bone windows of CT body images are often very informative, 
even more so than fluorodeoxyglucose (FDG)-uptake, which can be variable.21,22 FDG-uptake 
occurs in those lesions which have a lytic component.23 The advantage of whole-body CT 
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or CT- positron emission tomography (PET) is that other features of the disease are also seen: 
effusions, ascites, adenopathy, and hepatosplenomegaly. 
 
EXTRAVASCULAR VOLUME OVERLOAD 
Extravascular fluid overload most commonly manifests as peripheral edema, but pleural effusion, 
ascites, and pericardial effusions are also common. The composition of the ascites was studied in 
42 patients with POEMS syndrome. The ascitic fluid had low serum ascites albumin gradients 
consistent with an exudative rather than a portal hypertension process in 74% of cases.24 
 
VASCULAR ENDOTHELIAL GROWTH FACTOR AND OTHER CYTOKINES 
Plasma and serum levels of VEGF are markedly elevated in patients with POEMS and correlate 
with the activity of the disease.25-28 The principal isoform of VEGF expressed is VEGF165.25 VEGF 
levels are independent of M-protein size, and increased VEGF has been found in ascitic fluid and 
the cerebrospinal fluid.25,26,29 IL-1β, TNF-α and IL-6 levels are often also increased. Serum VEGF 
levels are 10-50 times higher than plasma levels of VEGF.30 In patients with POEMS, VEGF is 
found in both PCs and platelets.31-33 The higher level observed in serum is attributable to the release 
of VEGF from platelets in vitro during serum processing. Because plasma is a product of an 
anticoagulated sample, there is less platelet activation and therefore less platelet VEGF 
contributing to the plasma measurement than the serum sample. Tokashiki et al. suggest that 
serum VEGF is the better test because it reflects the VEGF contribution from both the serum and 
platelets.30 However, the counter-argument is that the amount of VEGF release by platelets may 
vary due to collection and processing technique, making serum measurements of VEGF less 
reliable. Investigators from the Mayo Clinic have demonstrated that a plasma VEGF level of 200 
pg/mL had a specificity of 95% with a sensitivity of 68% in support of a diagnosis of POEMS 
syndrome.17 Other diseases with high VEGF include connective tissue disease, vasculitis, and 
CD.27 Others have shown that a serum level of 1,920 pg/mL is diagnostic of POEMS with a 
specificity of 98% and a sensitivity of 73%.34 
 
ORGANOMEGALY 
As many as three-quarters of patients will have organomegaly, but other series would suggest that 
it occurs in only one-quarter of patients. 8-10,18,35,36 Any or all of liver, spleen, and lymph nodes can 
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also have documented CD or Castleman-like histology.9,10,18,35,37 In 30 patients with POEMS 
syndrome, 19 of 32 biopsied lymph nodes showed angiofollicular hyperplasia typical of CD.18 In 
another series, 25 of 43 biopsied lymph nodes were diagnostic of CD and 84% of these had hyaline 
vascular type.10 
CD (or angiofollicular lymph node hyperplasia) is a rare lymphoproliferative disorder which has 
many presentations, ranging from an asymptomatic unifocal mass to multifocal masses with a 
multitude of symptoms. The symptoms can range from simple B-symptoms to various autoimmune 
phenomenon to a severe inflammatory disorder leading to multi-organ failure and death.9,18,35,38-59 
 
ENDOCRINOPATHY 
Endocrinopathy is a central but poorly understood feature of POEMS. In one large series, 
approximately 84% of patients had a recognized endocrinopathy, with hypogonadism as the most 
common endocrine abnormality, followed by thyroid abnormalities, glucose metabolism 
abnormalities, and lastly by adrenal insufficiency.36 
 
SKIN FINDINGS 
A whole skin examination should be performed looking for hyperpigmentation, a recent out-
cropping of hemangioma, hypertrichosis, dependent rubor and acrocyanosis, lipodystrophy, white 
nails, sclerodermoid changes, facial atrophy, flushing or clubbing.8,10,35,60-64 
The histologic findings of the dermis have been reported to range from non-specific to glomeruloid 
hemangiomata to vascular abnormalities in apparently normal dermis.65-67  Biopsies of normal-
appearing skin demonstrated an extremely complex subpapillary vascular network with largely 
dilated and frequently anastomotic vessels.68 Capillary loops appeared more complex than normal, 
and most of them were probably clotted. 
 
PAPILLEDEMA 
Papilledema is present in at least one-third of patients. Of the 33 patients at the Mayo Clinic referred 
for a formal ophthalmologic examination during a 10-year period, 67% had ocular signs and 
symptoms, the most common of which was papilledema in 52% of those examined.69 The most 
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another series of 94 patients, papilledema, which was found in approximately 50% of patients, was 
an adverse prognostic feature for overall survival.70 
 
RESPIRATORY FINDINGS 
The pulmonary manifestations are protean, including pulmonary hypertension, restrictive lung 
disease, impaired neuromuscular respiratory function, and impaired diffusion capacity of carbon 
monoxide, but improve with effective therapy.71,72 Respiratory complaints are usually limited given 
patients’ neurologic status impairing their ability to induce cardiovascular challenges. In a series of 
137 POEMS syndrome patients seen at the Mayo Clinic between 1975 and 2003, at presentation, 
the frequency with which patients reported dyspnea, chest pain, cough, and orthopnea, were 20%, 
10%, 8%, and 7%, respectively.71 Nearly 25% had significant chest X-ray abnormalities. 
Pulmonary hypertension has been reported to occur in approximately 25% of patients with POEMS 
syndrome.72,73 It is more likely to occur in patients with extravascular overload. Whether the digital 
clubbing seen in POEMS is a reflection of underlying pulmonary hypertension and/or parenchymal 
disease is yet to be determined. Impaired diffusing capacity of the lungs for carbon monoxide 
(DLCO) has been shown to be an adverse prognostic factor in another series.70 
 
RENAL FINDINGS 
Serum creatinine levels are normal in most cases. Fewer than 10% of patients have proteinuria 
exceeding 0.5 g/24 hours, and only 6% have serum creatinine greater than or equal to 1.5 mg/dL. 
Four percent of patients developed renal failure as preterminal events.9 In another series from 
China, 37% of patients had a creatinine clearance (CrCl) of less than 60 ml/min/m2, and 9% had a 
CrCl of less than 30 ml/min and 15% had microhematuria.10 The estimate of CrCl less than 60 
mL/min/m2 has recently been revised to 22% of patients by the same group from China.74 In our 
experience, renal disease is more likely to occur in patients who have co-existing CD. In POEMS 
syndrome, the renal histologic findings are diverse with membranoproliferative features and 
evidence of endothelial injury being most common.75 On both light and electron microscopy, 
mesangial expansion, narrowing of capillary lumina, basement membrane thickening, sub-
endothelial deposits, widening of the sub-endothelial space, swelling and vacuolization of 
endothelial cells, and mesangiolysis predominate.76-82 Standard immunofluorescence is negative, 
which differentiates it from primary membranoproliferative glomerulitis.75,77,83 Rarely, infiltration by 
PCs nests or Castleman-like lymphoma can be seen.82 
 


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THROMBOSIS 
Patients are at increased risk for arterial and/or venous thrombosis during their course, with nearly 
20% of patients experiencing one of these complications.84,85 Lespirit et al. observed 4 of 20 
patients to have arterial occlusion.84 In the Mayo series, there were 18 patients suffering serious 
events such as stroke, myocardial infarction, and Budd-Chiari syndrome.9 Affected vessels include 
carotid, iliac, celiac, subclavian, mesenteric, and femoral.86-89 Ten percent of patients present with 
a cerebrovascular event, most commonly embolic or vessel dissection and stenosis.90 The POEMS 
associated strokes tend to end artery border-zone infarctions.89 The median time between 
peripheral neuropathy symptom onset and the cerebrovascular event was 23 months (range 0.5 to 
64 months). Risk factors for cerebral events included thrombocytosis and BM plasmacytosis. 
Aberrations in the coagulation cascade have been implicated in POEMS syndrome.91 
 
2.2 Treatment of POEMS Syndrome 
The therapy of POEMS syndrome is directed at the clonal PC disorder. Patients with isolated 
plasmacytomas, without generalized BM involvement, are treated with localized irradiation. Not 
only does radiation to an isolated (or even two or three isolated) lesion(s) improve the symptoms 
of POEMS syndrome over the course of 3–36 months, but it can be curative. In a series of 35 
patients with POEMS syndrome treated at the Mayo Clinic, radiation was used as primary therapy.92 
This resulted in a 4‐year OS of 97% and a 4‐year PFS of 52%. More than half the “failures” occurred 
within 12 months of radiation. An update of this series, which now included 91 patients receiving 
radiation therapy, the 10‐year OS was 70% and the 6‐year PFS was 62%.93,94 In a review of 
radiation therapy in the management of POEMS syndrome from South Korea, 6 patients had 
radiotherapy as primary therapy—two of whom had multiple lesions, but were deemed too sick for 
chemotherapy—and 7 patients received consolidative radiotherapy for persistent M‐spike and/or 
persistent clinical symptoms.95 The response rates in this series for radiation alone were 
comparable to that of the Mayo series, but in the Korean series, both OS and PFS were inferior 
among those patients who received radiation therapy alone largely due to the fact that these 
patients were sicker at time of treatment. 
Patients with a disseminated, clonal PC disorder, typically characterized by BM involvement, are 
treated with agents used for multiple myeloma. There are no published randomized clinical trials 
pertaining to POEMS syndrome, treatment recommendations are largely based on case series and 
anecdotes. Corticosteroids may provide symptomatic improvement, but response duration is 
limited. The most experience has been with an alkylator‐based therapy, either low dose or high 


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dose with PBSCT. The first prospective clinical trial to treat POEMS syndrome included 31 patients 
who were treated with 12 cycles of melphalan and dexamethasone.96 The authors found that 81% 
of patients had a hematologic response, 100% had VEGF response and 100% with at least some 
improvement in neurologic status. A limitation of this study is that follow‐up was only 21 months, 
so long‐term outcomes are not yet available.  
High dose alkylator therapy with melphalan followed by autologous PBSCT is considered by many 
to be the treatment of choice. It is highly effective, but selection bias may confound reports. Case 
series suggest 100% of patients achieve significant neurologic improvement.63,77,97-111 Doses of 
melphalan ranging from 140 to 200 mg/m2 have been used, with the lower doses used for sicker 
patients. Anecdotally, responses are durable, but relapses have been reported.112,113 Of the 59 
patients with POEMS syndrome treated at the Mayo Clinic Rochester, PFS was 98%, 94%, and 
75% at 1, 2, and 5 years, respectively.110 Updated data on a larger dataset of 80 patients revealed 
a 6‐year PFS of 72% and a 10‐year OS of 89%.93 However, there is considerable treatment-related 
morbidity and mortality associated with PBSCT including engraftment syndrome characterized by 
fevers, rash, diarrhea, and weight gain, occurring anytime between days 7 and 15 and more 
severely afflicted patients may be prone to pulmonary complications. Patients with splenomegaly 
may also have a complicated transplant course with delayed engraftment and more need for red 
cell and platelet transfusions. 
Targeting VEGF with the antibody bevacizumab is attractive, but has been met with mixed results. 
Five patients who had also received either radiation or alkylator during and/or predating the 
bevacizumab had benefit, including three who had improvement but was then consolidated with 
high‐dose chemotherapy with autologous PBSCT.114-116 However, three patients receiving 
bevacizumab died raising the concern that interruption of ‘dependence’ on VEGF can cause 
circulatory collapse.112,117,118 In view of these results most experts avoid the use of bevacizumab in 
POEMS syndrome. 
Thalidomide and bortezomib have also anti-VEGF effects and have been explored in POEMS 
syndrome. Bortezomib has been used in 25 patients.119-123 The first report is difficult to interpret 
since the patient had a number of chemotherapies prior to receiving a bortezomib, doxorubicin, and 
dexamethasone combination. There was early evidence of improvement even before starting the 
bortezomib regimen. The other reports as a single agent, with dexamethasone, or with 
dexamethasone and cyclophosphamide all showed significant improvements in patients without 
any worsening of the peripheral neuropathy. Finally, the largest series was from Shanghai 
Changzheng Hospital in which 20 patients with newly diagnosed POEMS syndrome were treated 
with 3–6 cycles of cyclophosphamide, reduced dose bortezomib, and dexamethasone.124 The 


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overall hematologic response rate was 76% with 7 patients achieving complete hematologic 
response; 88% had VEGF response. Ninety‐five percent of patients had a reduction of the ONLS 
by 1 or more. No neurologic worsening was observed. Thalidomide in combination with 
dexamethasone has also shown to produce responses in terms of VEGF, peripheral neuropathy, 
and extravascular volume overload, but hematologic responses have not been reported.125-128 
Enthusiasm for this therapy should be tempered by the risk of peripheral neuropathy induced by 
this drug. Misawa et al. have reported on a 25 patient 24‐week randomized double-blind trial of 
thalidomide plus dexamethasone versus dexamethasone alone for patients ineligible for 
autologous PBSCT.129 VEGF levels dropped faster in patients treated with thalidomide, though 
there were no significant differences in other endpoints between the two groups at 24 weeks. 
During the 72‐week open-label extension study, nerve conduction velocities increased as 
compared to baseline. 
Lenalidomide, which has a low incidence of peripheral neuropathy, is a more attractive alternative 
to thalidomide.  The French have reported in abstract form their results of a Phase 2 study of 
lenalidomide and dexamethasone for 2 cycles as neoadjuvant therapy preceding radiation or high 
dose therapy or as primary therapy as 9 cycles followed by 12 cycles of single-agent 
lenalidomide.130 They have treated 27 patients: 10 pre-radiation therapy, 8 pre‐ASCT, and 9 as 
primary therapy. Although follow‐up is short, the authors report that several patients had a rapid 
neurological response, no patient had died, and 1 patient had progressed. These results are similar 
to previous case reports and case series though relapses have been reported.131-133 In the largest 
case series of 20 patients, all patients responded, but 4 patients relapsed 3–10 months after the 
end of treatment.110 Three of these treatment failures responded to further therapy, including one 
who responded to reintroduction of the lenalidomide-dexamethasone combination. 
The anti-CD38 monoclonal antibody DARA in combination with lenalidomide is an important 
addition to the anti-MM therapeutic armamentarium. Excellent results have been reported in the 
treatment of both relapsed and newly diagnosed MM.134-137 In addition, several reports highlight the 
efficacy of DARA in AL- amyloidosis, which in analogy to POEMS syndrome, is characterized by 
the presence of a low-grade PC dyscrasia.  Lenalidomide has an immunostimulatory effect, which 
synergizes with the immunologic effects of DARA.  This prompted us to treat a POEMS patient who 
relapsed after autologous PBSCT with a combination of lenalidomide and DARA, which resulted in 
normalization of VEGF levels, complete hematologic response and major neurologic improvement. 
The clinical course of this patient is depicted in Figure 1.138 The combinatorial efficacy of 
lenalidomide and DARA in PC dyscrasia forms the rational of the present clinical trial exploring 
these agents in POEMS syndrome as a non-toxic alternative to autologous PBSCT and its 


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associated risks.  Both drugs have an excellent side effect profile and are well-tolerated both alone 
and in combination. 
 
Figure 1. Clinical Course of POEMS Patient Treated with Daratumumab. The percentage of myelomatous PCs by 
8-color flow cytometry in the BM (red) and serum levels of VEGF (yellow) and IgA (blue) are depicted. Noted treatments 
were applied (arrows) and response calls made (dashed lines) at indicated times calculated in months after initial 
disease presentation (x-axis).  
 
2.3 Monitoring Response of POEMS Syndrome 
There is no consensus regarding response to treatment criteria in POEMS syndrome. Evaluating 
the hematological response can sometimes prove difficult given the small size of the monoclonal 
peak often associated with a hypergammaglobulinemia and the light chain ratio can be normal.  On 
the other hand, the now routine minimal residual testing does allow for accurate quantification of 
the number of clonal cells in the BM; hematologic response will, therefore, be a secondary objective 
and will be assessed by standard criteria from the IMWG. Monitoring the VEGF levels has also 
been used and will be an additional secondary objective to measure response.  Organ toxicity, 
especially affecting the peripheral nervous system and overall functional status are the most 


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debilitating features of POEMS syndrome. The performance status is therefore a primary endpoint 
and will be evaluated by ECOG score. ONLS is a simple tool to evaluate neurologic functioning 
and will be a further primary endpoint.139 
 
2.4 Daratumumab 
DARA is a human IgG1k monoclonal antibody that binds with high affinity to a unique epitope on 
CD38. It is a targeted immunotherapy that attacks tumor cells that overexpress CD38, a 
transmembrane glycoprotein, in a variety of hematological malignancies including MM. 
DARA induces lysis of CD38-expressing tumor cells, including MM tumor cells that were freshly 
isolated from patients, by a wide spectrum of mechanisms including complement-dependent 
cytotoxicity, antibody- dependent cell-mediated cytotoxicity, and antibody-dependent cellular 
phagocytosis through activation of complement proteins, natural killer cells, and macrophages, 
respectively.140,141 
DARA is being developed by Janssen Scientific Affairs, LLC  and was approved in November 2015 
by the United States Food and Drug Administration (FDA) for the treatment of patients with multiple 
myeloma who have received at least three prior lines of therapy including a proteasome inhibitor 
(PI) and an IMiD or who are double refractory to a PI and IMiD. Since then it has received additional 
approvals to be used in combination with lenalidomide and dexamethasone or bortezomib and 
dexamethasone for patients that have received at least one prior therapy; in combination with 
bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple 
myeloma who are ineligible for autologous stem cell transplant; and in combination with 
pomalidomide and dexamethasone for the treatment of patients with multiple myeloma who have 
received at least two prior therapies included lenalidomide and a proteasome inhibitor 
2.5 Nonclinical Studies with Daratumumab 
Safety information on DARA has been derived from human and chimpanzee tissue cross-reactivity 
studies, a 6-week repeat dose toxicity study in chimpanzees with dose levels of 5 mg/kg and 
25mg/kg, and a local tolerance study in rabbits. Additionally, a cynomolgus tissue cross-reactivity 
study and a 2-dose study in cynomolgus monkeys have been conducted with the surrogate 
molecule HuMab-CD38. The primary toxicities identified in chimpanzees were infusion-related 
reactions during the first, but not subsequent, DARA infusions, thrombocytopenia, and neutropenia. 
The binding affinity of DARA is ≥15-fold higher for chimpanzee platelets than for human platelets, 
suggesting that thrombocytopenia may be less pronounced in humans. Anemia was observed in 
cynomolgus monkeys. The cynomolgus anti-CD38 binds strongly to cynomolgus monkey red blood 


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cells (RBCs), while DARA shows only a low level of binding to human RBCs, suggesting that the 
anemia may have limited clinical relevance in humans. The effects on platelets and red blood cells 
were reversible. Depletion of specific lymphocyte phenotypic cell populations, as expected, based 
on the intended pharmacological effect of DARA, was observed in both chimpanzees and 
cynomolgus monkeys. 
The local tolerability of subcutaneous infusion of DARA in combination with rHuPH20 was evaluated 
in rabbits. The combination was well tolerated and there were no DARA-related macroscopic or 
microscopic findings. 
 
2.6 Clinical Studies with Daratumumab 
Combination Treatment with Lenalidomide and Dexamethasone 
POLLUX (NCT02076009), an open-label, randomized, active-controlled Phase 3 trial, compared 
treatment with DARZALEX 16 mg/kg in combination with lenalidomide and low-dose 
dexamethasone (DRd) to treatment with lenalidomide and low-dose dexamethasone (Rd) in 
patients with multiple myeloma who had received at least one prior therapy. Lenalidomide (25 mg 
once daily orally on Days 1-21 of repeated 28-day [4-week] cycles) was given with low dose oral 
or intravenous dexamethasone 40 mg/week (or a reduced dose of 20 mg/week for patients 
>75 years or body mass index [BMI] <18.5). On DARZALEX infusion days, 20 mg of the 
dexamethasone dose was given as a pre-infusion medication and the remainder given the day after 
the infusion. For patients on a reduced dexamethasone dose, the entire 20 mg dose was given as 
a DARZALEX pre-infusion medication. Dose adjustments for lenalidomide and dexamethasone 
were applied according to manufacturer’s prescribing information. Treatment was continued in both 
arms until disease progression or unacceptable toxicity. 
 
A total of 569 patients were randomized; 286 to the DRd arm and 283 to the Rd arm. The baseline 
demographic and disease characteristics were similar between the DARZALEX and the control 
arm. The median patient age was 65 years (range 34 to 89 years), 11% were ≥75 years, 59% were 
male; 69% Caucasian, 18% Asian, and 3% African American. Patients had received a median of 1 
prior line of therapy. Sixty-three percent (63%) of patients had received prior autologous stem cell 
transplantation (ASCT). The majority of patients (86%) received a prior PI, 55% of patients had 
received a prior immunomodulatory agent, including 18% of patients who had received prior 
lenalidomide; and 44% of patients had received both a prior PI and immunomodulatory agent. At 
baseline, 27% of patients were refractory to the last line of treatment. Eighteen percent (18%) of 
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evaluated by progression free survival (PFS) based on International Myeloma Working Group 
(IMWG) criteria. 
 
POLLUX demonstrated an improvement in PFS in the DRd arm as compared to the Rd arm; the 
median PFS had not been reached in the DRd arm and was 18.4 months in the Rd arm (hazard 
ratio [HR]=0.37; 95% CI: 0.27, 0.52; p<0.0001), representing 63% reduction in the risk of disease 
progression or death in patients treated with DRd.  
 
 
Figure 2:  Kaplan-Meier Curve of PFS in POLLUX 
 
 
 
 


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Additional efficacy results from POLLUX are presented in Table 1 below. 
 
Table 1: Additional efficacy results from POLLUXa  
 
 
DRd (n=286) 
Rd (n=283) 
Overall response (sCR+CR+VGPR+PR) 
261 (91.3%) 
211 (74.6%) 
p valueb  
<0.0001 
 
Stringent complete response (sCR) 
51 (17.8%) 
20 (7.1%) 
Complete response (CR) 
70 (24.5%) 
33 (11.7%) 
Very good partial response (VGPR)  
92 (32.2%) 
69 (24.4%) 
Partial response (PR) 
48 (16.8%) 
89 (31.4%) 
DRd = daratumumab- lenalidomide-dexamethasone; Rd = lenalidomide-dexamethasone 
 a Based on Intent-to-treat population 
 b p-value from Cochran Mantel-Haenszel Chi-Squared test. 
 
In responders, the median time to response was 1  month (range: 0.9 to 13 months) in the DRd 
group and 1.1 months (range: 0.9 to 10 months) in the Rd group. The median duration of response 
had not been reached in the DRd group (range: 1+ to 19.8+ months) and was 17.4 months (range: 
1.4 to 18.5+ months) in the Rd group.  
With a median follow-up of 13.5 months, 75 deaths were observed; 30 in the DRd group and 45 in 
the Rd group. 
 
Combination Treatment with Bortezomib and Dexamethasone 
CASTOR (NCT02136134), an open-label, randomized, active-controlled Phase 3 trial, compared 
treatment with DARZALEX 16 mg/kg in combination with bortezomib and dexamethasone (DVd), 
to treatment with bortezomib and dexamethasone (Vd) in patients with multiple myeloma who had 
received at least one prior therapy. Bortezomib was administered by SC injection or IV infusion at 
a dose of 1.3 mg/m2 body surface area twice weekly for two weeks (Days 1, 4, 8, and 11) of 
repeated 21 day (3-week) treatment cycles, for a total of 8 cycles. Dexamethasone was 
administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the 8 
bortezomib cycles (80 mg/week for two out of three weeks of the bortezomib cycle) or a reduced 
dose of 20 mg/week for patients >75 years, BMI <18.5, poorly controlled diabetes mellitus or prior 
intolerance to steroid therapy. On the days of DARZALEX infusion, 20 mg of the dexamethasone 
dose was administered as a pre-infusion medication. For patients on a reduced dexamethasone 
dose, the entire 20 mg dose was given as a DARZALEX pre-infusion medication. Bortezomib and 
dexamethasone were given for 8 three-week cycles in both treatment arms; whereas DARZALEX 
was given until disease progression. However, dexamethasone 20 mg was continued as a 
DARZALEX pre-infusion medication in the DVd arm. 
Dose adjustments for bortezomib and dexamethasone were applied according to manufacturer’s 
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A total of 498 patients were randomized; 251 to the DVd arm and 247 to the Vd arm. The baseline 
demographic and disease characteristics were similar between the DARZALEX and the control 
arm. The median patient age was 64 years (range 30 to 88 years); 12% were ≥75 years, 57% 
were male; 87% Caucasian, 5% Asian and 4% African American. Patients had received a median 
of 2 prior lines of therapy and 61% of patients had received prior autologous stem cell 
transplantation (ASCT). Sixty-nine percent (69%) of patients had received a prior PI (66% received 
bortezomib) and 76% of patients received an immunomodulatory agent (42% received 
lenalidomide). At baseline, 32% of patients were refractory to the last line of treatment and the 
proportions of patients refractory to any specific prior therapy were in general well balanced 
between the treatment groups. Thirty-three percent (33%) of patients were refractory to an 
immunomodulatory agent only, with 24% patients in the DVd arm and 33% of patients in the Vd 
arm respectively refractory to lenalidomide. Efficacy was evaluated by progression free survival 
(PFS) based on International Myeloma Working Group (IMWG) criteria. 
 
CASTOR demonstrated an improvement in PFS in the DVd arm as compared to the Vd arm; the 
median PFS had not been reached in the DVd arm and was 7.2 months in the Vd arm (HR [95% 
CI]: 0.39 [0.28, 0.53]; p-value < 0.0001), representing a 61% reduction in the risk of disease 
progression or death for patients treated with DVd versus Vd. 
 
 
 


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Figure 3: Kaplan-Meier Curve of PFS in Castor 
 
 
 
Additional efficacy results from CASTOR are presented in Table 2 below. 
 
Table 2: Additional efficacy results from CASTORa 
 
DVd (n=251) 
Vd (n=247) 
Overall response (sCR+CR+VGPR+PR)  
199 (79.3%) 
148 (59.9%) 
P-valueb 
<0.0001 
 
Stringent complete response (sCR)  
11 (4.4%) 
5 (2.0%) 
Complete response (CR)  
35 (13.9%) 
16 (6.5%) 
Very good partial response (VGPR)  
96 (38.2%) 
47 (19.0%) 
Partial response (PR)  
57 (22.7%) 
80 (32.4%) 
DVd = daratumumab- bortezomib-dexamethasone; Vd = bortezomib-dexamethasone 
a Based on Intent-to-treat population 
b p-value from Cochran Mantel-Haenszel Chi-Squared test. 
 
 
 


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In responders, the median time to response was 0.8 months (range: 0.7 to 4 months) in the DVd 
group and 1.5 months (range: 0.7 to 5 months) in the Vd group. The median duration of response 
had not been reached in the DVd group (range: 1.4+ to 14.1+ months) and was 7.9 months (1.4+ 
to 12+ months) in the Vd group.  
 
With a median follow-up of 7.4 months, 65 deaths were observed; 29 in the DVd group and 36 in 
the Vd group were observed. 
 
2.7 Safety Profile of Daratumumab 
 
Daratumumab may cause serious reactions, including: 
2.7.1 Infusion reactions: 
Infusion reactions are common with Daratumumab and can be severe or serious. 
Infusions temporarily stopped or treatment with Daratumumab completely stopped 
for the following symptoms: 
• 
shortness of breath or trouble breathing 
• 
dizziness or lightheadedness (hypotension) 
• 
cough 
• 
wheezing 
• 
throat tightness 
• 
runny or stuffy nose 
• 
headache 
• 
itching 
• 
nausea 
• 
vomiting 
• 
chills 
• 
fever 
• 
high blood pressure or low blood pressure  
• 
fluid in the lungs (pulmonary edema) 
2.7.2 Changes in blood test: 
Daratumumab can affect the results of blood test to match blood type.  These 
changes can occur for up to 6 months after the final dose of Daratumumab.  Before 


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the start of treatment with Daratumumab a blood test to match blood type can be 
performed.  
2.7.3 Decreases in blood cell count: 
Daratumumab can decrease white blood counts and platelets. 
2.7.4 The most common side effects of Daratumumab include: 
• 
Infusion related reaction (see separate section) 
• 
Infection of the upper respiratory tract such as nose, sinuses throat or upper 
airway 
• 
Infection of the lower airway (bronchitis) 
• 
Infection of the lung (pneumonia) 
• 
Low platelets; may increase the risk of  bruising and bleeding 
• 
Low red blood cells (Anemia) (which can cause fatigue or weakness) 
• 
Low white blood cells (which can make it harder for your body to fight infection)  
• 
Decreased appetite 
• 
Abnormal sensation including numbness/tingling of hands, feet or limbs 
• 
Headache 
• 
Cough 
• 
Shortness of breath, including wheezing  
• 
Constipation 
• 
Diarrhea 
• 
Nausea 
• 
Vomiting 
• 
Rash, a noticeable change in the texture or color of your skin 
• 
Muscle spasms 
• 
Swelling of hands, feet or limbs 
• 
Fatigue, or lack of energy 
• 
Weakness, lack of strength 
• 
Fever 
• 
Back pain 
• 
Sleeplessness (insomnia) 
• 
Joint pain 


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2.7.5 Other common side effects of Daratumumab include: 
• 
Urinary Tract infection 
• 
Influenza or flu like symptoms 
• 
Sepsis (a life-threatening response to an infection) 
• 
High blood glucose levels (Blood sugar levels) 
• 
Low blood calcium levels 
• 
Dehydration (Loss of body fluids) 
• 
Irregular heartbeat 
• 
Chills 
• 
Fluid in lungs (pulmonary edema) 
• 
Dizziness 
• 
Inflammation of the pancreas(pancreatitis) 
• 
Itchy skin 
• 
Muscular pain in chest 
• 
Fainting 
• 
High blood pressure 
• 
Injection site reaction: local reaction reported as mild pain or a burning sensation 
at the site of injection in the abdominal wall. Redness and hardening of the skin 
at the injection site was also observed and usually disappeared within a few 
hours after the administration 
 
 
2.8 Daratumumab Pharmacokinetics 
Pharmacokinetic (PK) data are available from GEN501, MMY2002, and MMY1002 monotherapy 
studies. Doses across these studies ranged from 0.005 to 24 mg/kg. The PK profile was consistent 
with target-mediated disposition with rapid target-related clearance at low doses and slower 
clearance at higher doses. Preliminary PK data from Study GEN503 show that following both the 
first dose and multiple repeated doses, the PK profile of DARA in combination with lenalidomide 
and dexamethasone is similar to what was observed in Study GEN501 following the same dose 
and schedule. The data suggest that lenalidomide and dexamethasone do not affect the PK profile 
of DARA. 
 


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 STUDY POPULATION 
3.1 Number of Subjects 
Ten subjects, both males and females, ages 18 years and older, who meet inclusion and exclusion 
criteria will be eligible for participation in this study. Accrual is expected to take two years to 
complete. 
3.2 Inclusion Criteria 
3.2.1 Patients must have POEMS syndrome and meet the diagnostic criteria for POEMS 
syndrome as described in Appendix I. 
3.2.2 Both newly-diagnosed and relapsed POEMS syndrome will be eligible for inclusion. 
3.2.3 Patients must have a platelet count of ≥ 50,000/µL. 
3.2.4 Patients must be at least 18 years of age.  
3.2.5 Participants must have preserved renal function as defined by a serum creatinine level of < 
3 mg/dL. 
3.2.6 Participants must have an ejection fraction by ECHO or MUGA scan ≥ 40 percent.   
3.2.7 Eastern Cooperative Oncology Group ≥ 1,  
3.2.8 Overall Neuropathy Limitations Scale (ONLS) ≥ 1. 
3.2.9 Patients must have signed an institutional review board (IRB)-approved informed consent 
indicating their understanding of the proposed treatment and understanding that the 
protocol has been approved by the IRB. 
3.3 Exclusion Criteria 
3.3.1 Documented allergy to lenalidomide, DARA, mannitol, other monoclonal antibodies or 
human proteins and mammalian-derived products. 
3.3.2 Prior treatment with DARA or other CD38 monoclonal antibodies 
3.3.3 Patients with central nervous system (CNS) MM involvement.  
3.3.4 Patients who have received an investigational drug or device within 4 weeks prior to 
enrollment or received live attenuated vaccine within 4 weeks prior to enrollment. 
3.3.5 Poorly controlled hypertension, diabetes mellitus, or other serious medical illness or 
psychiatric illness that could potentially interfere with the completion of treatment according 
to this protocol. 
3.3.6 Poor performance status will not be an exclusion criterion since POEMS patients can be 
expected to have significant limitations. 


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3.3.7 Patients must not have prior malignancy, except for adequately treated basal cell or 
squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has 
not received treatment for one year prior to enrollment.  Other cancers will only be accepted 
if the patient’s life expectancy exceeds five years. 
3.3.8 Male and Female subjects and their partners of reproductive potential may not participate 
unless they have agreed to use an effective contraceptive while on study and for 3 months 
after cessation of DARA. 
3.3.9 Males who are unwilling to abstain from sperm donation while on study and for 3 months 
after cessation of DARA. 
3.3.10 Females of childbearing potential must have a negative pregnancy test documented within 
one week of registration. 
3.3.11 Females who are pregnant or nursing women may not participate.  
3.3.12 Patients with POEMS syndrome, who do not have disseminated BM involvement and have 
an isolated plasmacytoma; these patients should be considered for irradiation.  
3.3.13 Subjects has had major surgery within 2 weeks prior to enrollment. 
3.3.14 Clinically significant cardiac disease, including myocardial infarction within the past 6 
months or unstable or uncontrolled conditions (e.g., unstable angina or congestive heart 
failure) or other cardiac disease which in the opinion of the investigator would constitute a 
hazard for participating in the study. Some cardiac dysfunction is expected in this 
population.  
3.3.15 Participant has known chronic obstructive pulmonary disease (COPD) (defined as a forced 
expiratory volume in 1 second [FEV1] <50% of predicted normal, forced vital capacity 
(FVC), etc.] and diffusion capacity (DLCO) < 40% of predicted.), known moderate or severe 
persistent asthma within the last 2 years or currently has uncontrolled asthma of any 
classification (controlled intermittent asthma or controlled mild persistent asthma is 
allowed).  Exception may be granted if the principal investigator documents that the patient 
is a candidate for therapy since alternative therapies will at least have similar or not more 
toxicity.   
3.3.16 Participant with known or suspected COPD must have an FEV1 test during screening. 
3.3.17 Subjects who are seropositive for human immunodeficiency virus (HIV). 
3.3.18 Subjects who are seropositive for hepatitis B (defined by a positive test for hepatitis B 
surface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg 
negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies 
to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase 
chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are 


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PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of 
HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of 
prior HBV vaccination, do not need to be tested for HBV DNA by PCR. 
3.3.19 Subjects who are seropositive for hepatitis C except in the setting of a sustained virologic 
response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy). 
 
3.4 Design and Methods 
The treatment schema is defined in Table 3. Patients will receive DARA in the outpatient setting, 
with infusions being administered in Infusion 4. Safety and response assessments will occur prior 
to Cycles 1 through 6, and at the end of DARA treatment. Once DARA is completed, response 
assessments are completed every 6 months for the first year, then annually until disease 
progression. Subjects will also be followed for overall survival.  
 
 TREATMENT PLAN 
4.1 Treatment Overview 
Table 3. Schema 
Cycle 1*-2 
Daratumumab 
16 mg/kg IV Days 1*, 8, 15, 22 
*At the discretion of the investigator, the first DARA dose may be split over 2 
days, i.e., 8 mg/kg on day 1 and 8 mg/kg on day 2. 
Lenalidomide 
15mg PO Days 1-21 q28 
Cycle 3-6 
Daratumumab 
16 mg/kg IV Days 1, 15 
Lenalidomide 
15mg PO Days 1-21 q28 
Cycle 7-12 
Daratumumab 
16 mg/kg IV Day 1 
Lenalidomide 
15mg PO Days 1-21 q28 
Cycle 13+ 
(At PI Discretion) 
Lenalidomide 
15mg PO Days 1-21 q28 
 
 
 


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4.2 Investigational Agent 
4.2.1. Description 
DARA is a human monoclonal antibody that specifically recognizes the CD38 molecule that is 
expressed at a high level in a variety of hematological malignancies, including myeloma cells. Because 
MM tumor cells express high numbers of CD38, a treatment regimen targeting CD38 could be 
beneficial for subjects with MM. Product for the clinical trial will be provided by the manufacturer free 
of charge and sent to the UAMS Research Pharmacy. 
 
4.2.2 Preparation 
Infusion solution will be prepared as a dilution of DARA in sterile, pyrogen-free 0.9% NaCl. Preparation 
of infusion bags should be done on the day of the planned infusion. DARA must be administered as an 
IV infusion given through a well-functioning IV catheter by using an infusion pump or syringe pump. 
The study drug must be filtered by using an inline filter (0.2 μM) during the infusion. Preparation of 
DARA will be performed according to the package insert. 
 
4.2.3 Guidelines for the Prevention and Management of Infusion Reaction 
 
Pre-Infusion Medication 
On DARA infusion days, the subject will initially receive the following medications prior to infusion: 
• 
Acetaminophen 650 mg PO 
• 
An antihistamine (diphenhydramine 25-50 mg, or equivalent) 
• 
Dexamethasone 20 mg IV 
• 
Montelukast 10 mg PO; optional per investigator discretion 
 
Post-Infusion Medication as Prophylaxis 
For the prevention of delayed infusion-related reactions, subjects will receive corticosteroid orally (4 
mg  Dexamethasone) on the two days following DARA infusions (beginning the day after the infusion). 
For subjects with a higher risk of respiratory complications (e.g., subjects who have an 
FEV1%PRED<75%), the following post-infusion medication should also be considered: 
• 
Antihistamine (25-50 mg of diphenhydramine or equivalent) on the 2 days following all infusions 


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(beginning on the day after the infusion) 
• 
Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol 
• 
Control medications for lung disease (e.g., inhaled corticosteroids ± long-acting β2 adrenergic 
receptor agonists for subjects with asthma; long-acting bronchodilators such as tiotropium or 
salbumatol ± inhaled corticosteroids for subjects with chronic obstructive pulmonary disorder) 
Investigators may prescribe bronchodilators, antihistamines, and corticosteroids that are deemed 
necessary to provide adequate supportive care in the event a bronchospasm occurs after subjects 
are released from the clinic. 
Post-infusion medications will be administered after the infusion has completed, per the timing 
noted above. If, after 3 full doses, an at-risk subject experiences no major infusion-related 
reactions, then post-infusion medications may be stopped and DARA can be given by rapid 
infusion over 90 minutes at the investigator’s discretion.  
 
4.2.4 Management of Infusion-Related Reactions 
Subjects should be carefully observed during DARA infusions. Infusion reactions may occur, and 
resources necessary for resuscitation (e.g., agents such as epinephrine and aerosolized 
bronchodilator, medical equipment such as oxygen tanks, tracheostomy equipment, and a 
defibrillator) must be available. 
If an infusion-related reaction develops, then the infusion should be temporarily interrupted or the 
rate of infusion decreased. 
Subjects should be treated with acetaminophen, antihistamine, or corticosteroids as needed. 
Intravenous saline may be indicated. For bronchospasm, urticarial, or dyspnea, patients may 
require antihistamines, oxygen, corticosteroids, or bronchodilators.  For hypotension, patients may 
require vasopressors. 
In the event of a life-threatening infusion-related reaction (which may include pulmonary or cardiac 
events) or anaphylactic reaction, DARA should be discontinued and no additional DARA should be 
administered to the subject. Aggressive symptomatic treatment should be applied. 
If an infusion is paused or the infusion rate is decreased, then a longer-than-anticipated infusion 
time may occur. Overnight stays at the hospital because of slow infusion times should not be 
reported as an SAE. However, if the underlying cause of the delayed infusion time is an AE or SAE, 
then that should be reported as such. 


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Infusion-Related Events of Grade 1 or Grade 2 
If the investigator assesses an AE to be related to the DARA infusion, then the infusion should be 
interrupted. When the subject’s condition is stable, the infusion may be restarted at the investigator’s 
discretion. Upon restart, the infusion rate should be half of that used before the interruption. 
Subsequently, the infusion rate may be increased. 
If the subject experiences a Grade 2 or higher event of laryngeal edema or a Grade 2 or higher event 
of bronchospasm that does not respond to systemic therapy and does not resolve within 6 hours from 
the onset, then the subject must be withdrawn from DARA treatment. 
 
Infusion-Related Events of Grade 3 or higher 
For infusion-related adverse events that are Grade 4, the infusion should be permanently discontinued 
and treatment with DARA discontinued for that subject. 
For infusion-related adverse events that are Grade 3, the DARA infusion must be interrupted, and the 
subject must be observed until the resolution of the AE or until the intensity of the event decreases to 
Grade 1, at which point the infusion may be restarted. Upon restart, the infusion rate should be half of 
that used before the interruption. Subsequently, the infusion rate may be increased. 
If the intensity of the adverse event returns to Grade 3 after restart of the infusion, then the procedure 
described in this section may be repeated. Should the intensity of the adverse event increase to Grade 
3 for a third time, then treatment with DARA will be permanently discontinued for that subject. 
 
4.2.5  Dose Modifications 
No DARA dose modification (increase or decrease) will be permitted. Subjects who do not tolerate 
DARA will be removed from the study. Refer to Section 4.2.6.  
Revlimid dose reductions are allowed at study entry based on renal function. Refer to Section 5.0 
Table 4.  
 
4.2.6 Toxicity Management 
Refer to section 4.2.4 for details on management of infusion-related reactions. The DARA dose must 
be held if any of the following criteria below are met, to allow for recovery from toxicity related to the 
study treatment. The criteria for a dose delay are: 


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• 
Grade 4 hematologic toxicities 
• 
Grade 3 thrombocytopenia with bleeding 
• 
Febrile neutropenia of any grade 
• 
Neutropenia with infection, of any grade 
• 
Grade 3 or higher non-hematologic toxicities with the following exceptions: 
o Grade 3 nausea that responds to antiemetic treatment within 7 days 
o Grade 3 vomiting that responds to antiemetic treatment within 7 days 
o Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days 
o Grade 3 fatigue that was present at baseline or that lasts for 
<7 days after the last administration of DARA 
o Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last 
administration of DARA. 
DARA treatment should be resumed when the toxicity has resolved to ≤ Grade 2 or baseline, with the 
exception that Grade 2 laryngeal edema or Grade 2 bronchospasm must be fully recovered. If DARA 
administration does not commence within the pre-specified window of the scheduled administration 
date, then the dose will be considered a missed dose. Administration may resume at the next planned 
weekly dosing date. If two consecutive doses of DARA are missed due to DARA-related adverse 
events, DARA should be permanently discontinued. Note that maintenance therapy may continue as 
described in Section 6.2 even if DARA is permanently discontinued. 
A missed dose will not be made up. If a dose is delayed, then the date of all subsequent doses must 
be adjusted. 
 
Hepatitis B Virus Reactivation Management 
Primary antiviral prophylaxis is permitted as per local standard of care.  Per protocol, HBV DNA testing 
by PCR is mandatory for subjects at risk for HBV reactivation see Section 6.1 
For subjects who are diagnosed with HBV reactivation while on treatment, study treatment should be 
interrupted until the infection is adequately controlled. If the benefits outweigh the risks, study treatment 
may be resumed with concomitant antiviral prophylaxis as per local standard of care. Consult a liver 
disease specialist as clinically indicated.  
 
 


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4.3 Dosing Schedule 
DARA at a dose of 16 mg per kilogram will be intravenously administered weekly (on Days 1, 8, 
15, and 22) for 8 weeks during Cycles 1 and 2, every 2 weeks (on Days 1 and 15) for 16 weeks 
(Cycles 3 through 6), and every 4 weeks thereafter for a total of 6 months (Cycles 7 to 12). DARA 
treatment will be completed at one year. 
Lenalidomide will be given orally in a dose of 15mg Days 1-21 on a 28-day cycle. DARA therapy 
will cease after 12 cycles, but lenalidomide can be continued beyond one year at the Principal 
Investigator’s discretion. Standard herpes zoster prophylaxis will be given with acyclovir 400mg 
twice a day or similar drug (e.g. valacyclovir).  Thrombo-embolic prophylaxis will comprise aspirin 
81mg daily unless the patient is already on anticoagulation. 
 
4.4 Drug Accountability 
DARA will be supplied for this study from Janssen Scientific Affairs, LLC  and will be shipped to the 
UAMS Research Pharmacy, which will be responsible for drug maintenance and dispensing. 
Lenalidomide will be supplied via specialty pharmacy per REMS protocol, and is not provided by 
the study; subjects’ insurance will be billed for costs associated with lenalidomide. 
DARA (expired or end of study) should be destroyed on site according to the University of Arkansas 
for Medical Sciences (UAMS) Research Pharmacy’s standard operating procedure. Documentation 
of removal and destruction should be indicated on drug accountability logs. 
 
4.5 Radiation 
This study will only enroll patients with disseminate clonal PCs. Patients with isolated 
plasmacytoma are excluded.  However, rare patients with disseminated disease who also have a 
large plasmacytoma may receive radiation therapy concurrently with DARA and lenalidomide. 
These are patients in whom the plasmacytoma is unlikely to respond to DARA and lenalidomide if 
there is compression of a vital structure. Patients who have had plasmacytomas irradiated prior to 
study entry are eligible to participate.  
 


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 DOSAGE MODIFICATIONS 
Subjects will be evaluated for adverse events according to the National Cancer Institute (NCI) 
Common Terminology for Adverse Events, version 5.0 (CTCAE).  All subjects who are discontinued 
due to an adverse event should be followed for as long as necessary to document the resolution or 
stabilization of the event.   
There will be no dose modifications for DARA.  However, rules for dose delays and adjustment of 
infusion times have already been addressed under 4.1. Lenalidomide will most likely to contribute to 
any cytopenias. Grade 4 hematologic toxicity will have their dose held until toxicity has resolved to 
Grade 2 or better and then will have their dose reduced one level from the previous dose received. 
Dose levels of lenalidomide are 15mg, 10mg, and 5mg.  The lenalidomide dose will be adjusted based 
on renal function per Table 4. 
 
Table 4. Lenalidomide Dosing by Renal Function 
GFR (mL/min) 
Dose Delivery 
> 60 
15 mg Days 1-21 q28 
25 - 59 
10 mg Days 1-21 q28 
< 25 
5 mg Days 1-21 q28 
< 25 and Dialysis 
0 
 
Subjects who are unable to tolerate lenalidomide may be allowed to remain on study, receiving single-
agent DARA, at the discretion of the principal investigator. Subjects who do not tolerate DARA will be 
removed from the study. 
 
 SCHEDULE OF EVALUATIONS 
6.1 Laboratory Tests and Evaluations 
 


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Table 5. Study Calendar 
  
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Cycles 7-
12  
Events 
Screen 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Window 
Day -28 to 
-1 
Within 7 
days of 
C1D1 
  
  
  
Within 7 
days of 
C2D1 
  
  
  
Within 7 
days of 
C3D1 
  
Within 7 
days of 
C4D1 
  
 Within 7 
days of 
C5D1 
  
Within 7 
days of 
C6D1 
  
Within 7 
days of 
cycle start 
Physical Assessments 
H&P1 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Adverse Events2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
CBC with Differential3 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Basic Metabolic Panel 
(BMP)4 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Pregnancy Test 
(WoCBP only)5/6 
X5 
X5 
 
 
 
X6 
 
 
 
X6 
 
X6 
 
X6 
 
X6 
 
X6 
Serum VEGF levels7 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Serum Protein 
Electrophoresis 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum Quantitative 
Immunoglobulins 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
24-hour Urine for Total 
Protein & 
Electrophoresis8 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum Free Light 
Chains 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum/Urine IFE9 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
Hepatitis B Serology10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV QPCR10 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
prior to C7, 
C10 
Blood Type and 
Indirect Antiglobulin 
Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Blood 
Samples11 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Bone Marrow 
Aspirate/Biopsy12 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 


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Echo/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFTs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Daratumumab13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lenalidomide14 
  
Days 1-21 Q28 days 
Days 1-21 Q28 days 
Days 1-21  
Q28 days 
Days 1-21  
Q28 days 
Days 1-21  
Q28 days 
Days 1-21  
Q28 days 
Days 1-21 
Q28 days 
Events 
End of Dara 
Treatment15 
Cycles 13 and 
beyond16 
Follow Up for 
PFS/OS17 
Patient evaluation for the diagnosis of POEMS syndrome will be outside the realm of this study. Unless otherwise specified, tests 
completed within 7 days of Cycle 1 day 1 do not have to be repeated.  
1 H&P to include detailed medical and treatment history, weight, height, BSA, and Performance Status by ECOG.  ONLS to be 
recorded. 
2 Subjects will be followed continuously for adverse events (AEs) from the start of treatment through 30 days after the last dose of 
study treatment. For the remainder of the follow up period, only ongoing AEs and any new AEs possibly related to study treatment or 
participation will be documented.  
3 CBC with differential. 
4 BMP (Na, K, Cl, CO2, Ca, BUN, Cr, Glucose).  
5 WoCBP must have a documented negative serum or urine pregnancy test (sensitivity of at least 50 mIU/mL) within 2 weeks prior to 
the start of treatment and then again within 24 hours prior to C1D1.  
6 WoCBP must have a documented negative serum or urine pregnancy test (sensitivity of at least 50 mIU/mL).  Pregnancy 
testing/counseling performed as required through the Revlimid REMS® program. 
7 VEGF levels will be supported by the study.  
8 Per clinical lab SOP, the UPEP is cancelled when the total protein is < 6 mg/dL because the results of the UPEP are not quantifiable 
at this level. If the UPEP is unable to be performed, the UIFE will be performed to determine the presence or absence of the urine 
monoclonal protein. 
9 As clinically indicated to assess response (i.e. upon disappearance monoclonal protein on SPEP and UPEP).  
10 Hepatitis B serology: HBsAb, HBcAb, HBsAg. Patients with positive Hepatitis B serology will be excluded, unless HBsAg negative 
and no clinical evidence of infection, as recommended by the FDA. Eligible patients with positive HBV serology will be monitored for 
re-activation of HBV every three monthly by QPCR for the duration of DARA therapy and up to 6 months after stopping DARA 
treatment. 
Note all myeloma program patients are screened routinely for HIV, HBV, HCV at their first visit. 
11 Research Peripheral Blood Sample. See Ancillary Studies 10.2. 
12 BM Aspirate & Biopsy are for routine studies (pathology, flow for MRD, cytogenetics, and FISH). Correlative BM scientific studies 
(Section 10.0) will be obtained at the same time in consenting patients. The screening bone marrow does not have to be repeated if 
completed per standard of care within the last 42 days.  
13 Daratumumab: Cycle 1-2 weekly on days 1, 8, 15, 22; cycles 3-6 every 2 weeks on days 1, 15; Cycles 7-12  every 4 weeks on day 1 
(28 day cycles); discontinued after 12 cycles. At the discretion of the investigator, the first DARA dose may be split over 2 days, i.e., 8 
mg/kg on cycle 1 day 1 and 8 mg/kg on cycle 1 day 2. 
14 Lenalidomide can continue beyond 12 cycles per PI discretion 
15 End of Dara Treatment: Visit will occur after the completion of 12 cycles of daratumumab or at the discontinuation of daratumumab 
if it is discontinued early. Treatment with lenalidomide may continue per PI discretion.  
16 Assessments for cycles 13 and beyond: Completed every 6 months (+/- 4 weeks). BM only as clinically indicated.  
17 Follow up for PFS/OS: PFS testing to be completed to every 6 months (+/- 4 weeks) for the first year then yearly thereafter (+/- 4 
weeks) until disease progression. PFS testing will also be completed at disease progression and to confirm response. BM only as 
clinically indicated. OS will be followed by an annual phone call if the subject is not returning to UAMS for treatment  
Window 
Within 8 weeks 
discontinuation 
 +/- 4 weeks 
+/- 4 weeks 
Physical Assessments 
H&P1 
X 
X 
X 
Adverse Events2 
X 
X 
X 
Laboratory 
CBC with 
Differential3 
X 
 
 
Basic Metabolic 
Panel (BMP)4 
X 
 
 
Pregnancy Test 
(WoCBP only)5/6 
X6 
X6 
 
Serum VEGF levels7 
X 
 
X 
Serum Protein 
Electrophoresis 
X 
X 
X 
Serum Quantitative 
Immunoglobulins 
X 
X 
X 
24-hour Urine for 
Total Protein & 
Electrophoresis8 
X 
X 
X 
Serum Free Light 
Chains 
X 
X 
X 
Serum/Urine IFE9 
X 
X 
X 
HBV QPCR10 
X 
X 
X 
Blood Type and 
Indirect 
Antiglobulin Test 
 
 
 
Research Blood 
Samples11 
X 
 
 
Bone Marrow 
Aspirate/Biopsy12 
X 
X 
X 
Echo/MUGA 
 
 
 
PFTs 
 
 
 
Treatment 
Daratumumab13 
 
 
 
Lenalidomide14 
 
Days 1-21 Q28 
days 
 
 


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6.2 Screening Procedures 
After written consent has been obtained, subjects will be screened in order to assess eligibility for 
study participation.  All screening laboratory assessments must be performed within 28 days prior 
to Cycle 1 Day 1. PFTs, Echo/MUGA and Bone Marrow assessments must be performed within 42 
days of Cycle 1 Day 1. For WOCPB pregnancy test must be performed within 2 weeks of Cycle 1 
Days 1.  
Subjects who meet inclusion and exclusion criteria will be eligible to be enrolled in the study. 
The results should be available prior to the start of study treatment: 
• 
Confirmation of signed ICF 
• 
H&P (including detailed medical and treatment history, weight, height, BSA, ECOG, and 
ONLS) 
• 
Adverse Event Assessment 
• 
Laboratory assessments (CBC with differentials, BMP, Pregnancy Test for WOCBP, Serum 
VEGF levels, SPEP, SIFE, UPEP, UIFE, QIGS, SFLC, hepatitis serology, blood type, 
indirect antiglobulin test, and research blood samples) 
• 
Bone Marrow Aspirate/Biopsy (pathology, flow for MRD, cytogenetics, and FISH) 
• 
Echo/MUGA 
• 
PFTs 
6.3 Treatment Procedures 
The following procedures will be completed during the treatment period at the times designated in 
the Study Calendar (Table 5): 
• 
H&P 
• 
Adverse Event Assessment 
• 
Laboratory assessments (CBC with differentials, BMP, Pregnancy Test for WOCBP, Serum 
VEGF levels, SPEP, SIFE, UPEP, UIFE, QIGS, SFLC, hepatitis serology, and research 
blood samples) 
• 
Bone Marrow Aspirate/Biopsy (pathology, flow for MRD, cytogenetics, and FISH) 
• 
Administration of protocol required therapies 
6.4 End of Dara Treatment Procedures 
The EOT visit will occur after the completion of 12 cycles of daratumumab or within 8 weeks of 
discontinuation of daratumumab if it is discontinued early. Treatment with lenalidomide may 
continue per PI discretion. 
The following procedures will be completed during the EOT visit: 


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• 
H&P (including detailed medical and treatment history, weight, height, BSA, ECOG, and 
ONLS) 
• 
Adverse Event Assessment 
• 
Laboratory assessments (CBC with differentials, BMP, Pregnancy Test for WOCBP, Serum 
VEGF levels, SPEP, SIFE, UPEP, UIFE, QIGS, SFLC, hepatitis serology and research 
blood samples) 
• 
Bone Marrow Aspirate/Biopsy (pathology, flow for MRD, cytogenetics,  and FISH) 
 
6.5 Progression Free Survival/Overall Survival Follow Up Procedures 
The PFS/OS Follow Up will be completed every 6 months for the first year then yearly thereafter 
until disease progression occurs. The following procedures may be completed during these time 
periods: 
• 
H&P (including detailed medical and treatment history, weight, height, BSA, ECOG, and 
ONLS) 
• 
Adverse Event Assessment 
• 
Laboratory assessments (Serum VEGF levels, SPEP, SIFE, UPEP, UIFE, QIGS, and 
SFLC,) 
• 
Bone Marrow Aspirate/Biopsy (pathology, flow for MRD, cytogenetics,  and FISH) 
 
OS will be followed by an annual phone call if the subject is not returning to UAMS for treatment.  
 
 DEFINITIONS OF SAFETY EVENTS 
7.1 Definitions 
7.1.1 Adverse Events (AE) 
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product.  An adverse event does not necessarily have a causal 
relationship with the treatment.  An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not related to that medicinal product. This includes any occurrence that 
is new in onset or aggravated in severity or frequency from the baseline condition. Abnormal results of 
diagnostic procedures are considered to be AEs if the abnormality: 
• 
Results in study withdrawal 
• 
Is associated with an SAE 


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• 
Is associated with clinical signs or symptoms 
• 
Leads to additional treatment or to further diagnostic tests 
• 
Is considered by the investigator to be of clinical significance 
 
 
Abnormal Laboratory Values Defined as AEs 
An abnormal laboratory value is considered to be an AE if the laboratory abnormality 
is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Requires treatment, modification of study drug dose, or any other 
therapeutic intervention 
• 
Is judged by the Investigator to be of significant clinical impact/importance 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only 
the diagnosis or syndrome should be recorded as an AE.  If the laboratory 
abnormality was not a part of a diagnosis or syndrome, then the abnormality should 
be recorded as the AE 
7.1.1.2 
Safety Events of Interest for a Janssen Medicinal Product that Require Expediting 
Reporting and/or Safety Evaluation including but not limited to: 
• 
Drug exposure during pregnancy (maternal and paternal) 
• 
Overdose of a Janssen medicinal product  
• 
Exposure to a Janssen medicinal product from breastfeeding  
• 
Suspected abuse/misuse of a Janssen medicinal product 
• 
Inadvertent or accidental exposure to a Janssen medicinal product  
• 
Any failure of expected pharmacological action (i.e., lack of effect) of a 
Janssen medicinal product 
• 
Medication error involving a Janssen medicinal product (with or without 
patient exposure to the Janssen medicinal product, e.g., name confusion) 
• 
Suspected transmission of any infectious agent via administration of a 
medicinal product 
• 
Unexpected therapeutic or clinical benefit from use of a Janssen medicinal 
product 
These safety events may not meet the definition of an adverse event; however, from a Janssen 
Scientific Affairs, LLC perspective, they are treated in the same manner as adverse events. Special 
situations should be recorded on the Adverse Event page of the CRF 


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Any special situation that meets the criteria of a serious adverse event should be recorded on a Serious 
Adverse Event Report Form and be reported to Janssen Scientific Affairs, LLC . 
7.1.2 Serious Adverse Event (SAE) 
An event is “serious” based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products 
for Human Use if it involves considerable detriment or harm to one or more persons (who may or may 
not be participants), or required intervention to prevent one or more persons from experiencing 
considerable detriment or harm. SAEs include: 
• 
Results in death 
• 
Is life-threatening:(The subject was at risk of death at the time of the event. It does not refer to 
an event that hypothetically might have caused death if it were more severe.) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is a suspected transmission of any infectious agent via a medicinal product 
• 
Any other important medical event that, based upon appropriate medical judgment, may 
jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed above. Examples include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, the development of drug dependency or drug abuse, suicidal 
ideation or attempts, or the unintentional revealing of some genetic information to insurers. 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A SERIOUS ADVERSE EVENT. 
 
 7.1.2.1  Hospitalization 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the 
hospitalization that is the serious event for which details must be provided. 
Any event requiring hospitalization or prolongation of hospitalization that occurs during the 
study must be reported as a serious adverse event, except hospitalizations for the following: 
• 
Hospitalizations not intended to treat an acute illness or adverse event (e.g., social 
reasons such as pending placement in long-term care facility) 
• 
Surgery or procedure planned before entry into the study. [Note: Hospitalizations that 
were planned before the start of data collection and where the underlying condition for 
which the hospitalization was planned has not worsened will not be considered serious 


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adverse events. Any adverse event that results in a prolongation of the originally 
planned hospitalization is to be reported as a new serious adverse event.] 
 
7.1.2.2  
Life-Threatening Conditions 
Disease progression should not be recorded as an adverse event or serious adverse 
event term; instead, signs and symptoms of clinical sequelae resulting from disease 
progression/lack of efficacy will be reported if they fulfill the serious adverse event 
definition. 
7.1.2.3  
 Adverse Events of Special Interest 
Adverse events of special interest are events that Janssen Scientific Affairs, LLC is 
actively monitoring as a result of a previously identified signal (even if non-serious). 
These adverse events are: 
• 
Infusion reactions: ≥ grade 3 
• 
Infections: ≥ grade 4  
• 
Cytopenias: ≥ grade 4  
• 
Tumor lysis syndrome 
• 
Other malignancies 
• 
Intravascular hemolysis – all grades 
Any Adverse Event of Special Interest that is identified should be recorded on an 
SAE Report Form and be reported to Janssen within 24 hours of knowledge of the 
event.  
 
7.1.2.4  
Pregnancy  
All initial reports of pregnancy must be reported to Janssen Scientific Affairs, LLC using 
the Serious Adverse Event Form. Abnormal pregnancy outcomes (e.g. spontaneous 
abortion, fetal death, stillbirth, congenital anomaly, ectopic pregnancy) are considered 
serious adverse events and must be reported to Janssen within 24 hours of knowledge 
of the event using the SAE Report Form.  
Any subject who becomes pregnant during the study must be promptly withdrawn from 
the study and discontinue further study treatment. 
Because the effect of the Janssen medicinal product on sperm is unknown, pregnancies 
in partners of male subjects exposed to a Janssen medicinal product will be reported 
using the Serious Adverse Event Form.  Depending on local legislation this may require 
prior consent of the partner. 


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Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required. 
 
7.1.3 Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet regulatory reporting 
requirements. 
• 
an identifiable subject (but not disclosing personal information such as the subject’s name, 
initials or address) 
• 
an identifiable reporter (investigational site) 
• 
a Janssen medicinal product 
• 
an adverse event, outcome, or certain special situations 
The minimum information required is: 
• 
suspected Janssen medicinal product (doses, indication) 
• 
date of therapy (start and end date, if available) 
• 
batch or lot number, if available 
• 
subject details (subject ID and country) 
• 
gender 
• 
age at AE onset 
• 
reporter ID 
• 
adverse event detail (AE verbatim in English), onset date, relatedness, causality, action 
taken, outcome, (if available) 
• 
Janssen protocol ID 
 
7.1.4 Product Quality Complaint (PQC) 
A product quality compliant is defined as any suspicion of a product defect related to a potential 
quality issue during manufacturing, packaging, release testing, stability monitoring, dose 
preparation, storage or distribution of the product, or delivery system.  Not all PQCs involve a 
subject.  Lot and batch numbers are of high significance and need to be collected whenever 
available. 
Examples of PQC include but not limited to: 
• 
Functional Problem: e.g., altered delivery rate in a controlled release product 
• 
Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
• 
Potential Dosing Device Malfunction: e.g., autoinjector button not working, needle detaching 
from syringe 


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• 
Suspected Contamination 
• 
Suspected Counterfeit 
7.1.5 Related 
An event is “related” if more likely than not it was caused by the research activity. 
 
7.1.6 Unexpected 
An event is “unexpected” when its specificity, nature, severity or incidence is not accurately 
reflected in the consent form, protocol, or investigator’s brochure previously reviewed and approved 
by the IRB. Examples include a lower rate of response to treatment or a side effect that is more 
severe than initially expected.  A current list of expected adverse reactions/events can be found at:
 
 http://www.darzalex.com/shared/product/darzalex/darzalex-prescribing-information.pdf 
 
7.1.7 Study Period 
All AEs will be recorded on the Case Report Forms (CRFs) by the Investigator from the time of the 
start of study drug until 30 days after the last dose of study treatment. All relevant historical medical 
conditions that are known/diagnosed prior to the administration of study drug(s) are to be recorded 
as medical history. 
 
7.2 Monitoring, Recording, and Reporting of Safety Events 
7.2.1 Adverse Events (AEs) 
All subjects will be monitored for AEs during the study period.  Assessments may include 
monitoring the patient's clinical symptoms; laboratory, pathological, radiological, or surgical 
findings; physical examination; or other appropriate tests and procedures. 
All AEs occurring during the study period must be recorded.  The clinical course of each 
event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.   
AE data collection and reporting are done to ensure the safety of subjects enrolled in the 
studies and those who will enroll in future protocols.  AEs are to be reported in a routine 
fashion at scheduled times during the trial, such as with the annual reports to the IRB.  
Certain AEs must be reported in an expedited fashion to allow for more timely monitoring 
of subject safety and care.  


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Steps to Determine if the Event Requires Expedited Reporting 
1. Identify the type of event using NCI CTCAE version 5.0 
2. Grade the event using NCI CTCAE version 5.0 
3. Determine whether the adverse event is related to protocol therapy (investigational or 
commercial).  Attribution categories are as follows: 
• 
Related - there is a reasonable possibility that the study drugs and/or procedures 
caused or contributed to the adverse event 
• 
Not Related - a causal relationship of the adverse event to the study drugs and/or 
procedures is unlikely 
4. Determine expectedness of the event.  Expected events are those previously 
identified resulting from administration of the agent. 
An adverse event is considered unexpected when the type or severity of the event is not 
listed in: 
• 
The investigator’s brochure or drug package insert (commercial drug) 
• 
Consent form 
5. Determine if this event involves a new or increased risk(s) to subjects. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment.  Any event occurring more than 30 days after the last dose that is possible, 
probably, or definitely attributable to the agent(s) must be reported according to the 
instructions above. 
7.2.2 Serious Adverse Events (SAEs) 
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject’s participation in the study, must be followed 
until any of the following occurs: 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline if a baseline value/status is available 
• 
The event can be attributed to agents other than the study drug or to factors unrelated 
to study conduct 


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• 
It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts) 
 
7.2.2.1 Expedited Reporting of SAEs 
Any adverse event meeting IRB policy 10.2, Unanticipated Problem Involving Risks to 
Subjects or Others (UPIRTSO), must be reported to the IRB within 10 days of 
notification of the event. Per this policy, any problem, event, or new information that 
meets the following criteria would require expedited reporting as Reportable New 
Information:  
1) unanticipated or unexpected 
2) related to the research 
3) involves new or increased risk to the subject(s).  
All other adverse events not meeting UPIRTSO criteria should be recorded and reported 
to the UAMS IRB at the continuing review in a summary format. Events which have 
resulted in death or are life-threatening should be reported immediately to the IRB if 
these events meet the requirements of IRB policy 10.2. Deaths due to disease 
progression would be considered anticipated and not related to the research and 
therefore would not be immediately reported under this policy. 
All SAEs, UPIRTSOs and any special situations that meet the criteria of a serious 
adverse event should be recorded on a Serious Adverse Event Report Form and be 
reported to Janssen Scientific Affairs, LLC using the MedWatch 3500A form within 24 
hours of becoming aware of the event. Ensure that the MedWatch 3500A form 
contains all the ICSR elements in section 7.1.3. 
 
7.2.3 PQC Reporting 
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, and 
complete reporting and analysis of PQC information from studies are crucial for the protection of 
patients, investigators, and Janssen Scientific Affairs, LLC, and are mandated by regulatory 
agencies worldwide. Janssen Scientific Affairs, LLC has established procedures in conformity with 
regulatory requirements worldwide to ensure appropriate reporting of PQC information. Lot and/or 
Batch #s shall be collected or any reports failure of expected pharmacological action (i.e., lack of 
effect). The product should be quarantined immediately and if possible, take a picture. 


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All initial PQCs involving a Janssen medicinal product under study must be reported to Janssen 
Scientific Affairs, LLC using the MedWatch 3500A form within 24 hours after being made aware 
of the event. Ensure that the MedWatch 3500A form contains all the PQC elements in section 
7.1.4. The Janssen contact will provide additional information/form to be completed. 
If the defect for a Janssen medicinal product under study is combined with either a serious adverse 
event or non-serious adverse event must report the PQC to Janssen Scientific Affairs, LLC 
according to the serious adverse event reporting timelines.  A sample of the suspected product 
should be maintained for further investigation if requested by Janssen Scientific Affairs, LLC. 
 
7.2.4 Transmission Methods  
The following methods are acceptable for transmission of safety information to Janssen Scientific 
Affairs, LLC: 
• 
Electronically via Janssen SECURE Email service (preferred) 
• 
For business continuity purposes, if SECURE Email is non-functional: 
o Facsimile (fax), receipt of which is evidenced in a successful fax transmission report 
• 
Telephone (if fax is non-functional). 
Please use the contact information and process information provided by Janssen Scientific 
Affairs, LLC.  
 
7.2.5 Maintenance of Safety Information 
All safety data will be maintained in a clinical database in a retrievable format and all adverse 
events, both serious and non-serious, in report format. However, in certain circumstances more 
frequent provision of safety data may be necessary, e.g. to fulfill a regulatory request, and as such 
the data shall be made available within a reasonable timeframe at Janssen Scientific Affairs, LLC 
request. 
 
7.2.6 Dissemination of Safety Information 
IND safety reports for the Study Product will be sent to the IRB in accordance with Federal 
regulations 21 CFR 312.66.   
Janssen Scientific Affairs, LLC agrees to provide to the principal investigator IND safety reports for 
the Janssen Medicinal Product as they become available until all subjects in the Protocol have 
completed their last Study visit according to the Protocol (i.e. Last Subject Last Visit has occurred). 
 


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7.2.7 Non-Serious AEs 
All non-serious adverse events should be reported to Janssen Scientific Affairs, LLC according to the 
timeframe outlined in the Research Funding Agreement section entitles Reporting of Data.  
 
7.2.8 Final Study Report 
The Investigator will prepare a final report including a complete and full summary of all adverse events, 
special situations, and pregnancy reports according to the timeframe outlined in the Research Funding 
Agreement.  
 
7.3 Subject Confidentiality 
The Myeloma Center affirms the subject’s right to protection against invasion of privacy. In 
compliance with United States Federal regulations, representatives of the FDA, NCI and other 
regulatory authorities may review medical records and copy relevant research records in 
accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual. 
 
7.4 Investigator Responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice and the Code 
of Federal Regulations. 
The Investigator will permit IRB review and regulatory inspection(s) (e.g. FDA, EMEA, TPP), 
providing direct access to the facilities where the study took place, source documents, and all other 
study documents. 
The Investigator or a designated member of the Investigator’s staff must be available at some time 
during auditing visits to review data and resolve any queries and to allow direct access to the subject’s 
records (e.g. medical records, office charts, hospital charts, and study related charts) for source data 
verification. All study documents must be made available to the auditing representative so that the 
accuracy and completeness of study documents may be confirmed.  
 
 


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7.5 Protocol Amendments 
If modification of the protocol is necessary, the modification must be confirmed in writing, and the 
Investigator will inform the IRB after modifications have been approved by Janssen.  Written 
verification of IRB approval will be obtained before any amendment that affects patient safety or 
efficacy, is implemented. Amendments that are administrative in nature do not require IRB approval 
but will be submitted to the IRB for information.   
 
7.6 Suspension of Study 
If conditions arise requiring further clarification before the decision to proceed with or terminate the 
study can be reached, the study will be suspended until the situation has been resolved. 
 
7.7 Protocol Deviations 
When an emergency occurs that requires a deviation from the protocol for a study subject, a 
deviation will be made only for that subject. The Principal Investigator or other physician in 
attendance in such an emergency will, if circumstances and time permit, contact the IRB 
immediately by telephone. If time does not allow for this, the Investigator will notify of the IRB of 
the deviation as soon as possible in writing. 
Such contacts will be made as soon as possible to determine whether or not the subject (for whom 
the deviation from protocol was effected) is to continue in the study.  The subjects’ medical and/or 
research record will completely describe the deviation from the protocol and state the reasons for 
such deviation.   
 
7,8 Early stopping rules 
Early stopping rules will be put in place to protect the patients from excess toxicity. The trial will be 
halted if treatment-related death occurs in two of the first three patients. If ≤ 1 treatment related 
death occurs in the first 3 patients, then a further 3 patients will be enrolled. The trial will be halted 
if > 2 treatment-related deaths occur in the first 6 patients. If ≤ 2 treatment-related deaths occur in 
the first 6 patients, then a further 4 patients will be enrolled completing the enrollment of the 10 
patients. 
 
 ETHICAL AND REGULATORY CONSIDERATIONS 
8.1 Informed Consent 


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The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports: Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
The formal consent of each subject, using the IRB-approved consent form, will be obtained before 
that subject is submitted to any study procedure.  All subjects for this study will be provided a 
consent form describing this study and providing sufficient information in language suitable for 
subjects to make an informed decision about their participation in this study.  The person obtaining 
consent will thoroughly explain each element of the document and outline the risks and benefits, 
alternative treatments, and requirements of the study.  The consent process will take place in a 
quiet and private room, and subjects may take as much time as needed to make a decision about 
their participation.  Participation privacy will be maintained and questions regarding participation 
will be answered.  No coercion or undue influence will be used in the consent process.  This consent 
form must be signed by the subject or legally acceptable surrogate, and the individual obtaining the 
consent.  A copy of the signed consent will be given to the participant, and the informed consent 
process will be documented in each subject’s research record. 
 
8.2 Institutional Review 
This study must be approved by the UAMS IRB, as defined by Federal Regulatory Guidelines (Ref 
Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the Office for Protection from 
Research Risks Reports Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). 
The Investigator will be responsible for preparing documents for submission to the relevant IRB 
and obtaining written approval for this study. The approval will be obtained prior to the initiation of 
the study.   
Any modifications/amendments to the protocol after receipt of IRB approval must be submitted by 
the Investigator to the IRB for approval. The Investigator is also responsible for notifying the IRB of 
any serious deviations from the protocol, or anything that may involve added risk to study subjects. 
 
8.3 Case Report Forms 
The Principal Investigator and/or his designee(s) will prepare and maintain adequate and accurate 
case histories with observations and data pertinent to the study. Study-specific CRFs will be used 


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and should be completed as soon as possible upon completion of a study visit.  Information 
collected on CRFs shall be identical to that appearing in original source documents.  In accordance 
with federal regulations, the Principal Investigator is responsible for the accuracy and authenticity 
of all clinical and laboratory data entered onto CRFs. The Principal Investigator will review and 
approve completed CRFs to attest that the information contained is true and accurate. 
8.4 Subject Confidentiality 
The Myeloma Center affirms the subject’s right to protection against invasion of privacy. In 
compliance with United States Federal regulations, representatives of the FDA, NCI and other 
regulatory authorities may review medical records and copy relevant research records in 
accordance with local laws. 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual. 
 
8.5 Record Retention 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and 
amendments, IRB correspondence and approval, signed patient consent forms).  All study records 
will be retained in accordance with applicable institutional policies and regulatory requirements. 
 
 STATISTICAL CONSIDERATIONS 
This is a phase II clinical trial with the objective to assess the efficacy and safety of DARA and 
lenalidomide for POEMS syndrome in a small cohort (n=10) of patients. All subjects meeting the 
eligibility criteria who have signed a consent form and have begun treatment will be evaluable for 
response. Outcome parameters will be described using simple descriptive statistics. 
 
9.1 Definition of Success 
An evaluable patient will be classified as a treatment success of the primary endpoint if: 
a) There is a one-point improvement in ECOG performance score; and/or 
b)  ≥ 50% reduction in ONLS score at Day 360.  
 Of note, a ≤ 50% reduction in ONLS score will constitute a partial response (PR). 


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9.2 Accrual and Study Duration 
We anticipate an accrual rate of approximately five eligible subjects per year. Thus 10 subjects will 
be accrued in approximately two years. The primary endpoint will be assessed after all subjects 
have been accrued and followed for an additional year, approximately three years after the opening 
of the study. 
 
9.3 Sample Size and Power 
The sample size of this rare disorder is too small to allow for formal comparisons. Ten subjects to 
be enrolled are not through formal sample size/power calculation. Descriptive statistics will be used 
to measure outcome. 
 
9.4 Toxicity 
There is no formal data and safety monitoring committee for Phase II studies. Toxicity and accrual 
monitoring are done routinely by the principal investigator and the study statistician. In addition, the 
maximum grade for each type of toxicity regardless of causality will be recorded and reported for 
each patient and frequency tables will be reviewed to determine toxicity patterns. 
 
9.5 Secondary Endpoints 
• 
Hematologic response will be measured by IMWG response criteria see Appendix III for 
response criteria definitions.   
• 
Normalization of VEGF levels will be considered a complete response (CR) for the VEGF 
levels. Rare POEMS patients with normal VEGF levels will not be evaluable for this 
parameter; such patients will not be replaced.   
• 
Duration of response will be recorded and analyzed using descriptive parameters to 
characterize the outcome of the cohort.  
• 
OS and PFS will be assessed using Kaplan-Meier Curves see Appendix III for survival 
outcome definitions. 
 
 
ANCILLARY STUDIES 
10.1 
Participation, Confidentiality, and Future Studies 


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Participation in laboratory research studies related to this trial is voluntary. The informed consent 
document shall outline that research is voluntary and allow subjects to opt in or out of these studies. 
Subjects who choose to participate shall be notified that their samples, and data attributed to their 
samples, will be coded; only the principal investigator and his designees shall have access to 
identifying information or to a key that may be used to decode and link samples to their identities. 
Samples will be stored for an indefinite period of time for future research provided the subject 
consents to such.  
In order to initiate any ancillary research utilizing data and specimens from patients who opted in 
to future research collections for this protocol, authorization from Janssen Scientific Affairs, LLC 
will be sought.  
 
10.2 
Molecular Studies of CD138-purified Plasma Cells and Bone Marrow Biopsies 
BM aspirates and biopsies for genetic studies (RNA sequencing), aCGH, and proteomics profiling 
will be performed. Approximately 10mL of BM aspirate will be collected in an EDTA syringe and 
sent to the Myeloma Accessioning Lab. Samples will be collected at 3 time points: screening/before 
the first dose of DARA; prior to Cycle 3 Day 1; and at the end of treatment. All correlative studies 
will be funded by other mechanisms and not as part of this protocol. 
 
10.3 
Mass Cytometry/Proteomics Profiling Studies of Peripheral Blood 
PB comprises major components of the immune system, such as T and B cell subsets and NK and 
dendritic cells, all of which have been shown to be altered/important in MM. We envision that mass 
cytometry and proteomics profiling of PB, both un-separated and separated into distinct subset 
components, may provide important information regarding the immunologic profile of POEMS 
patients.  
Approximately 40mL of peripheral blood will be collected at the time points specified in Section 10.2 
above. 
 
 
 


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Ku A, Lachmann E, Tunkel R, Nagler W. Severe polyneuropathy: initial manifestation of 
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APPENDIX I – DIAGNOSTIC CRITERIA FOR POEMS SYNDROME 
Mandatory Major Criteria 
1. Polyneuropathy (typically demyelinating) 
 
2. Monoclonal PC proliferative disorder (almost always lambda) 
Other Major Criteria  
3. Castleman Disease 
(One Required) 
4. Sclerotic bone lesions 
 
5. VEGF elevation 
Minor Criteria 
6. Organomegaly (splenomegaly, hepatomegaly, or  
lymphadenopathy) 
 
7. Extravascular volume overload (edema, pleural effusion, or 
ascites) 
 
8. Endocrinopathy (adrenal, thyroid,  pituitary, gonadal, 
parathyroid, pancreatic) 
 
9. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid 
hemangiomata, plethora, acrocyanosis, flushing, white nails) 
 
10. Papilledema 
 
11. Thrombocytosis / polycythemia 
Other Symptoms and 
Signs 
Clubbing, weight loss, hyperhidrosis, pulmonary 
hypertension/restrictive lung disease, thrombotic diatheses, 
diarrhea, low vitamin B12 values 
(Taken from Dispenzieri Am J Hematol. 2015;90(10):951-962) 
 
 


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APPENDIX II – OVERALL NEUROPATHY LIMITATIONS SCALE 
 


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APPENDIX III – IMWG RESPONSE CRITERIA AND SURVIVAL OUTCOME DEFINITIONS 
Timing of Response Evaluation 
Response will be evaluated according to the Schedule of Evaluations listed above (Section 6.0)  
 
Stringent Complete Response (sCR):   
• 
Meets all of the criteria for Complete Response (CR) and   
• 
Normal serum free light chain ratio and 
• 
Absence of clonal cells in BM by immunohistochemistry or immunofluorescence 
 
Complete Response (CR): 
• 
Disappearance of all evidence of serum and urine M proteins on immunofixation 
electrophoresis studies and 
• 
≤ 5% plasma cells in BM and 
• 
Disappearance of any soft tissue plasmacytomas 
 
 
Very Good Partial Response (VGPR): 
• 
Meets all of the criteria for PR and 
• 
Serum and urine M proteins detectable by immunofixation but not on electrophoresis or  
• 
≥ 90% reduction in serum M protein and urine M protein < 100 mg/24 hrs. 
 
Partial Response (PR): 
• 
If the patient had soft tissue plasmacytomas present at baseline and they were assessed 
at this disease assessment: ≥ 50% reduction in size of soft tissue plasmacytomas (see 
Appendix; Notes h.) and 
• 
If the patient had ≥ 30% plasma cells in BM at baseline and a BM biopsy was done: ≥ 50% 
reduction in plasma cells and 
• 
≥ 50% reduction in serum M protein and reduction in urine M protein ≥ 90% or to < 200 
mg/24 hours or 


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• 
If patient had serum M protein < 1 g/dL, urine M protein < 200 mg/24 hours, and an involved 
serum free light chain level ≥ 10 mg/dL at baseline: ≥ 50% decrease in the difference 
between involved and uninvolved serum free light chain levels 
 
Stable Disease (STA): 
• 
Patient does not meet criteria for sCR, CR, VGPR, PR, or Progression (PROG). 
 
Progression (PROG):  Any one or more of the following: 
• 
Serum M protein increase ≥ 25% from baseline (or an increase of ≥ 1 g/dL if serum M protein 
was ≥ 5 g/dL at baseline), with an absolute increase of ≥ 0.5 g/dL or 
• 
Urine M protein increase ≥ 25% from baseline, with an absolute increase of ≥ 200 mg/24 
hrs or 
• 
If patient had serum M protein < 1 g/dL, urine M protein < 200 mg/24 hrs, and an involved 
serum free light chain level ≥ 10 mg/dL at baseline: ≥ 25% increase in the difference 
between involved and uninvolved serum free light chain level, with an absolute increase of 
≥ 10 mg/dL or 
• 
BM plasma cell percentage increase ≥ 25% from baseline, with the absolute plasma cell % 
≥ 10% or 
• 
New bone lesions or soft tissue plasmacytomas, or definite increase in size of existing bone 
lesions or soft tissue plasmacytomas (see Appendix III: Note 8.) or 
• 
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that 
can be attributed solely to MM 
 
NOTES:  
1. If a disease assessment indicates that a patient is experiencing a sCR, CR, VGPR, PR, or 
PROG, this should be confirmed by a second disease assessment and this should be done 
prior to the institution of any new therapy.  The second disease assessment may be done 
at any time. 
2. “M protein” may also be known by the following synonyms: M-spike, monoclonal protein, 
myeloma protein, monoclonal paraprotein, M-component. 


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3. Urine M protein measurement is estimated using 24-hour urine protein electrophoresis 
(UPEP) only.  Random or 24-hour urine tests measuring kappa and lambda light chain 
levels are not reliable and are not recommended. 
4. Patients with ‘measurable disease’ in both the serum and urine (serum M protein ≥ 1g/dL 
and urine M protein ≥ 200 mg/24 hours) at baseline need to be followed by both SPEP and 
UPEP for response assessment. 
5. Except for assessment of CR, patients with ‘measurable disease’ restricted to the serum 
(serum M protein ≥ 1 g/dL and urine M protein < 200 mg/24 hours) at baseline may be 
followed by SPEP only.  Likewise, except for assessment of CR, patients with ‘measurable 
disease’ restricted to the urine (serum M protein < 1 g/dL and urine M protein ≥ 200 mg/24 
hours) at baseline may be followed by UPEP only. 
6. Patients with serum M protein ≥ 1 g/dL and/or urine M protein ≥ 200 mg/24 hours at baseline 
will be assessed for response based on SPEP and/or UPEP results only.  Except for 
assessment of sCR, serum free light chain (FLC) assay response requirements are only 
applicable to patients who had serum M protein < 1 g/dL, urine M protein < 200 mg/24 
hours, and an involved serum free light chain level ≥ 10 mg/dL at baseline.  A normal serum 
free light chain ratio is required for all patients for a sCR. 
7. To qualify for a CR, both serum and urine immunofixation must be carried out and must be 
negative, regardless of the size of the baseline M protein in the serum or urine. 
8. Skeletal survey is not required for assessment of response unless clinically indicated, but 
is recommended once a year in clinical practice.  sCR, CR, VGPR, PR, and STA all require 
no known evidence of progressive or new bone lesions if radiographic studies were 
performed, but radiographic studies are not required to satisfy these response 
requirements. 
9. The size of the soft tissue plasmacytomas is defined as the sum of the products of the cross-
diameters of each plasmacytoma.  The size of the bone lesions will be determined in a 
similar manner.  A definite increase in the size is defined as a ≥ 50% increase (and at least 
1 cm2) of this sum. 
 
 
 


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Best Response 
This is calculated from a sequence of Objective Status evaluations 
 
Stringent Complete Response 
An objective status of sCR on at least two sequential disease assessments.  Only one BM biopsy, 
done during one of these two disease assessments, is required to confirm the response. 
 
Complete Response 
An objective status of CR on at least two sequential disease assessments.  Only one BM biopsy, 
done during one of these two disease assessments, is required to confirm the response.  
  
Very Good Partial Response 
An objective status of VGPR on at least two sequential disease assessments.  
 
Partial Response  
An objective status of PR on at least two sequential disease assessments. 
 
Unconfirmed sCR (UsCR) 
One objective status of sCR (based on evidence from serum and urine studies and, if drawn, BM 
biopsy) but the confirmation studies are either not done, or when done, do not meet the 
requirements necessary to confirm response.  This must be documented before progression and 
at least three weeks after registration. 
 
Unconfirmed CR (UCR) 
One objective status of CR (based on evidence from serum and urine studies and, if drawn, BM 
biopsy) but the confirmation studies are either not done, or when done, do not meet the 
requirements necessary to confirm response.  This must be documented before progression and 
at least three weeks after registration. 
 


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Unconfirmed VGPR (UVGPR) 
One objective status of VGPR, but the confirmation studies are either not done, or when done, do 
not meet the requirements necessary to confirm response.  This must be documented before 
progression and at least three weeks after registration. 
 
Unconfirmed PR (UPR) 
One objective status of PR, but the confirmation studies are either not done, or when done, do not 
meet the requirements necessary to confirm response.  This must be documented before 
progression and at least three weeks after registration. 
 
Stable / No Response 
At least one objective status of STA at least three weeks after registration, but not qualifying as any 
of the above.  If radiographic studies were performed there should be no known progressive or new 
bone lesions. 
 
Increasing Disease (lNC) 
First objective status recorded (other than Unknowns or those before three weeks) of Progression, 
provided this occurs within eight weeks of registration. 
 
Inadequate Assessment. Response Unknown (NASS) 
Progression greater than eight weeks after registration and either all objective statuses prior to 
registration are unknown or the only known objective statuses occurred less than three weeks after 
registration. 
 
Relapse 
In patients with a confirmed response as described above, relapse is defined as the first occurrence 
of any of the following, reconfirmed by repeat analysis of serum and/or 24-hour urine M protein, 
done more than 2 weeks apart:  
 


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• 
Myeloma protein increase by more than 100% from the lowest level recorded on study, or a 
rise of 2.0 g/dl (this increase must be to a level > 1.0 g/dL if it is to constitute the sole 
manifestation of relapse). 
• 
Myeloma protein increase above the response criteria for PR. 
• 
Reappearance of M-protein in blood or urine not related to immune recovery or recent 
infection.  
• 
Increase in the size and number of lytic bone lesions recognized on radiographs.  New 
skeletal or MRI lesions, preferentially confirmed by fine needle aspirate. 
• 
Myeloma-related cytogenetic abnormalities. 
• 
BM plasmacytosis > 10% or > 5% light chain restricted, non-diploid, plasma cells on cIg/DNA. 
• 
Hypercalcemia, not explained by any other cause. 
 
Survival Outcomes 
Overall Survival 
Measured as the time from initial registration to death from any cause. 
Progression-Free Survival 
Measured as the time from initial registration to progression/relapse of disease or death from any cause 
 
 


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APPENDIX IV - PERFORMANCE STATUS SCALE AND ADVERSE EVENT GRADING 
ECOG Grading Scale 
Participants will be graded according to the current ECOG grading scale: 
 
Grade  
Scale 
0 
Fully active; able to carry on all pre-disease activities without restriction.  (Karnofsky 
90-100). 
 
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.  (Karnofsky 70-80). 
 
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.  (Karnofsky 50-60). 
 
3 
Capable of only limited self-care; confined to be or chair more than 50% of waking 
hours (Karnofsky 30-40). 
 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair 
(Karnofsky 10-20). 
 
Adverse Event Criteria 
This study will utilize the CTCAE Version 5.0 for toxicity and performance reporting.  A copy of the 
CTCAE version 5.0 can be downloaded from the CTEP home page at http://ctep.info.nih.gov). 
Additionally, the toxicities are to be reported in the appropriate data collection tools. 
 
 


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APPENDIX V - CRITERIA FOR REMOVAL FROM TREATMENT AND STUDY 
Criteria for Removal from Treatment: 
a. Completion of protocol therapy 
b. Progressive disease or relapse 
c. Delay of > 2 months in the start of subsequent cycles 
d. Unacceptable toxicity (i.e., non-reversible Grade 3 or Grade 4 life-threatening toxicity probably or 
definitely related to protocol therapy) 
e. Major deviation in protocol therapy 
f. Discontinuation of DARA due to safety or tolerability 
g. Development of second neoplasm (SMN) 
h. Pregnancy 
i. 
The patient may withdraw from the study at any time for any reason 
 
Notes: 
• 
Subjects may remain on study if lenalidomide intolerance requires discontinuation; the subject 
may continue on single-agent DARA at the discretion of the principal investigator. 
• 
All reasons for discontinuation of treatment must be clearly documented in source documents 
and database.  
 
Criteria for Removal from Protocol Follow-Up/Off study Criteria 
a. 
Death 
b. 
Lost to follow-up 
c. 
Withdrawal of consent for any further data collection 
 
 


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APPENDIX V - INSTITUTIONAL DARATUMUMAB PROTOCOL 
17.1 
Background 
DARA is an IgG1κ human monoclonal antibody directed against CD38. CD38 is a cell surface 
glycoprotein which is highly expressed on myeloma cells, yet is expressed at low levels on 
normal lymphoid and myeloid cells. By binding to CD38, DARA inhibits the growth of CD38 
expressing tumor cells by inducing apoptosis. 
 
17.2 
Usual Dosage 
Weeks 1-8:  
16 mg/kg once weekly for 8 doses 
Weeks 9-24:  16 mg/kg once every 2 weeks for 8 doses 
Weeks 25+:  16 mg/kg once every 4 weeks until disease progression 
All doses to be based on patient’s actual body weight. 
 
17.3 
Standard Dilution and Titration Parameters 
 
Dilution 
Volume 
Initial rate 
(First Hour) 
Rate Increments+ 
Maximum 
Rate 
First infusion* 
1000 mL 
50 mL/hour 
50 mL/hour every 
hour 
200 mL/hour 
Second 
Infusion 
500 mL 
50 mL/hour 
50 mL/hour every 
hour 
200 mL/hour 
Subsequent 
Infusion 
500 mL 
100 mL/hour 
50 mL/hour every 
hour 
200 mL/hour 
*if adverse reaction occurs, use first infusion instructions for all future doses 
+only increase rate if patient is without adverse reaction 
 
17.4 
Rapid Infusion 
Rapid infusion parameters may be initiated for the third dose of DARA and beyond if the patient 
has not experienced any prior infusion-related adverse effects. 
• 
Must be denoted on patient’s written chemo orders from the physician. 
• 
Intended for outpatient administration only. 


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• 
Drug will be diluted in 500 mL of normal saline and infused at 240 mL/hour for first 30 
minutes (20% of dose), then 480 mL/hour for remaining 60 minutes (80% of dose). 
Entire volume of bag should be infused. 
 
17.5 
Pre- and Post-Infusion Medications 
Indicated to reduce the risk of infusion reactions and delayed infusion reactions, which are 
frequently respiratory in nature. Administer pre-medications at least 1 hour prior to initiating the 
infusion. Pre- and post-medications may vary at the discretion of the oncologist. 
 
Standard Pre-and Post-Medications: 
• 
Dexamethasone 20 mg IV prior to infusion 
• 
Tylenol 650 mg PO prior to infusion 
• 
Benadryl 25 mg PO prior to infusion 
• 
Albuterol 90 mcg 2 puffs prior to infusion and PRN 
• 
Singulair 10 mg days 1, 2 and 3 
• 
Allegra 180 mg days 1, 2 and 3 
• 
Dexamethasone 4 mg days 2 and 3 
 
17.6 
Recommended Monitoring 
• 
Standard Infusion: Patient’s vitals (blood pressure, heart rate, respiratory rate, and 
temperature) should be monitored prior to the start of the infusion, every 30 minutes 
during the infusion, and repeated at the end of the infusion. 
• 
Rapid Infusion: Patient’s vitals should be monitored prior to the infusion and every 15 
minutes during the first hour, and repeated at the end of the infusion. 
 
17.7 
Common Side Effects 
 
Fatigue, nausea, joint pain, back pain, fever, chills, dizziness, cough, shortness of breath, 
nasal congestion, cold-like symptoms (upper respiratory infection), swollen hands, ankles or 
feet, thrombocytopenia, anemia. 
 


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17.8 
Management of Adverse Reactions 
• 
For infusion reactions of any grade/severity, immediately stop infusion, manage symptoms, 
and notify MD/APRN. 
• 
Grade 1-2 (mild to moderate): Once reaction symptoms resolve, resume the infusion at no 
more than HALF the rate at which the reaction occurred. If the patient does not experience 
any further reaction symptoms, infusion rate escalation may resume at increments and 
intervals as clinically appropriate. 
• 
Grade 3 (severe): Once reaction symptoms resolve, consider restarting the infusion at no 
more than HALF the rate at which the reaction occurred. If the patient does not experience 
additional symptoms, resume infusion rate escalation at increments and intervals as 
appropriate. 
• 
Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently 
discontinue daratumumab upon the third occurrence of a Grade 3 or greater infusion reaction. 
• 
Grade 4 (life threatening): Permanently discontinue daratumumab treatment. 
• 
Notify “DARA INFUSION REACTION” email group, so pharmacist and MD may adjust 
orders as indicated. 
 
 
 


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APPENDIX VI – LIST OF ABBREVIATIONS 
aCGH  
Microarray-based Comparative Genomic Hybridization 
AE  
 
Adverse Event 
BM  
 
Bone Marrow 
BMP 
 
Basic Metabolic Panel 
CBC   
Complete Blood Count 
CIDP  
Chronic Inflammatory Demyelinating Polyneuropathy 
CR  
 
Complete Response 
CrCl 
 
Creatinine Clearance 
CRF 
 
Case Report Form 
CT  
 
Computed Tomography 
CTCAE  
NCI Common Terminology for Adverse Events 
DARA  
Daratumumab 
DLCO  
Diffusing Capacity of the Lungs for Carbon Monoxide 
ECOG  
Eastern Cooperative Oncology Group 
FDA   
Food and Drug Administration 
FDG   
Fluorodeoxyglucose 
FEV1  
Forced Expiration Volume in One Second 
FVC 
 
Forced Vital Capacity 
GEP   
Gene Expression Profiling 
H&P 
 
History and Physical 
HBV 
 
Hepatitis B Virus 
HIPAA  
Health Insurance Portability and Accountability Act 
ICH  
 
International Conference on Harmonization 
IMiD 
 
Immunomodulatory Drug 
IMWG  
International Myeloma Working Group 
INC 
 
Increasing Disease 
IRB  
 
Institutional Review Board 
MGUS  
Monoclonal Gammopathy of Undetermined Significance 
MM  
 
Multiple Myeloma 
NCI  
 
National Cancer Institute 
nCR   
Near Complete Response 
ONLS  
Overall Neuropathy Limitations Scale 
OS  
 
Overall Survival 
PB  
 
Peripheral Blood 


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PBSCT 
Peripheral Blood Stem Cell Transplant 
PC  
 
Plasma Cells 
PET-CT 
Positron Emission Tomography – Computed Tomography 
PFS   
Progression Free Survival 
PI  
 
Proteasome Inhibitor 
PK  
 
Pharmacokinetics 
PO  
 
By Mouth 
PR  
 
Partial Response 
PROG  
Disease Progression 
RBCs  
Red Blood Cells 
RNA 
 
Ribonucleic acid 
SAE   
Serious Adverse Event 
sCR 
 
Stringent Complete Response 
SoC 
 
Standard of Care 
STA 
 
Stable Disease 
UAMS  
University of Arkansas for Medical Sciences 
UCR 
 
Unconfirmed Complete Response 
UPR 
 
Unconfirmed Partial Response 
UsCR  
Unconfirmed Stringent Complete Response 
UVGPR 
Unconfirmed Very Good Partial Response 
VEGF  
Vascular Endothelial Growth Factor 
VGPR  
Very Good Partial Response 
WoCBP 
Women of Child Bearing Potential