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10.4 serious adverse events

When the principal investigator has determined that a Serious Adverse Event has occurred, the principal investigator is responsible for providing all Serious Adverse Events to ProductLife LTD by fax [0 800 022 4815] within 24 hrs of the site becoming aware of the event and to the IRB within respective required guidelines. If fax is not available, the form may be scanned and emailed to safety@productlife-group.com. This applies to initial and follow-up information.
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follow-up reports

The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she should follow up the outcome of any Serious Adverse Event and complete follow-up forms as necessary. The patient must be followed up until recovery, stabilization or return to baseline. This may mean that follow-up will continue after the patient has completed the trial and that additional investigations may be necessary.  
Any reportable Serious Adverse Events brought to the attention of the Investigator at any time after cessation of the trial and considered by him/her to be reasonably associated with medication administered during the period should also be submitted to the IRB and to Medivation Inc via ProductLife Ltd.  
As with the initial submission to the IRB, the principal investigator is also responsible for providing all follow-ups of Serious Adverse Events to the IRB and to Medivation Inc, designated pharmacovigilance representative, ProductLife Ltd, using the forms provided by Medivation Inc. for this purpose.
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10.5 reporting of adverse event

Collection of safety information following the end of investigational product administration is important in assisting in the identification of possible delayed toxicities or withdrawal effects. All SAEs must be collected which occur within 30 days of discontinuation of dosing or completion of the patient's participation in the study if the last scheduled visit occurs at a later time.
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10.6 pregnancy statement and use

All women of childbearing potential MUST have a negative pregnancy test as required by the RevAssist program. If the pregnancy test is positive, the patient must not receive any investigational product and must not be enrolled in the study.  
Definition of Childbearing Potential: For the purposes of this study, a female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months). Thalidomide, an analog of lenalidomide causes fetal harm and birth defects when administered to a pregnant woman. There are, however no adequate and well-controlled studies of lenalidomide in pregnant women. In New Zealand white rabbits at 10 and 20 mg/kg/day, lenalidomide was maternally toxic (reduced body weight gain and feed consumption; at 20 mg/kg/day, weight loss and one abortion). Developmental toxicity at 10 and 20 mg/kg/day included reduced fetal body weights and increased postimplantation losses and fetal variations (morbidity/purple-discolored skin, undeveloped intermediate lung lobe, irregular nasal-frontal suture, and delayed metacarpal ossification)60. The maternal and developmental no observed adverse effect levels (NOAELs) was 3mg/kg/day. If the drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. During the course of the trial, all patients of childbearing potential should be instructed to contact the treating physician immediately if they suspect they might have conceived a child. In addition, a missed or late menstrual period should be reported to the treating physician. If a female patient or the treating physician suspects that the female patient may be pregnant prior to administration of study drugs, the study drugs must be withheld until the results of a pregnancy test are available. If pregnancy is confirmed the patient must not receive study medications and must be withdrawn from the study. Throughout the entire pregnancy, additional contact should be made with the patient, and in some cases with the healthcare provider, to identify spontaneous abortions and elective terminations, as well as any medical reasons for elective termination. In addition, the study investigator should include perinatal and neonatal outcome. Infants should be followed for a minimum of 4 weeks. If a male patient is suspected of having fathered a child while on study drugs, the pregnant female partner must be notified and counseled regarding the risk to the fetus. In addition, the treating physician must follow the course of the pregnancy, including prenatal and neonatal outcome. Infants should be followed for a minimum of eight weeks. Upon live-birth delivery, the minimum information that should be collected includes date of birth, length of pregnancy, sex of infant, major and minor anomalies identified at birth. Outcomes can be obtained via mailed questionnaires, maternal interviews, medical record abstraction, or a combination of these methods. All serious adverse event reports relating to the pregnancy, including spontaneous abortion, elective abortion and congenital anomalies, should be forwarded to the FDA & Medivation Inc. (See Safety reporting section). It is not known whether lenalidomide or CT-011 is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from lenalidomide, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
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10.7 patient withdrawal and study

A patient should be withdrawn from the trial treatment if, in the opinion of the investigator, it is medically necessary, or if it is the wish of the patient. If a patient does not return for a scheduled visit, every effort should be made to contact the patient. In any circumstance, every effort should be made to document patient outcome, if possible. Patients should be removed from therapy if any of the following occurs:
The occurrence of unacceptable toxicity indicating the need for cessation of treatment.  
Patients may continue with correlative studies.  
Patient has progressive disease while receiving treatment The physician feels it is in the best interest of the patient to stop treatment and the physician may determine whether to continue with correlative studies.  
Patient refusal to continue with therapy. Non-compliance by the patient with protocol requirements. Patient is lost to follow-up. If a patient does not return for scheduled visits, every effort should be made to re-establish contact. In any circumstance, every effort should be made to document patient outcome, if possible.  
Patient becomes pregnant.  
Termination of the study.  
If a patient withdraws from protocol therapy, it should be clearly documented with additional notation of whether the patient has agreed to complete follow up as outlined in the protocol. Subsite institutions must notify the OSU Subsite Coordinator as soon as possible if the patient withdraws from protocol therapy and must provide the documentation of the reason and whether the patient will complete follow up. The reason and date of discontinuation are to be documented in the patient's medical record and in the CRF. The investigator should complete all end of treatment procedures when a patient withdraws from treatment. All patients who discontinue the trial secondary to an adverse event should be followed until resolution, stabilization or return to a baseline condition. Patients who fail to complete treatment for reasons other than adverse event or unacceptable toxicity may be replaced. All patients who receive one dose of study treatment should be included in any safety analysis.  
The investigator may discontinue the trial at any time. Reasons for early trial discontinuation may include, but are not limited to, unacceptable toxicity of study treatment, a request to discontinue the trial from a regulatory authority or an IRB, or poor enrollment.
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11.0 references

1. Cook G, Campbell JD. Immune regulation in multiple myeloma: the host-tumour conflict. Blood Rev. 1999;13:151-162. 2. Mozaffari F, Hansson L, Kiaii S, et al. Signalling molecules and cytokine production in T cells of multiple myeloma-increased abnormalities with advancing stage. Br J Haematol. 2004;124:315-324. 3. Frassanito MA, Cusmai A, Dammacco F. Deregulated cytokine network and defective Th1 immune response in multiple myeloma. Clin Exp Immunol. 2001;125:190-197. 4. Ratta M, Fagnoni F, Curti A, et al. Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. Blood. 2002;100:230-237. 5. Chauhan D, Singh AV, Brahmandam M, et al. Functional interaction of plasmacytoid dendritic cells with multiple myeloma cells: a therapeutic target. Cancer Cell. 2009;16:309-323. 6. Beyer M, Kochanek M, Giese T, et al. In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma. Blood. 2006;107:3940-3949.  
7. Nielsen H, Nielsen HJ, Tvede N, et al. Immune dysfunction in multiple myeloma. Reduced natural killer cell activity and increased levels of soluble interleukin-2 receptors. APMIS. 1991;99:340-346. 8. Pilarski LM, Andrews EJ, Mant MJ, Ruether BA. Humoral immune deficiency in multiple myeloma patients due to compromised B-cell function. J Clin Immunol. 1986;6:491-501.  
9. Spisek R, Kukreja A, Chen LC, et al. Frequent and specific immunity to the embryonal stem cellassociated antigen SOX2 in patients with monoclonal gammopathy. J Exp Med. 2007;204:831-840.  
10. Carbone E, Neri P, Mesuraca M, et al. HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells. Blood. 2005;105:251-258. 11. Nucci M, Anaissie E. Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents. Clin Infect Dis. 2009;49:1211-1225. 12. Benson DM, Jr., Bakan CE, Mishra A, et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood. 2010;116:2286-2294. 13. Osterborg A, Nilsson B, Bjorkholm M, Holm G, Mellstedt H. Natural killer cell activity in monoclonal gammopathies: relation to disease activity. Eur J Haematol. 1990;45:153-157. 14. Gonzalez M, San Miguel JF, Gascon A, et al. Increased expression of natural-killer-associated and activation antigens in multiple myeloma. Am J Hematol. 1992;39:84-89. 15. Garcia-Sanz R, Gonzalez M, Orfao A, et al. Analysis of natural killer-associated antigens in peripheral blood and bone marrow of multiple myeloma patients and prognostic implications. Br J Haematol. 1996;93:8188. 16. Davies FE, Raje N, Hideshima T, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001;98:210-216. 17. Shi J, Tricot GJ, Garg TK, et al. Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma. Blood. 2008;111:1309-1317. 18. Frassanito MA, Silvestris F, Cafforio P, Silvestris N, Dammacco F. IgG M-components in active myeloma patients induce a down-regulation of natural killer cell activity. Int J Clin Lab Res. 1997;27:48-54. 19. Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004;4:336-347. 20. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. 21. Brown JA, Dorfman DM, Ma FR, et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol. 2003;170:1257-1266. 22. Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 2003;63:6501-6505. 23. Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 2004;10:5094-5100. 24. Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A. 2007;104:3360-3365. 25. Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114:1537-1544. 26. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99:12293-12297. 27. Liu J, Hamrouni A, Wolowiec D, et al. Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6- , and MEK-dependent pathway. Blood. 2007;110:296-304. 28. Romagne F, Andre P, Spee P, et al. Preclinical characterization of 1-7F9, a novel human anti-KIR
receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells. Blood.  
2009;114:2667-2677. 29. Mumprecht S, Schurch C, Schwaller J, Solenthaler M, Ochsenbein AF. Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression. Blood. 2009;114:1528-1536. 30. Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood. 2009;114:1545-1552. 31. Kinter AL, Godbout EJ, McNally JP, et al. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol. 2008;181:6738-6746. 32. Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108:3458-3464. 33. Richardson P, Jagannath S, Hussein M, et al. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 2009;114:772-778. 34. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133-2142. 35. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123-2132. 36. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an openlabel randomised controlled trial. Lancet Oncol;11:29-37.  
37. Hardy B, Kovjazin R, Raiter A, Ganor N, Novogrodsky A. A lymphocyte-activating monoclonal antibody induces regression of human tumors in severe combined immunodeficient mice. Proc Natl Acad Sci U S A. 1997;94:5756-5760. 38. Hardy B, Galli M, Rivlin E, Goren L, Novogrodsky A. Activation of human lymphocytes by a monoclonal antibody to B lymphoblastoid cells; molecular mass and distribution of binding protein. Cancer Immunol Immunother. 1995;40:376-382. 39. Hardy B, Yampolski I, Kovjazin R, Galli M, Novogrodsky A. A monoclonal antibody against a human B lymphoblastoid cell line induces tumor regression in mice. Cancer Res. 1994;54:5793-5796. 40. Frauwirth KA, Thompson CB. Activation and inhibition of lymphocytes by costimulation. J Clin Invest. 2002;109:295-299. 41. Quaglino E, Mastini C, Iezzi M, et al. The adjuvant activity of BAT antibody enables DNA vaccination to inhibit the progression of established autochthonous Her-2/neu carcinomas in BALB/c mice. Vaccine. 2005;23:3280-3287. 42. Raiter A, Rodionov G, Novogrodsky A, Hardy B. CD4+ T lymphocytes as a primary cellular target for BAT mAb stimulation. Int Immunol. 2000;12:1623-1628. 43. Hardy B, Indjiia L, Rodionov G, Raiter A, Inbal A. Treatment with BAT monoclonal antibody decreases tumor burden in a murine model of leukemia/lymphoma. Int J Oncol. 2001;19:897-902. 44. Hardy B, Morgenstern S, Raiter A, Rodionov G, Fadaeev L, Niv Y. BAT monoclonal antibody immunotherapy of human metastatic colorectal carcinoma in mice. Cancer Lett. 2005;229:217-222. 45. Hardy B, Kovjazin R, Raiter A, Ganor N, Novogrodsky A. Immune stimulatory and anti-tumor properties of anti-CD3 and BAT monoclonal antibodies: a comparative study. Hum Antibodies. 1997;8:95-98. 46. Feinmesser M, Raiter A, Hardy B. Prevention of melanoma metastases in lungs of BAT treated and peptide immunized mice. Int J Oncol. 2006;29:911-917. 47. Hardy B, Niv Y, Fadaeev L, Raiter A. BAT mAb induces lymphopoiesis in nude mice. Int Immunol. 2005;17:615-619. 48. Rosenblatt J, Glotzbecker B, Mills H, et al. CT-011, Anti-PD-1 Antibody, Enhances Ex-Vivo T Cell Responses to Autologous Dendritic/Myeloma Fusion Vaccine Developed for the Treatment of Multiple Myeloma. ASH Annual Meeting Abstracts. 2009;114:781-. 49. Benson DM, Jr., Bakan CE, Mishra A, et al. The PD-1 / PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel, monoclonal anti-PD-1 antibody.  
Blood.  
50. Berger R, Rotem-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14:3044-3051. 51. Rotem-Yehudar R, Armand P, Devine S, et al. The Humanized Anti PD-1 Antibody, CT-011, Increases Specific CD4+ Effector/Memory and Memory T Lymphocytes in Patients with Diffuse Large B Cell Lymphoma (DLBCL) Following Autologous Stem Cell Transplantation (AuSCT). ASH Annual Meeting Abstracts. 2009;114:1216-. 52. Schafer PH, Gandhi AK, Loveland MA, et al. Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. J Pharmacol Exp Ther. 2003;305:1222-1232. 53. Hayashi T, Hideshima T, Akiyama M, et al. Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application. Br J Haematol. 2005;128:192-203.  
54. Zhu D, Corral LG, Fleming YW, Stein B. Immunomodulatory drugs Revlimid (lenalidomide) and CC4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation. Cancer Immunol Immunother. 2008;57:1849-1859. 55. Wang M, Dimopoulos MA, Chen C, et al. Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood. 2008;112:4445-4451.  
56. Stadtmauer EA, Weber DM, Niesvizky R, et al. Lenalidomide in combination with dexamethasone at first relapse in comparison with its use as later salvage therapy in relapsed or refractory multiple myeloma. Eur J Haematol. 2009;82:426-432. 57. Gandhi AK, Kang J, Capone L, et al. Dexamethasone synergizes with lenalidomide to inhibit multiple myeloma tumor growth, but reduces lenalidomide-induced immunomodulation of T and NK cell function. Curr Cancer Drug Targets;10:155-167. 58. Chu F FM, Qin H, et. al. In vitro and in vivo effects of CT-011, a humanized anti-PD-1 monoclonal antibody, in combination with rituximab against human B-cell lymphomas. Blood. 2009;114. 59. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127:759-767. 60. Christian MS, Laskin OL, Sharper V, Hoberman A, Stirling DI, Latriano L. Evaluation of the developmental toxicity of lenalidomide in rabbits. Birth Defects Res B Dev Reprod Toxicol. 2007;80:188-207. 61. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467-1473.
appendix a ecog/kps scale
11.0 references

| ECOG Performance Status Scale                                                                                                                                                              | Karnofsky Performance Scale                                   |                                                                           |                                                                        |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|---------------------------------------------------------------------------|------------------------------------------------------------------------|
| Grade                                                                                                                                                                                      | Descriptions                                                  | Percent                                                                   | Description                                                            |
| 100                                                                                                                                                                                        | Normal, no complaints, no evidence  of disease.               |                                                                           |                                                                        |
| Normal activity. Fully active, able                                                                                                                                                        |                                                               |                                                                           |                                                                        |
| 0                                                                                                                                                                                          | to carry on all pre-disease  performance without restriction. | 90                                                                        | Able to carry on normal activity;  minor signs or symptoms of disease. |
| Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work). | 80                                                            | Normal activity with effort; some  signs or symptoms of disease.          |                                                                        |
| 1                                                                                                                                                                                          | 70                                                            | Cares for self, unable to carry on  normal activity or to do active work. |                                                                        |
| In bed <50% of the time.  Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  more than 50% of waking hours.                             | Requires occasional assistance, but                           |                                                                           |                                                                        |
| 60                                                                                                                                                                                         | is able to care for most of his/her  needs.                   |                                                                           |                                                                        |
| 2                                                                                                                                                                                          | 50                                                            | Requires considerable assistance and  frequent medical care.              |                                                                        |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                                                     | 40                                                            | Disabled, requires special care and  assistance.                          |                                                                        |
| 3                                                                                                                                                                                          | 30                                                            | Severely disabled, hospitalization  indicated. Death not imminent.        |                                                                        |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                   | 20                                                            | Very sick, hospitalization indicated.  Death not imminent.                |                                                                        |
| 4                                                                                                                                                                                          | 10                                                            | Moribund, fatal processes  progressing rapidly.                           |                                                                        |
| 5                                                                                                                                                                                          | Dead.                                                         | 0                                                                         | Dead.                                                                  |
| Mor V, Laliberte L, Morris JN, Wiemann M. The Karnofsky Performance Status Scale: an examination of its  reliability and validity in a research setting. Cancer 1984;53:2002-2007.         |                                                               |                                                                           |                                                                        |
appendix b imwg response criteria
11.0 references

Serum and urine M-protein estimates will be performed every 4 weeks; except for assessment of CR,
patients with measurable disease restricted to the SPEP (or UPEP) will need to be followed only by SPEP (or UPEP).  Responses will be assessed according to the criteria of the International Myeloma  
| Working Group 61 , and characterized as follows:                      |                                                                   |
|-----------------------------------------------------------------------|-------------------------------------------------------------------|
| Response Category                                                     | Response Criteria®                                                |
| SCR                                                                   | CR as defined below plus                                          |
| Normal FLC ration and                                                 |                                                                   |
| .                                                                     | Absence of clonal cells in bone marrow by                         |
| immunohistochemistry or immunofluorescence                            |                                                                   |
| CR                                                                    | Negative immunofixation on the serum and urine and disappearance  |
| of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone        |                                                                   |
| marrow                                                                |                                                                   |
| VGPR                                                                  | Serum and urine M-protein detectable by immunofixation but not on |
| electrophoresis or 90% or greater reduction in serum M-protein plus   |                                                                   |
| urine M-protein level < 100 mg per 24 hours                           |                                                                   |
| PR                                                                    | ≥ 50% reduction of serum M-Protein and reduction in 24 hour       |
| urinary M-protein by ≥ 90% or to < 200 mg per 24 hours                |                                                                   |
| If the serum and urine M-protein are unmeasurable d a ≥ 50%           |                                                                   |
| decrease in the difference between involved and uninvolved FLC        |                                                                   |
| levels is required in place of the M-protein criteria                 |                                                                   |
| If serum and urine M-protein are unmeasurable, and the serum free     |                                                                   |
| light assay is also unmeasurable, ≥ 50% reduction in plasma cells is  |                                                                   |
| required in place of M-protein provided baseline bone marrow          |                                                                   |
| plasma cell percentage was ≥ 30%                                      |                                                                   |
| In addition to the above, if present at baseline a ≥ 50% reduction in |                                                                   |
| the size of soft tissue plasmacytomas is also required                |                                                                   |
| SD                                                                    | Not meeting criteria for CR, VGPR, PR, or progressive disease     |
| Relapse Category                                                      | Relapse Criteria                                                  |
| Requires only one of the following :                                  |                                                                   |
| Progressive disease                                                   | Increase of > 25% from baseline in:                               |
| Serum M-component and/or (the absolute increase must                  |                                                                   |
| .                                                                     | be ≥ 0.5 g/dl) 8                                                  |
| .                                                                     | Urine M-component and/or (the absolute increase must              |
| be ≥ 200 mg/24 hours)                                                 |                                                                   |
| .                                                                     | In patients without measurable serum and urine M-                 |
| protein levels the difference between involved and                    |                                                                   |  
| uninvolved FLC levels, the absolute increase must be >                                                                 |                                                         |                                                     |
|------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------|-----------------------------------------------------|
| 10 mg/dl.                                                                                                              |                                                         |                                                     |
| .                                                                                                                      | Bone marrow plasma cell percentage, the absolute %      |                                                     |
| must be ≥ 10% n .                                                                                                      |                                                         |                                                     |
| .                                                                                                                      | Definite development of new bone lesions or soft tissue |                                                     |
| plasmacytomas increase in the size of existing bone                                                                    |                                                         |                                                     |
| lesions or soft tissue plasmacytomas.                                                                                  |                                                         |                                                     |
| .                                                                                                                      | Development of hypercalcemia (corrected serum calcium   |                                                     |
| > 11.5 mg/dl or 2.65 mmol/l) that can be attributed                                                                    |                                                         |                                                     |
| solely to the plasma cell proliferative disorder.                                                                      |                                                         |                                                     |
| Clinical relapse                                                                                                       | Clinical relapse requires one or more of:               |                                                     |
| (Not used for TTP or                                                                                                   | .                                                       | Development of new soft tissue plasmacytoma or bone |
| PFS)                                                                                                                   | lesions                                                 |                                                     |
| .                                                                                                                      | Definite increase in the size of existing plasmacytomas |                                                     |
| or bone lesions.  A definite increase is defined as a 50%                                                              |                                                         |                                                     |
| (and at least 1 cm) increase as measured serially by the                                                               |                                                         |                                                     |
| sum of the products of the cross-diameters of the                                                                      |                                                         |                                                     |
| measurable lesion                                                                                                      |                                                         |                                                     |
| Hypercalcemia (> 11.5 mg/dl [2.65 mmol/l])                                                                             |                                                         |                                                     |
| .                                                                                                                      | Decrease in hemoglobin of ≥ 2 g/dl (1.25 mmol/l)        |                                                     |
| .                                                                                                                      | Rise in serum creatinine by 2 mg/dl or more (177 µmol/l |                                                     |
| .                                                                                                                      | or more)                                                |                                                     |
| Relapse from CR i                                                                                                      | Any one or more of the following:                       |                                                     |
| .                                                                                                                      | Reappearance of serum or urine M-protein by             |                                                     |
| immunofixation or electrophoresis                                                                                      |                                                         |                                                     |
| Development of ≥ 5% plasma cells in the bone marrow 1                                                                  |                                                         |                                                     |
| .                                                                                                                      | Appearance of any other sign or progression             |                                                     |
| .                                                                                                                      |                                                         |                                                     |
| a. All response categories require two consecutive assessments made at anytime before the institution of any new       |                                                         |                                                     |
| therapy, all categories also require no known evidence of progressive or new bone lesions if radiographic studies      |                                                         |                                                     |
| were performed. Radiographic studies are not required to satisfy these response criteria.                              |                                                         |                                                     |
| b. Confirmation with repeat biopsy not necessary.                                                                      |                                                         |                                                     |
| c. Presence/absence of clonal cells is based upon the κ/λ ratio by immunohistochemistry and/or immunofluorescence      |                                                         |                                                     |
| requires a minimum of 100 plasma cells for analysis.  An abnormal ration reflecting presence of an abnormal clone      |                                                         |                                                     |
| is κ/λ of > 4:1 or < 1:2.                                                                                              |                                                         |                                                     |
| d . Applicable only to patients who have 'measurable' disease defined by at least one of the following three           |                                                         |                                                     |
| measurements: Serum M-protein ≥ 1 g/dl, Urine M-protein ≥ 200 mg/24hour, Serum FLC assay involved FLC level            |                                                         |                                                     |
| ≥ 10 mg/dl provided serum FLC ration is abnormal.                                                                      |                                                         |                                                     |
| e. Not recommended for use as an indicator of response; stability of disease is best described by providing the time   |                                                         |                                                     |
| too progression estimates).                                                                                            |                                                         |                                                     |
| f. All relapse categories require two consecutive assessments made at anytime before classification as relapse or      |                                                         |                                                     |
| disease progression and/or the institution of any new therapy.                                                         |                                                         |                                                     |
| g. For progressive disease, serum M-component increases of ≥ 1 gm/dl are sufficient to define relapse if starting M-   |                                                         |                                                     |
| component is ≥ 5 g/dl.                                                                                                 |                                                         |                                                     |
| h. Relapse from CR has the 5% cutoff versus 10% for other categories or relapse.                                       |                                                         |                                                     |
| 1. To only be used if the end point studied is disease free survival.  For purposes of calculating time to progression |                                                         |                                                     |  
and progression-free survival, CR patients should also be evaluated using criteria listed above for progressive disease.  
j . Relapse from CR has the 5% cutoff versus 10% for other categories of relapse.
appendix b imwg response criteria
appendix c nyha cardiac disease

| Class                                                                                                                                                                                                    | Functional Capacity                                                                                                                                                                                                                                           | Objective Assessment                                              |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|
| I                                                                                                                                                                                                        | Patients with cardiac disease but without resulting limitations of  physical activity. Ordinary physical activity does not cause undue  fatigue, palpitation, dyspnea, or anginal pain.                                                                       | No objective evidence  of cardiovascular  disease.                |
| II                                                                                                                                                                                                       | Patients with cardiac disease resulting in slight limitation of physical  activity. They are comfortable at rest. Ordinary physical activity  results in fatigue, palpitation, dyspnea, or anginal pain.                                                      | Objective evidence of  minimal  cardiovascular disease.           |
| III                                                                                                                                                                                                      | Patients with cardiac disease resulting in marked limitation of  physical activity. They are comfortable at rest. Less than ordinary  activity causes fatigue, palpitation, dyspnea, or anginal pain.                                                         | Objective evidence of  moderately severe  cardiovascular disease. |
| IV                                                                                                                                                                                                       | Patients with cardiac disease resulting in inability to carry on any  physical activity without discomfort. Symptoms of heart failure or  the anginal syndrome may be present even at rest. If any physical  activity is undertaken, discomfort is increased. | Objective evidence of  severe cardiovascular  disease.            |
| Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis of  Diseases of the Heart and Great Vessels. 9th Ed. Boston, MA: Little, Brown & Co; 1994:253-256. |                                                                                                                                                                                                                                                               |                                                                   |
appendix b imwg response criteria
appendix d fact/gog-neurotoxicity

By circling one (1) number per line, please indicate how true each statement has been for you during the
appendix b imwg response criteria
past 7 days.

| Not                                                                                 | A little   | Somewhat     | Quite   | Very   |    |
|-------------------------------------------------------------------------------------|------------|-----|---------|--------|----|
| ADDITIONAL CONCERNS                                                                 | at all     | bit | a bit   | much   |    |
| I have numbness or tingling in my hands………                                          | 0          | 1   | 2       | 3      | 4  |
| I have numbness or tingling in my feet…………                                          | 0          | 1   | 2       | 3      | 4  |
| I feel discomfort in my hands………………….                                               | 0          | 1   | 2       | 3      | 4  |
| I feel discomfort in my feet……………………                                                | 0          | 1   | 2       | 3      | 4  |
| I have joint pain or muscle cramps……………                                             | 0          | 1   | 2       | 3      | 4  |
| I feel weak all over……………………………                                                     | 0          | 1   | 2       | 3      | 4  |
| I have trouble hearing…………………………                                                    | 0          | 1   | 2       | 3      | 4  |
| I get a ringing or buzzing in my ears…………                                           | 0          | 1   | 2       | 3      | 4  |
| I have trouble buttoning buttons………………                                              | 0          | 1   | 2       | 3      | 4  |
| I have trouble feeling the shape of small objects when they are in my hand……………………… | 0          | 1   | 2       | 3      | 4  |
| I have trouble walking…………………………                                                    | 0          | 1   | 2       | 3      | 4  |  
Sources: Cella DF, Tulsky DS, Gray G, Sarafian B, Lloyd S, Linn E, et al. The functional assessment of cancer therapy
(FACT) scale: development and validation of the general measure. *J Clin Oncol* 1993;11(3):570-79.
appendix b imwg response criteria
appendix e ethical and regulatory

The study should be conducted according to the principles outlined by the 18th World Medical Assembly (Helsinki, 1964) and all applicable amendments; the International Conference on Harmonization Guidelines for Good Clinical Practice; and FDA regulations regarding the conduct of clinical trials and the protection of human subjects.
appendix b imwg response criteria
protocol compliance and protocol revisions

The study must be conducted as described in this approved protocol. All revisions to the protocol must be provided to Medivation Inc. The investigator should not implement any deviation or change to the protocol without prior review and documented approval/favorable opinion from the IRB of an Amendment, except where necessary to eliminate an immediate hazard(s) to study patients. Documentation of approval signed by the chairperson or designee of the IRB(s) must be sent to Medivation Inc. If the revision is an administrative letter, the investigator(s) must inform the IRB.
appendix b imwg response criteria
informed consent data safety and

It is the responsibility of the investigator to obtain written informed consent from a patient or a patient's legal representative before any study related procedures are performed. The Investigator will provide an informed consent in compliance with ICH GCP and U.S. FDA guidelines (21 CFR 50). The informed consent document must clearly describe the potential risks and benefits of the trial, and each prospective participant must be given adequate time to discuss the trial with the Investigator or site staff and to decide whether or not to participate. The informed consent must be approved by the IRB prior to being presented to a potential patient. One copy of the patient's signed, dated and witnessed written consent will be kept in the patient's medical record and one copy will be given to the patient or the patient's legal representative. Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) and in the US Code of Federal Regulations. Investigators must enter study data into a secure data collection system that will be accessible to only parties involved in the trial. The Investigator will permit studyrelated monitoring visits and audits by Medivation Inc. or its representatives, IRB, providing direct access to the facilities where the study took place, to source documents, and to all other study documents. The Investigator, or a designated member of the Investigator's staff, must be available at some time during monitoring 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. The data collection must be completed prior to each visit and be made available to the Medivation Inc. representative so that the accuracy and completeness may be checked.
appendix b imwg response criteria
data safety monitoring plan

The data and safety monitoring plan will involve the continuous evaluation of safety, data quality and data timeliness. Investigators will conduct continuous review of data and patient safety at their regular Disease Group meetings (at least monthly) and the discussion will be documented in the minutes. The PI of the trial will review toxicities and responses of the trial where applicable at these disease center meetings and determine if the risk/benefit ratio of the trial changes. Frequency and severity of adverse events will be reviewed by the PI and compared to what is known about the agent/device OSU-13128 - Amd v26Jan2016 57 from other sources; including published literature, scientific meetings and discussions with the sponsors, to determine if the trial should be terminated before completion. Serious adverse events and responses will also be reviewed by the OSUCCC Data and Safety Monitoring Committee (DSMC). The PI will also submit a progress report quarterly that will be reviewed by the committee per the DSMC plan. All reportable Serious Adverse Events (SAE) will also be reported to the IRB of record as per the policies of the IRB.  
Subsite institutions are expected to perform internal data and safety monitory and must submit the findings to the OSU Subsite Coordinator. Likewise, the OSU Data and Safety Monitoring reports will be distributed to the subsite institutions participating in this study.  
Monthly safety and trial review teleconferences will be scheduled and moderated by the MultiInstitution Program. All sites involved in the study are expected to have a representative present every month to review and discuss patients on study and other applicable agenda items. Meeting minutes will be used to document each monthly teleconference. The minutes will be stored in the Multi-Institution Program protocol files.
appendix b imwg response criteria
institutional review board (irb) approval

The Investigator must obtain the approval of the protocol, the informed consent document and any other material used to inform the patient about the nature of the trial from the local IRB in the form of a written letter. On the approval letter, which must be signed by the chairperson of the IRB or the chairperson's designee, the following items should be clearly stated: trial title, protocol number and version, study-related documents (protocol, informed consent material, advertisement when applicable), IRB review date, and IRB decision. The trial should not start until a copy of this written approval has been received by the Investigator. If the investigator is a member of the IRB, the Investigator may participate in any discussion of the study, but may not participate in the final vote deciding whether to approve the study. Annually, or more often if stipulated by the IRB, and at the completion or termination of the study, the Investigator will report the progress of the trial to the IRB and Medivation Inc. (see contact information in section "Serious Adverse Events") All subsite consents must be sent to the OSU Subsite Coordinator for review and approval prior to submission to the local IRB. In addition, all subsite IRB approval letters for amendments and annual renewals must be sent to the OSU Subsite Coordinator in a timely manner.
appendix b imwg response criteria
additional responsibilities of the investigator

The investigator(s) agrees to perform the study in accordance with ICH Good Clinical Practice and FDA regulations. The Investigator is required to ensure compliance with respect to the investigational drug schedule, visit schedule and procedures required by the protocol. The investigator should be able to recruit the required number of suitable patients and should have sufficient time to properly conduct and complete the trial. The Investigator should have available an adequate number of qualified staff and adequate facilities for the duration of the trial, and should ensure that all persons assisting with the trial are adequately informed about the protocol, the protocol-defined procedures, protocol therapy and trial related duties and functions.. The Investigator should be responsible for all trial-related medical decisions. During and following a patient's participation in a trial, the investigator should ensure that adequate medical care is provided to a patient for any adverse events related to the trial.
appendix b imwg response criteria
use and completion of case

It is the responsibility of the Investigator to monitor the preparation and accurate use of CRFs to record all observations and other data pertinent to the clinical investigation. All CRFs should be completed in their entirety to ensure accurate interpretation of data. Should a correction be made, the information to be modified must not be overwritten. The corrected information will be transcribed next to the previous value, initialed and dated by the authorized person. All subsite data is to be submitted within 2 weeks of completion of each cycle of therapy. Refer to the Data Submission Form in the Supplemental Forms Document for submission information.
appendix b imwg response criteria
confidentiality

It is the responsibility of the investigator to ensure that the confidentiality of all patients participating in the trial and all of their medical information is maintained. Case report forms must never contain the name of a trial patient. All case report forms and any identifying information must be kept in a secure location with access limited to the study staff directly participating in the trial. Personal medical information may be reviewed by a representative of Medivation Inc., of the IRB, or of regulatory authorities in the course of auditing the trial. Every reasonable effort will be made to maintain such information as confidential. The investigator is required to retain, in a confidential manner, sufficient information on each participant (specifically, full name; current address; and social security number), so the participant may be contacted by the FDA or the Ohio State University, should the need arise.
appendix b imwg response criteria
appendix f rev-assist guidelines as

1. For females of childbearing potential, obtain two negative pregnancy tests sensitive to at least 50 mlU/mL
even if continuous abstinence is the chosen method of birth control. One test must be obtained within 10-14 days and one test within 24 hours prior to writing an initial prescription of REVLIMID® (lenalidomid 2. Obtain a baseline Complete Blood Count 3. Provide mandatory counseling: no drug sharing, no blood or sperm donation, and appropriate contraceptic 4. Complete, print, and sign REVLIMID® Patient-Physician Agreement Form
- Males (adults and children) - Females of childbearing potential include females who have not undergone a natural menopause for at least 24 consecutive months
- Females not of childbearing potential include females who have been postmenopausal natu for at least 24 consecutive months, or had a hysterectomy, or a bilateral oophorectomy 5. Fax completed and signed REVLIMID® Patient-Physician Agreement Form to 1-888-432-9325 6. Instruct patient to complete phone survey by calling 1-888-423-5436 prior to prescriber obtaining an authorization number
- All males: REVLIMID® Patient-Physician Agreement Form is considered the initial phone survey
- All females: Complete the appropriate phone survey 7. Complete a prescriber phone survey for all patients by calling 1-888-423-5436 and obtain a new authorization number for each prescription
- You will need to enter the following information:
- Prescriber's DEA number or Social Security number
- Patient's Social Security number
- Date and result of patient's pregnancy test(s) (if applicable); valid only for 7 days
- Daily dose - Total number of days supplied (cannot exceed 28 days)
8. Provide the authorization number on the prescription; authorization number and prescription are valid for 7 days for females of childbearing potential and 14 days for all other patients 9. Healthcare provider contacts a RevAssist® contract pharmacy to fill the prescription  
10. RevAssist® contract pharmacy contacts patient for counseling and dispenses REVLIMID® with the FDA-approved MEDICATION GUIDE and educational material
appendix b imwg response criteria
subsequent revlimid prescriptions (for all

1. For females of childbearing potential, obtain scheduled pregnancy tests weekly during the first 4 weeks of use; then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks 2. Obtain Complete Blood Counts as necessary 3. Provide mandatory counseling: no drug sharing, no blood or sperm donation, and appropriate contraception 4. Instruct patient to complete surveys as scheduled, prior to prescriber obtaining an authorization number  
and filling prescription
- Monthly:
- Males (adults and children) - Females of childbearing potential (adults and children), female children not of childbearing potential
- Every 6 months:
- Adult females not of childbearing potential (who have been postmenopausal naturally for at least 24 consecutive months, or had a hysterectomy, or a bilateral oophorectomy)
5. Complete a prescriber phone survey for all patients by calling 1-888-423-5436 and obtain a new authorization number for each prescription
- You will need to enter the following information:  
- Prescriber's DEA number or Social Security number - Patient's Social Security number - Date and result of patient's last pregnancy test (if applicable); valid only for 7 days - Daily dose
- Total number of days supplied (cannot exceed 28 days)
6. Provide the authorization number on the new prescription; authorization number and prescription are valid for 7 days for females of childbearing potential and 14 days for all other patients 7. Healthcare provider contacts RevAssist® contract pharmacy to fill the prescription 8. RevAssist® contract pharmacy contacts patients for counseling and dispenses REVLIMID® with the FDA-approved MEDICATION GUIDE
appendix b imwg response criteria
appendix g instructions for sample

The total amount of whole blood withdrawn for the laboratory tests will depend on the visit number. Whole blood should be divided and processed as follows:
appendix b imwg response criteria
a. immunogenicity

3.0mL of whole blood should be transferred to a tube without anticoagulant for the generation of serum for the performance of immunogenicity evaluation (serum will be generated as per the standard Center's procedure). Approximately 1.5 mL serum will be collected per patient per sampling time and will be divided into separate test tubes that will be clearly labeled with the following information: test type (IMM), patient study identification number, visit number, date and time of blood withdrawal. 4 tubes, each containing 200 µL serum will be stored at -80°C pending shipment instructions by Medivation Inc. or a designated laboratory. A -20°C freezer could serve as an alternative in the event that the center does not have access to a -80°C freezer. In such an instance, shipment of of serum samples will be made within 30 days from date of serum collection. The kits containing tubes, packaging material, shipment forms will be provided by Medivation Inc. Each kit contains all the material that is needed to collect the samples for one visit. The packaging material and shipment forms will be provided by the courier company.
appendix b imwg response criteria
b. pharmacokinetics

3.0 mL of whole blood should be transferred to a tube without anticoagulant for the generation of serum for the performance of immunogenicity evaluation (serum will be generated as per the standard Center's procedure). Approximately 0.6 mL serum will be collected per patient per sampling time and will be divided into separate test tubes that will be clearly labeled with the following information: test type (PK), patient study identification number, visit number, date and time of blood withdrawal. 4 tubes, each containing 200 µL serum will be stored at -80°C pending shipment instructions by Medivation Inc. A -20°C freezer could serve as an alternative in the event that the center does not have access to a -80°C freezer. In such an instance, shipment of serum samples to the testing lab will be made within 30 days from date of serum collection. The kits containing tubes, packaging material, shipment forms will be provided by Medivation Inc. Each kit contains all the material that is needed to collect the samples for one visit. The packaging material and shipment forms will be provided by the courier company.