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13 pharmaceutical information 13.1 carfilzomib(ind

13.1.1 Source Carfilzomib was provided to investigator by Onyx Pharmaceuticals, Inc. under a CRADA. Onyx provided carfilzomib during the active recruitment and treatment of this study. However, ongoing communication and sharing of information, including updated risks for carfilzomib, is through an agreement with Amgen. 13.1.2 Toxicity A comprehensive listing of all toxicities (i.e., very common, common, etc.) are listed in the informed consent document. The approved USPI may also be referenced for current information related to this agent. Amendment P, new information from Amgen, Inc: As of July 2019, carfilzomib has been examined in approximately 11,000 people in a research setting. It has been found that carfilzomib can cause a reactivation of hepatitis B virus. Additionally, there have been 4 cases of Progressive Multifocal Leukoencephalopathy (PML) possibly linked to Carfilzomib 13.1.3 Formulation and Preparation Carfilzomib for Injection will be provided as a lyophilized powder which, when reconstituted, contains 2 mg/mL isotonic solution of carfilzomib Free Base in 10 mM sodium citrate buffer
(pH 3.5) containing 10% (w/v) sulfobutylether--cyclodextrin (SBE--CD, Captisol®).  
Lyophilized Carfilzomib for Injection is stored in a refrigerator at 2°C–8°C. Water for injection is the only acceptable solution for reconstitution. After addition of the appropriate amount of water for injection and vigorous mixing, the solution is administered as an IV infusion. Vials are for single use. A volume of carfilzomib appropriate for a patient's dose will be added to 5%
Dextrose Injection (D5W) in a sufficient amount to yield a volume to administer 100 mL (qs. 100 mL) in a polyvinyl chloride or polyolefin container. For clinical use, Carfilzomib products will contain excess drug-containing fluid to compensate for product container and administration set priming volumes. Before dispensing Carfilzomib products from the Pharmacy, an administration set suitable for a portable pump (e.g., Gemstar set 13758-28) will be attached, the administration set tubing will be primed with drug-containing fluid, air will be purged from the tubing (but not the product container), and the administration set will be capped with a Luer locking cap. Lyophilized Drug Product: Lyophilized Carfilzomib for Injection is an investigational therapeutic agent provided in a single-dose vial as a sterile, lyophilized powder in the following dosages:  
- 25 mg Single-Use Glass Vial / 8 pk Carton Each single-dose vial contains 25 mg of carfilzomib in a 20 mL labeled glass vial with an elastomeric stopper and Red flip-off lid. The product is supplied to the site in labeled carton(s) containing eight (8) single-use vials/carton and is shipped and stored between 2°C - 8°C (36°F - 46°F). Remove the Red flip-off lid on the vial and aseptically add 12 mL of Water for Injection, USP to the lyophilized drug. Gently invert the vial multiple times and let stand to yield a clear solution containing 2 mg/mL carfilzomib. After reconstitution as instructed, a maximum total of 12.5 mL deliverable volume containing 25 mg of carfilzomib can be withdrawn from the vial.  
- 45 mg Single-Use Glass Vial / 6 pk Carton Each single-dose vial provides 45 mg of carfilzomib in a 30 mL labeled glass vial with an elastomeric stopper and Yellow flip-off lid. The product is supplied to the site in labeled carton(s) containing six (6) single-use vials/carton and is shipped and stored between 2°C - 8°C (36°F - 46°F). Remove the Yellow flip-off lid on the vial and aseptically add 22 mL of Water for Injection, USP to the lyophilized drug. Gently invert the vial multiple times and let stand to yield a clear solution containing 2 mg/mL carfilzomib. After reconstitution as instructed, a maximum total of 22.5 mL deliverable volume containing 45 mg of carfilzomib can be withdrawn from the vial.  
- 60 mg Single-Use Glass Vial / 4 pk Carton Each single-dose vial provides 60 mg of carfilzomib in a 50 mL labeled glass vial with an elastomeric stopper and Blue flip-off lid. The product is supplied in labeled carton(s) containing four (4) single-use vials/carton and is shipped and stored between 2°C - 8°C (36°F - 46°F). Remove the Blue flip-off lid on the vial and aseptically add 29 mL of Water for Injection, USP to the lyophilized drug. Gently invert the vial multiple times and let stand to yield a clear solution containing 2 mg/mL carfilzomib. After reconstitution as instructed, a maximum total of 30 mL deliverable volume containing 60 mg of carfilzomib can be withdrawn from the vial.
Inspection: The reconstituted drug solution in the vial should be a clear liquid. Inspect all vials for the presence of any suspended particles, particulate matter, discoloration or hazy solution prior to administration. If the solution is not clear or particles exist in inspected vials, record the observation in the appropriate Drug Accountability Log and notify Amgen immediately.  
- DO NOT USE THE DRUG. - Place the vial(s) into a plastic bag labeled as "Quarantined" with the date. - Store labeled quarantined drug in a temperature-monitored refrigerator and ensure they are physically segregated from the drug that is available for use.  
- Amgen will instruct the clinical site on how to proceed with quarantined vial(s).  
Calculation of Dose: Each dose will consist of Carfilzomib for Injection administered on a mg/m2 basis, and should be based on the patient's actual calculated body surface area (BSA).
The BSA should be calculated based upon the institution's practice and method of calculation should remain consistent throughout a subject's participation in the trial. Subjects with a BSA > 2.2 m2 will receive a dose based upon a 2.2 m2 BSA. Dose adjustments do not need to be made for weight gains/losses of ≤ 20%. 13.1.4 Stability and Storage Lyophilized Drug Product: Lyophilized Carfilzomib for Injection must be kept in the labeled drug cartons and stored at 2°C - 8°C (36°F - 46°F) in a refrigerator. If procedures permit, the refrigerator should be continuously monitored and temperature records retained for review.  
The refrigerator should also be on a backup generator and alarmed for temperature deviations if available. Lyophilized Carfilzomib for Injection exposed at any time to temperatures exceeding 30°C / 86°F must be discarded Reconstituted Drug Product: Once a drug vial is reconstituted and inspected, the clear solution can be stored in a refrigerator (recommended) controlled from 2°C - 8°C (36°F - 46°F) or at room temperature from 15°C - 30°C (59°F - 86°F) until use. Once reconstituted, Carfilzomib for Injection must be used on the day of reconstitution or else it must be destroyed. Prior to administration, all reconstituted drug should be equilibrated to room temperature. DO NOT FREEZE LYOPHILIZED OR RECONSTITUTED DRUG. Diluted Drug Product: After dilution with D5W for clinical use, Carfilzomib should be stored
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under refrigeration.

13.1.5 Administration Procedures Carfilzomib will be administered by intravenous infusion over 30-minutes through a peripheral or central venous access device via portable (ambulatory) pump. Care should be taken in placing and maintaining the product container at a level physically higher than the pump to avoid advancing air into the administration set tubing. If the patient has a dedicated line for carfilzomib administration, the line must be flushed with a minimum of 20 mL of normal saline prior to and after drug administration. 13.1.6 Incompatibilities In an in vitro study using human liver microsomes, carfilzomib showed modest direct and timedependent inhibitory effect on human cytochrome CYP3A4/5. Given that the clearance of carfilzomib likely occurs extrahepatically via the activity of epoxide hydrolase and peptidase activities, the clinical relevance of these in vitro results is not clear. No clinically significant drug interactions have been noted to date in patients receiving a variety of agents metabolized by CYP3A4. Moreover, no dose adjustments have been required for any concomitant medication in patients receiving carfilzomib. However, caution should be exercised in administration of concomitant medications which are substrates of human CYP3A4.
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13.2 lenalidomide

13.2.1 Source REVLIMID® (lenalidomide) is provided to investigator by Celgene Inc. under Cooperative Research and Development Agreement (CRADA). 13.2.2 Toxicity A comprehensive listing of all toxicities (i.e., very common, common, etc.) are listed in the informed consent document. The approved USPI may also be referenced for current information related to this agent. See below information regarding most significant toxicities: Fetal Risk: Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or death to a developing baby. In women of childbearing potential, obtain 2 negative pregnancy tests before starting REVLIMID® treatment. Women of childbearing potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. In the pooled MM studies Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dexamethasone than in patients treated with dexamethasone alone. Deep Vein Thrombosis and Pulmonary Embolism: Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with MM treated with lenalidomide combination therapy. A significantly increased risk of DVT and PE was observed in patients with MM who were treated with REVLIMID and dexamethasone therapy in a clinical trial. Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.  
Most common adverse reactions (≥20%): Fatigue, neutropenia, constipation, diarrhea, muscle cramp, anemia, pyrexia, peripheral edema, nausea, back pain, upper respiratory tract infection, dyspnea, dizziness, thrombocytopenia, tremor and rash 13.2.3 Formulation and Preparation Lenalidomide will be supplied as capsules for oral administration. Celgene Inc. will provide lenalidomide 5, 10, 15 and 25 mg capsules for the Induction Phase of the protocol and for the extended dosing phase(s). 13.2.4 Stability and Storage Lenalidomide should be stored at room temperature away from direct sunlight and protected from excessive heat and cold. 13.2.5 Administration Procedures Celgene Corporation will supply Revlimid® (lenalidomide) to the Clinical Center Pharmacy to be dispensed to study participants at no charge through the REMS®program. Lenalidomide will be shipped directly to patients or picked up directly from the Clinical Center pharmacy. Bottles will contain a sufficient number of capsules for one cycle of dosing; no more than a one-month supply of lenalidomide may be dispensed at one time.  
13.2.6 Incompatibilities Results from human in vitro metabolism studies and nonclinical studies show that REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450- based metabolic drug interactions in man. Digoxin: When digoxin was co-administered with lenalidomide, the digoxin AUC was not significantly different; however, the digoxin Cmax was increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of lenalidomide. Warfarin: Co-administration of multiple doses of 10 mg of lenalidomide had no effect on the single dose pharmacokinetics of R- and S-warfarin. Co-administration of single 25-mg dose warfarin had no effect on the pharmacokinetics of total lenalidomide. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant lenalidomide administration.  
Concomitant Therapies That May Increase the Risk of Thrombosis: Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution in MM patients receiving lenalidomide with dexamethasone
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13.3 dexamethasone

13.3.1 Source Dexamethasone will be provided from commercial sources by the NIH Clinical Center Pharmacy Department. 13.3.2 Toxicity  
Serious: - Endocrine metabolic: Hyperglycemia, Primary adrenocortical insufficiency - Ophthalmic: Conjunctival hemorrhage (22%), Glaucoma, Vitreous detachment (2%)
13.3.3 Formulation and Preparation
- Oral Tablet (Scored): 4 mg - Injection, solution, as sodium phosphate: 4 mg/mL (1 mL, 5 mL, 30 mL)
13.3.4 Administration Procedures
- Oral: Administer with meals to decrease GI upset. - I.V.: Administer intravenously over 10 minutes. Common: - Cardiovascular: Hypertension - Dermatologic: Atrophic condition of skin, Finding of skin healing, Impaired - Endocrine metabolic: Cushing's syndrome, Decreased body growth - Gastrointestinal: Disorders of gastrointestinal tract - Immunologic: At risk for infection - Musculoskeletal: Osteoporosis - Ophthalmic: Cataract (5%), Raised intraocular pressure (25%) - Psychiatric: Depression, Euphoria - Respiratory: Pulmonary tuberculosis
13.3.5 Incompatibilities  
- Contraindicated: Praziquantel (theoretical), Rotavirus Vaccine, Live (established) - Major: Aldesleukin (theoretical), Bupropion (theoretical), Darunavir (theoretical),
Dasatinib (theoretical), Etravirine (theoretical), Fosamprenavir (theoretical), Imatinib (theoretical), Ixabepilone (theoretical), Lapatinib (theoretical), Nilotinib (theoretical), Quetiapine (probable), Romidepsin (theoretical), Sunitinib (theoretical), Temsirolimus (theoretical), Thalidomide (probable)
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14 references

1. Altekruse S KC, Krapcho M, et al. . SEER Cancer Statistics Review, 1975-2007. 2010. 2. International Myeloma Working G. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. *Br J Haematol.* 2003;121(5):749-57. 3. Kristinsson SY, Landgren O, Dickman PW, Derolf AR, and Bjorkholm M. Patterns of survival in multiple myeloma: a population-based study of patients diagnosed in Sweden from 1973 to 2003. *J Clin Oncol.* 2007;25(15):1993-9.  
4. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. *Blood.* 2008;111(5):2516-20.  
5. Groll M, Ditzel L, Lowe J, Stock D, Bochtler M, Bartunik HD, et al. Structure of 20S
proteasome from yeast at 2.4 A resolution. *Nature.* 1997;386(6624):463-71. 6. Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. *N Engl J Med.* 2005;352(24):2487-98. 7. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. *N Engl J* Med. 2008;359(9):906-17. 8. Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. *Blood.* 2010;116(5):679-86. 9. Mateos MV. Management of treatment-related adverse events in patients with multiple myeloma. *Cancer Treat Rev.* 2010;36 Suppl 2:S24-32. 10. Kumar S BJ, Crowley J, . Relapsing After Therapy with IMiDs and Bortezomib: A
Multicenter International Myeloma Working Group Study. . *Blood (ASH Annual Meeting* Abstracts). 2009;114.  
11. Demo SD, Kirk CJ, Aujay MA, Buchholz TJ, Dajee M, Ho MN, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. *Cancer Res.* 2007;67(13):6383-91. 12. Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk KD, Sun CM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. *Blood.* 2007;110(9):3281-90. 13. Parlati F, Lee SJ, Aujay M, Suzuki E, Levitsky K, Lorens JB, et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. *Blood.* 2009;114(16):3439-47. 14. Alsina M TS, Vallone M, et al. . Phase 1 Single Agent Antitumor Activity of Twice Weekly Consecutive Day Dosing of the Proteasome Inhibitor Carfilzomib (PR-171) in Hematologic Malignancies. *Blood (ASH Annual Meeting Abstracts).* 2007;110.  
15. Jagannath S VR, Stewart K, et al. . Final results of PX-171-003-A0, part 1 of an openlabel, single-arm, phase II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). . *J Clin Oncol* 2009;27.  
16. Vij R WM, Orlowski R, et al. . Initial Results of PX-171-004, An Open-Label, SingleArm, Phase II Study of Carfilzomib (CFZ) in Patients with Relapsed Myeloma (MM). . *Blood*
(ASH Annual Meeting Abstracts). 2008;112. 17. Dimopoulos M SA, Attal M, et al. . Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. . *N Engl J Med* 2007;357:2123-32. 18. Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, et al.  
Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J
Med. 2007;357(21):2133-42.  
19. Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. *Lancet Oncol.* 2010;11(1):29-37. 20. Niesvizky R WL, Orlowski RZ, et al. . Phase Ib Multicenter Dose Escalation Study of Carfilzomib Plus Lenalidomide and Low Dose Dexamethasone (CRd) in Relapsed and Refractory Multiple Myeloma (MM). . *Blood (ASH Annual Meeting Abstracts).* 2009;114. 21. Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. *Blood.* 2012;120(9):1801-9. 22. Paiva B, Vidriales MB, Cervero J, Mateo G, Perez JJ, Montalban MA, et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. *Blood.* 2008;112(10):401723. 23. Martinez-Sanchez P, Montejano L, Sarasquete ME, Garcia-Sanz R, Fernandez-Redondo E, Ayala R, et al. Evaluation of minimal residual disease in multiple myeloma patients by fluorescent-polymerase chain reaction: the prognostic impact of achieving molecular response.  
Br J Haematol. 2008;142(5):766-74.  
24. Mena E, Choyke P, Tan E, Landgren O, and Kurdziel K. Molecular imaging in myeloma precursor disease. *Semin Hematol.* 2011;48(1):22-31. 25. McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. *N Engl J Med.* 2012;366(19):1770-81. 26. Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. *N Engl J Med.*
2012;366(19):1759-69. 27. Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. *N Engl J Med.* 2012;366(19):1782-91. 28. Thomas A, Mailankody S, Korde N, Kristinsson SY, Turesson I, and Landgren O.  
Second malignancies after multiple myeloma: from 1960s to 2010s. *Blood.* 2012;119(12):27317.
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14 references

29. Dimopoulos MA, Richardson PG, Brandenburg N, Yu Z, Weber DM, Niesvizky R, et al. A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide. *Blood.* 2012;119(12):2764-7.  
30. Lane C, Brown M, Dunsmuir W, Kelly J, and Mangos G. Can spot urine protein/creatinine ratio replace 24 h urine protein in usual clinical nephrology? Nephrology (Carlton). 2006;11(3):245-9. 31. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, Kyle R, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. *Blood.* 2011;117(18):4691-5.  
32. Guimaraes C, Bergantim R, Ramalho R, Couto N, Guimaraes JT, and Trigo F. Prognostic value of unrelated atypical serum immunofixation patterns during multiple myeloma therapy. J Hematol Oncol. 2012;5:33. 33. Mark T, Jayabalan D, Coleman M, Pearse RN, Wang YL, Lent R, et al. Atypical serum immunofixation patterns frequently emerge in immunomodulatory therapy and are associated with a high degree of response in multiple myeloma. *Br J Haematol.* 2008;143(5):654-60.
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15 appendices 15.1 appendix a

Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods
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requirements for rems

- Patients should be instructed never to give lenalidomide to another person.  
- Patients will be asked to take part in a mandatory confidential survey prior to initiation of lenalidomide. To take the survey, they will be instructed to call the Celgene Customer Care Center at 1-888-423-5436. Male patients will be asked to take the survey monthly. Female patients will be asked to take survey periodically (monthly if females of childbearing potential and every 6 months if females of not childbearing potential).  
- Female patients should not donate blood during therapy and for at least 28 days following discontinuation of lenalidomide.  
- Male patients should not donate blood, semen or sperm during therapy or for at least 28 days following discontinuation of lenalidomide.  
- Only enough lenalidomide for one cycle of therapy may be prescribed with each cycle of therapy. Monthly phone counseling is required per the REMS® program in order to prescribe a one-month supply of lenalidomide.  
- All patients will be required to sign the REVLIMID, Patient-Physician Agreement Form. - Males must practice complete abstinence or use a condom during sexual contact with pregnant females or females of childbearing potential throughout the entire duration of lenalidomide treatment, during dose interruptions and for at least 28 days following lenalidomide discontinuation, even if he has undergone a successful vasectomy. See below for further details
- Females of childbearing potential must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) throughout the entire duration of lenalidomide treatment; 3) during dose interruptions; and 4) for at least 28 days after lenalidomide discontinuation. See below for further details.  
Females not of childbearing potential must sign the REVLIMID, Patient-Physician Agreement Form that says you are presently not pregnant and do not have the ability to have children.
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risks associated with pregnancy

The use of lenalidomide in pregnant females and nursing mothers has not been studied nor has the effect of the lenalidomide on human eggs and sperm. Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe lifethreatening birth defects. An embryofetal development study in animals indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy. The teratogenic effect of lenalidomide in humans cannot be ruled out. Therefore, a risk minimization plan to prevent pregnancy must be observed. All study participants must be registered into the mandatory REMS® program, and be willing and able to comply with the requirements of REMS®.
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criteria for females of childbearing

This protocol defines a female of childbearing potential as a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). The investigator must ensure that:  
- Females of childbearing potential comply with the conditions for pregnancy risk minimization, including confirmation that she has an adequate level of understanding
- Females NOT of childbearing potential acknowledge that she understands the hazards and necessary precautions associated with the use of lenalidomide
- Male patients taking lenalidomide acknowledge that he understands that traces of lenalidomide have been found in semen, that he understands the potential teratogenic risk if engaged in sexual activity with a female of childbearing potential, and that he understands the need for the use of a condom even if he has had a vasectomy, if engaged in sexual activity with a female of childbearing potential.
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contraception

Females of childbearing potential (FCBP) enrolled in this protocol must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) throughout the entire duration of lenalidomide treatment; 3) during dose interruptions; and 4) for at least 28 days after lenalidomide discontinuation. The two methods of reliable contraception must include one highly effective method and one additional effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if needed. The following are examples of highly effective and additional effective methods of contraception:  
- Highly effective methods:
- Intrauterine device (IUD) - Hormonal (birth control pills, injections, implants) - Tubal ligation
- Partner's vasectomy
- Additional effective methods:
- Male condom
- Diaphragm
- Cervical Cap
Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended. If a patient is currently using combined oral contraception the patient should switch to one of the effective method listed above. The risk of venous thromboembolism continues for 4−6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids may be reduced during co-treatment with dexamethasone. Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in patients with neutropenia.
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pregnancy testing

Medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/mL must be performed for females of childbearing potential, including females of childbearing potential who commit to complete abstinence, as outlined below.
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before starting lenalidomide female patients

FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to prescribing lenalidomide. The first pregnancy test must be performed within 10-14 days prior to prescribing lenalidomide and the second pregnancy test must be performed within 24 hours prior to prescribing lenalidomide. The patient may not receive lenalidomide until the Investigator has verified that the results of these pregnancy tests are negative.
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male patients

Must agree to practice complete abstinence or agree to use a condom during sexual contact with pregnant females or females of childbearing potential throughout the entire duration of lenalidomide treatment, during dose interruptions and for at least 28 days following lenalidomide discontinuation, even if he has undergone a successful vasectomy.
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during study participation and for

Female Patients:  
- FCBP with regular or no menstrual cycles must agree to have pregnancy tests weekly for the first 28 days of lenalidomide treatment, including dose interruptions and then every 28 days throughout the remaining duration of lenalidomide treatment, including dose interruptions, at lenalidomide discontinuation, and at Day 28 following lenalidomide discontinuation. If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days of lenalidomide treatment, including dose interruptions, and then every 14 days throughout the remaining duration of lenalidomide treatment, including dose interruptions, at lenalidomide discontinuation, and at Day 14 and Day 28 following lenalidomide discontinuation.  
- At each visit, the Investigator must confirm with the FCBP that she is continuing to use two reliable methods of birth control at each visit during the time that birth control is required.  
- If pregnancy or a positive pregnancy test does occur in a study patient, lenalidomide must be immediately discontinued.  
- Pregnancy testing and counseling must be performed if a patient misses her period or if her pregnancy test or her menstrual bleeding is abnormal. Lenalidomide treatment must be temporarily discontinued during this evaluation.  
- Females must agree to abstain from breastfeeding during study participation and for at least 28 days after lenalidomide discontinuation.  
Male Patients:
- Must practice complete abstinence or use a condom during sexual contact with pregnant females or females of childbearing potential throughout the entire duration of lenalidomide
treatment, during dose interruptions and for at least 28 days following lenalidomide discontinuation, even if he has undergone a successful vasectomy.  
- If pregnancy or a positive pregnancy test does occur in the partner of a male study patient during study participation, the investigator must be notified immediately.
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15.2 appendix b bone marrow

NOTE: Refer to Section 5.1 for correlative study bone marrow timepoints and study calendar Section 3.4
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collection of bone marrow

- Orders for bone marrow biopsies should be placed in the Clinical Research Information System (Clinical Research Center, NIH, Bethesda, MD).  
- Notify the CCR Hematology lab that flow immunophenotyping is being performed (301496-4473). The hematology BM collection tech will bring a 10 mL tube sodium heparin Vacutainer tube to the specimen collection site and prepare an extra smear for the Flow Cytometry Laboratory.  
- Get sterile heparin suitable for injection from the nurse's station. Rinse syringe and needle with sterile heparin, leaving no less than 0.5 mL in syringe.  
- Bone marrow samples will be collected as bone marrow core biopsies and aspirates for analyses. Aspirate first 2 cc of marrow for morphology first and give specimen to Hematology lab technician to be given to Hematology Section, Department of Lab Medicine (1 mL will go to Hematopathology and 1 mL (optionally) will be delivered to Irina Maric, MD for research assessing proteasomes). Reposition needle and, for cellular specimens, slowly aspirate 5-8 mL of bone marrow for flow cytometry and cell sorting.  
- Bone marrow core biopsies and one fraction of marrow aspirates will be fixed and paraffin-embedded for histological/immunohistochemical analysis and long term storage. One fraction of marrow aspirates will be stored as air-dried aspirate smears and the rest will be frozen.  
- After processing in the pathology department, clot sections will be sent to the Molecular Diagnostics Core Laboratory, LP, NCI under the direction of Mark Raffeld, MD for determination immunoglobulin heavy and/or light chain rearrangement, and KRAS/NRAS mutations.  
- For aspirate specified for flow cytometry under the direction of Maryalice StetlerStevenson, immediately discharge 1 mL of aspirated marrow syringe into a 10mL sodium heparin Vacutainer, cap tube tightly and mix by gentle inversion 5-6 times. Label tube with patient name, unique identifier number and date. Deliver immediately to the Flow Cytometry Laboratory B1B58 (specimens containing hematopoietic neoplasms have a tendency to clot and must be processed immediately). Call for STAT Escort pickup and delivery if you cannot deliver the specimen yourself (301-496-9295). Aspirate from marrows at baseline, end of cycle 8/or CR reached between cycles 1-8, end of cycle 20/or CR reached between cycles 9-20 and during treatment termination/or CR reached between cycles 21 and beyond will be sent for plasma cell flow cytometry immunophenotyping at Maryalice Stetler-Stevenson's lab.  
- For aspirate specified for flow cytometry under the direction of Jane Trepel, immediately discharge 1 mL of aspirated marrow syringe into heparin syringe tube.  
- For aspirate designated for CD138 sorting, VDJ sequencing, exome sequencing, and microenvironment studies, send remaining aspirate sampleCalvo Laboratory in the Department of Laboratory Medicine Clinical Center (Attn: Dr. Weixin Wang, Building 10 Room 2C418A). Place aspirate sample in EDTA syringe immediately on ice. Transfer within 30 minutes of sampling to the lab for processing. CD138+ plasma cells will be viably frozen and batched to be sent to Adaptive Technologies for VDJ  
sequencing and to MSKCC for exome sequencing. CD138- fractions will be studied by Dr.'s Wang and Calvo. At subsequent time points, CD138+ sorting will not be done if the patient is in remission.  
- For aspirate specified for cytogenetics/FISH, aspirate will be sent to Diane Arthur.  
(**NOTE:** D. Arthur no longer at NIH/NCI, her involvement ended and these studies no longer being done as of Amendment M.)
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15.3 appendix c research peripheral

NOTE: Refer to Sections 3.4 Study Calendar and 5.1 for research blood and urine collection time points for samples to the Blood Processing Core (BPC).
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venipuncture

a. Up to 100 mL of peripheral blood will be collected into serum separator tubes (SST),
sodium heparin tubes (GGT), or EDTA tubes. The amount of blood collected will be dictated by the number of experiments to be performed, and by the patient's peripheral blood count.  
b. Serum
- Collect 7-10 mL blood in a serum separator tube (SST).  
- Allow the blood to clot by standing at room temperature for 30 minutes. - Separate serum from cells by centrifuging at 4 degrees C for 5 minutes at 1200xg.  
- Pipette 2 aliquots of 1.5mLs each into two 2mL cryovials.  
- Freeze immediately at -20 or lower - Maintain in -80 freezer for storage until shipment c. Plasma
- Collect 7 mL blood in a sodium heparin tube (green top). - Place immediately on wet ice and refrigerate until time of processing. - Separate plasma from cells by centrifuging at 4 degrees C for 5 minutes at 1200xg.  
- Pipette 2 aliquots of 1.5mLs each into two 2mL cryovials.  
- Freeze and store in -80C freezer.  
d. Complete blood count
- A venous blood sample for a CBC will be collected in a 10ml EDTA lavender top (BD EDTA 366643) tube. Keep at room temperature until processing begins.
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urine sample collection

a. Approximately 45 mL of urine will be collected into a standard urine collection cup for further analysis. The amount of urine collected will be dictated by the number of experiments to be performed.  
b. Transfer to a screw-cap conical tube c. Freeze immediately at -20 or lower d. Maintain in -80 freezer for storage until shipment
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labeling of samples

a. All specimens are to be labeled per the local site's standard procedures. The following information, if not provided on the specimen label, must be linked to the specimen label and provided on the inventory sheet:
- patient study ID \#
- sample type
- date/time of draw (DD/MMM/YY 24:00) - timepoint (ex. C1D1 pre, C1D1 24hr post)
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labeling of samples

- any collection issues (short draw, delayed processing, etc.)
- protocol title/number
- institute name - contact information b. Do not include the patient name, medical record number, or initials.