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Moderator Neil Love, MD Faculty Challenging Cases in Multiple Myeloma Oncologist and Nurse Investigators Consult on Actual Patients from the Practices of the Invited Faculty Saturday, May 3, :00 AM – 7:30 AM Charise L Gleason, MSN, ANP-C, AOCNP Tiffany Richards, MS, ANP-BC, AOCNP P Leif Bergsagel, MD Jeffrey L Wolf, MD

Oncology 6-Part Case Series: Key Themes Mechanisms of action of novel agents and tissue assays to predict response Side effects and toxicities of novel agents; dose adjustments Assessment and management of adherence Specific goals of therapy and likely outcomes; sequencing of agents in advanced disease Local and systemic complications of cancer: Fatigue, pain, CNS involvement Care of older, frail patients and those with comorbidities

Oncology 6-Part Case Series: Key Themes Clinical trials as a means to access new treatments earlier Management of anxiety and depression Key determinants of patient satisfaction: What do people with cancer want and need? Quality, value and cost: Investing resources optimally End-of-life care and planning Impact of the cancer experience on family and loved ones, including minor children Impact of the oncology experience on oncology health professionals

Agenda Two Younger Patients Who Were Candidates for ASCT 46 yo woman who completed RVDD and has been in remission for 5 years while on maintenance lenalidomide (Ms Gleason) 66 yo man who received RVD followed by ASCT and lenalidomide/ixazomib maintenance (Ms Richards) An Elderly Patient with Multiple Myeloma 85 yo non-English-speaking Vietnamese man who is receiving carfilzomib/dexamethasone for relapsed disease (Ms Richards)

Agenda Two Patients with Relapsed Multiple Myeloma 74 yo man with relapsed multiple myeloma and early signs of dementia (Ms Gleason) 64 yo man with relapsed mutliple myeloma who is experiencing corticosteroid-related symptoms (Ms Richards) A Patient with Plasma Cell Leukemia and Adverse Cytogenetics 54 yo mother of a teenage daughter who is now in complete remission (Ms Gleason)

Two Younger Patients Who Were Candidates for ASCT 46 yo woman who completed RVDD and has been in remission for 5 years while on maintenance lenalidomide (Ms Gleason) 66 yo man who received RVD followed by ASCT and lenalidomide/ixazomib maintenance (Ms Richards)

Case 1 (from the practice of Ms Gleason) A 46-year-old woman was initially diagnosed with standard-risk MM in 2008, shortly after the birth of her second child She enrolled on a clinical trial of RVDD (lenalidomide/bortezomib/dexamethasone/doxorubicin) x 8 cycles –After cycle 4, stem cells were collected for future ASCT –The patient was started on lenalidomide maintenance, which she has now received for almost 5 years She currently lives a normal lifestyle, working out at the gym regularly and taking care of her 2 young children She has maintained a daily journal of her experience since diagnosis

Key Education Points for Patients with Newly Diagnosed Multiple Myeloma Induction therapy Stem cell transplant Maintenance therapy Relapsed disease Induction therapy Maintenance therapy Relapsed disease Transplant-Eligible Transplant-Ineligible

Potential curability of MM; correlation between depth of response and long- term outcome Discussion Point

Getting to Minimal Residual Disease (MRD) S.S. Patient 1×10 12 Stringent CR Molecular/Flow CR ?Cure? Disease burden Newly diagnosed 1×10 8 1× CR

Role of common genetic abnormalities in patient risk assessment and therapeutic decision-making Discussion Point

mSMART: Mayo Stratification for Myeloma and Risk-Adapted Therapy FISH -Del 17p -t(14;16) -t(14;20) GEP -High-risk signature All others including: Hyperdiploidy t(11;14) t(6;14) FISH - t(4;14) Cytogenetic deletion 13 or hypodiploidy PCLI ≥3% High-Risk 20%Intermediate-Risk 20% Standard-Risk 60% Mikhael JR et al. Mayo Clin Proc 2013;88(4): years4-5 years8-10 years

Rationale for the use of 3-drug combinations (versus 2) in the induction setting Discussion Point

Preferred Induction Regimens: Transplantation Eligible RD/Rd: Lenalidomide/dexamethasone VD: Bortezomib/dexamethasone RVD: Bortezomib/lenalidomide/dexamethasone VTD: Bortezomib/thalidomide/dexamethasone CyBorD: Bortezomib/cyclophosphamide/dexamethasone PAD: Bortezomib/doxorubicin/dexamethasone NCCN. Clinical practice guidelines in oncology: multiple myeloma. v

% of respondents Research To Practice Patterns of Care Study 2014 (N = 101 practicing oncologists) An otherwise healthy 60-year-old patient presents with fatigue. Workup reveals Hb 9.0 g/dL, normal renal function, an M-spike with an IgG lambda component of 4.9 g/dL and bone marrow consistent with MM (ISS Stage II). Conventional cytogenetics, FISH and skeletal survey are normal. Which induction treatment would you most likely recommend for this patient?

SubQ Bortezomib (n = 148) N = 222 Relapsed MM 1-3 prior lines of therapy R Best response (up to 10 cycles): 52% vs 52% Median PFS: 9.3 vs 8.4 mo 1-yr OS: 76% vs 78% Moreau P et al. Lancet Oncol 2011;12(5): Arnulf B et al. Haematologica 2012;97(12): Intravenous Bortezomib (n = 74) 2:1 Phase III Noninferiority Trial of Subcutaneous versus Intravenous Bortezomib

Research To Practice Patterns of Care Study 2014 (N = 101 practicing oncologists) When administering bortezomib for the following situations, which route of administration and schedule do you generally use? % of respondents INDUCTION THERAPY

Moreau P et al. Proc ASH 2010;Abstract 312. SC Injection Site Rotation Within the same cycle Injections at the same site should be avoided Alternate between –Right and left abdomen –Upper and lower quadrant or between –Right and left thigh –Proximal and distal sites

Moreau P et al. Lancet Oncol 2011;12(5): Moreau P et al. Proc ASH 2010;Abstract 312. Subcutaneous (SC) Administration of Bortezomib: Local Side Effects of Injections In a Phase III noninferiority trial of SC versus IV bortezomib: –≥1 SC injection site reaction: 6% pts –Most common reaction: redness (57% pts) –Injection site reactions 100% resolved in median of 6 days

Preventing herpes zoster reactivation in patients who are receiving bortezomib Discussion Point

Thromboprophylaxis in patients receiving IMiDs; other side effects; assessment of adherence to oral medications Discussion Point

Prophylaxis for Thromboembolism Aspirin –None or one patient- or myeloma-related risk factor LMWH or Full-Dose Warfarin (INR 2-3) –≥2 patient- or myeloma-related risk factors –All patients, independent of other risk factors, receiving: High-dose dexamethasone Doxorubicin Multiagent chemotherapy Palumbo A et al. Leukemia 2008;22(2):

Post-transplant consolidation and maintenance therapy; impact of cytogenetic profile Discussion Point

N Engl J Med 2012;366: N Engl J Med 2012;366:

Post-Transplant Maintenance Lenalidomide Study DetailsnTreatmentOutcome IFM (Median follow-up 67 mo) 307 Lenalidomide Placebo PFS 46 mo 24 mo Median OS 82 mo 81 mo CALGB (Median follow-up 34 mo) Lenalidomide Placebo TTP 46 mo 27 mo Median OS Not reached 73 mo 1 Attal M et al. Proc ASH 2013;Abstract McCarthy PL et al. N Engl J Med 2012;366:

% of respondents Research To Practice Patterns of Care Study 2014 (N = 101 practicing oncologists) In general, when administering lenalidomide maintenance therapy for a younger (60-year-old) otherwise healthy patient with MM who responded to induction therapy and ASCT, what is your usual preferred starting dose?

Risk of second cancers in patients receiving lenalidomide Discussion Point

IFM : Second Primary Cancers (SPMs) Attal M et al. N Eng J Med 2012;366(19): Type of lesion Lenalidomide (n = 306) Placebo (n = 302) Hematologic cancer 13 (4%)5 (2%) Solid tumors10 (3%)4 (1%) Nonmelanoma skin cancer5 (2%)3 (1%) Total26 (8%)11 (4%) The incidence of second primary cancers (p = 0.002): - Lenalidomide: 3.1 SPMs per 100 patient-years - Placebo: 1.2 SPMs per 100 patient-years

CALGB : Disease Progression and Second Primary Cancers McCarthy PL et al. N Engl J Med 2012;366(19): OutcomeLenalidomidePlacebo 3-year PFS66%39% Second primary cancersLenalidomidePlacebo Hematologic8 (3.5%)1 (0.4%) Solid tumors 10 (4.3%)5 (2.2%) At a median follow-up of 34 months, a total of 92 of the 231 patients in the lenalidomide group (40%) as compared to 133 of the 229 patients in the placebo group (58%) had progressive disease, had died or had received a diagnosis of a second primary cancer (p < 0.001).

CALGB : Death McCarthy PL et al. N Engl J Med 2012;366(19): At a median follow-up of 34 months, a total of 35 patients who received lenalidomide (15%) and 53 patients who received placebo (23%) had died (2-sided p = 0.03).

Case 2 (from the practice of Ms Richards) A 66-year-old man presented with anemia and was found to have standard-risk, ISS Stage III multiple myeloma (MM) He received lenalidomide/bortezomib/dexamethasone (RVD) x 4 cycles followed by ASCT, after which he was enrolled on a nonrandomized Phase II clinical trial of maintenance therapy with ixazomib (MLN9708) and lenalidomide The patient is currently in complete remission and would like to travel this spring for a month-long visit to his home in Palestine

Patient Serum Paraprotein Levels After RVD and Transplant Bortezomib/Lenalidomi de/Dexamethasone Transplant 3/9/2013 4/20/20136/1/20137/12/20138/23/201310/4/201311/14/ /26/2013 2/6/2014 3/19/2014 Date g/dL

Novel proteasome inhibitors in the management of MM Discussion Point

Cellular Impact of Proteasome Inhibition in Nonclinical Studies Proteasomes are enzyme complexes that degrade intracellular proteins in a regulated manner in all cells, both healthy and cancerous 2. Cancer cells depend upon proteins regulated by the proteasome for proliferation, metastasis and survival 3. Inhibition of the proteasome by bortezomib prevents the degradation of intracellular proteins, affecting multiple signaling cascades within cells 4. The disruption of signaling cascades in cancer cells can lead to cancer cell death and inhibit tumor growth 1 Invest New Drugs 2000;18: Physiol Rev 2002;82: Sci Am 2001;284: Cell 1998;92:

Available data on carfilzomib as part of up-front induction therapy and in the relapsed setting Discussion Point

ORR: All patients: 23.7% Patients with adverse cytogenetics (n = 71): 29.6% Siegel DS et al. Blood 2012;120(14): Intravenous CFZ 20 mg/m 2 twice wkly for 3 of 4 wks in cycle 1, then 27 mg/m 2 for ≤12 cycles Phase II Study of Carfilzomib (CFZ) Monotherapy in Relapsed/Refractory MM N = 266 Relapsed/refractory MM ≥2 regimens for relapsed MM Refractory to most recent Tx including bortezomib

Possible Side Effects Associated with Carfilzomib Grade ≥3 adverse events are mainly hematologic –Low rates of neutropenia Nonhematologic adverse events include –Fatigue –Nausea –Dyspnea Infrequent peripheral neuropathy Siegel DS et al. Blood 2012;120(14):

After a median of 12 cycles: -nCR = 62%sCR = 42% Grade ≥3 PN = 0% Phase I/II Study of Front-Line Carfilzomib (CFZ) in Combination with Lenalidomide and Dexamethasone CRd Cycles 9–24 CRd Induction CRd Maintenance CRd Cycles 1–4 CRd Cycles 5–8 LEN Cycles 25+ Continued lenalidomide recommended (off protocol) Transplant-eligible with ≥PR may undergo ASCT Transplant- eligible and ineligible patients Jakubowiak AJ et al. Blood 2012;120(9):

Phase III ECOG-E1A11 Trial Accessed April Primary endpoint: Overall survival for maintenance-therapy analysis Select secondary endpoints: Progression-free survival, overall response rate, duration of response Carfilzomib + lenalidomide + low-dose dexamethasone  lenalidomide maintenance* Bortezomib + lenalidomide + low-dose dexamethasone  lenalidomide maintenance* R Trial Identifier: NCT Estimated enrollment: 756 (open) * Maintenance may be limited to 24 courses or indefinite Eligibility Newly diagnosed standard-risk MM ECOG PS 0-2 No history of Grade ≥2 peripheral neuropathy

Incidence and management of carfilzomib-associated peripheral neuropathy Discussion Point

Siegel DS et al. Blood 2012;120(14): Incidence and Management of CFZ-Associated Peripheral Neuropathy CFZ is associated mostly with Grade 1/2 PN All-grade CFZ-related PN was observed in 8.3% of patients No Grade 4 PN observed on study PN can be resolved with drug interruption

Other rare but important toxicities with carfilzomib: pulmonary hypertension and cardiac events Discussion Point

Oral proteasome inhibitors in development (ixazomib, oprozomib) Discussion Point

Key Features of Ixazomib and Bortezomib Bortezomib Adapted from Fostier K et al. OncoTargets and Therapy 2012;5: CompoundChemicalBindingAdmStatus BortezomibBoronateReversibleIV/SC FDA approved IxazomibBoronateReversibleOral/IVPhase I-III Ixazomib

Phase I/II Study of Weekly Ixazomib Combined with Lenalidomide and Dexamethasone in Previously Untreated MM Kumar SK et al. Proc ASH 2012;Abstract MLN9708 maintenance Days 1, 8, day cycles Induction: up to 12 x 28-day treatment cycles Maintenance MLN9708 Dex 40 mg Lenalidomide 25 mg, days 1–21 ORR = 92% ≥VGPR = 55% Grade 3 PN = 3%

Ongoing Phase I/II Trials of Oprozomib in Newly Diagnosed MM Trial IdentifierClinical SettingTreatment Arms Estimated Primary Completion Date NCT Transplant ineligible Oprozomib + lenalidomide + dexamethasone Oprozomib + cyclophosphamide + dexamethasone August 2016 NCT Transplant ineligible Oprozomib + melphalan + prednisone October Accessed April 2014.

Case 3 (from the practice of Ms Richards) An 85-year-old Vietnamese man was diagnosed with MM in February 2013 and received melphalan/prednisone/thalidomide with the melphalan being discontinued due to episodes of neutropenia In August 2013 he switched treatment centers and began receiving bortezomib/dexamethasone, which resulted in a response –However, therapy was stopped because of peripheral neuropathy The patient experienced disease progression and is currently responding to carfilzomib/dexamethasone He speaks no English and his daughter, who comes with him for clinic visits, insists on translating for him

Patient Serum Paraprotein Levels During Treatment Course 7/26/2013 8/23/20139/20/201310/18/201311/14/201312/12/20131/9/2014 2/6/2014 3/5/2014 4/22/2014 Date g/dL Bortezomib/Dexamethasone Carfilzomib/Dexamethasone

Preferred Induction Regimens: Transplantation Ineligible Rd: Lenalidomide/low-dose dexamethasone VD: Bortezomib/dexamethasone MPV: Melphalan/prednisone/bortezomib MPR: Melphalan/prednisone/lenalidomide MPT: Melphalan/prednisone/thalidomide NCCN. Clinical practice guidelines in oncology: multiple myeloma. v

The diminishing role of melphalan for older patients: Implications of the FIRST trial (ASH 2013) comparing Rd (lenalidomide/low-dose dexamethasone) to MPT (melphalan/prednisone/thalidomide) Discussion Point

Eligibility (n = 1,623) Symptomatic NDMM Transplant ineligible or ≥65 years old Renal impairment allowed, but patients requiring dialysis excluded Primary endpoint: PFS Patients were stratified by age, country and ISS stage. Rd until progression (n = 535) Rd for 18 cycles (Rd18) (n = 541) MPT for 12 cycles (n = 547) Phase III FIRST Trial Design Facon T et al. Proc ASH 2013;Abstract 2. 1:1:1 R R: 25 mg d1-21, every 4 weeks d: 40 mg d1, 8, 15, 22, every 4 weeks M: 0.25 mg/kg d1-4, every 6 weeks P: 2 mg/kg d1-4, every 6 weeks T: 200 mg d1-42, every 6 weeks

FIRST: Progression-Free Survival Hazard ratio Rd vs. MPT: 0.72; p = Rd vs. Rd18: 0.70; p = Rd18 vs. MPT: 1.03; p = Time (months) Patients (%) wks With permission from Facon T et al. Proc ASH 2013;Abstract 2. Median PFS Rd (n = 535)25.5 mo Rd18 (n = 541)20.7 mo MPT (n = 547)21.2 mo

% of respondents Research To Practice Patterns of Care Study 2014 (N = 101 practicing oncologists) An otherwise healthy 77-year-old patient presents with fatigue. Workup reveals Hb 9.0 g/dL, normal renal function, an M-spike with an IgG lambda component of 4.9 g/dL and bone marrow consistent with MM (ISS Stage II). Conventional cytogenetics, FISH and skeletal survey are normal. The patient is not eligible for transplant. Which induction treatment would you most likely recommend for this patient? Any regimen containing melphalan: 22%

Preemptive dose reductions for older patients; “RVD lite” and other regimens Discussion Point

Palumbo A et al. Blood 2011;118: Preemptive Dose Reductions for Patients of Advancing Age AgentDOSE LEVEL 0DOSE LEVEL -1DOSE LEVEL -2 Dexamethasone 40 mg/d d 1, 8, 15, 22 / 4 wk 20 mg/d d 1, 8, 15, 22 / 4 wk 10 mg/d d 1, 8, 15, 22 / 4 wk Melphalan 0.25 mg/kg or 9 mg/m 2 d 1-4 / 4-6 wk 0.18 mg/kg or 7.5 mg/m 2 d 1-4 / 4-6 wk 0.13 mg/kg or 5 mg/m 2 d 1-4 / 4-6 wk Thalidomide100 mg/d50 mg/d50 mg qod Lenalidomide 25 mg/d d 1-21 / 4 wk 15 mg/d d 1-21 / 4 wk 10 mg/d d 1-21 / 4 wk Bortezomib 1.3 mg/m 2 twice weekly d 1, 4, 8, 11 / 3 wk 1.3 mg/m 2 once weekly d 1, 8, 15, 22 / 5 wk Prednisone 60 mg/m 2 d 1-4 or 50 mg qod 30 mg/m 2 d 1-4 or 25 mg qod 15 mg/m 2 d 1-4 or 12.5 mg qod Cyclophosphamide 100 mg/d d1-21 / 4 wk or 300 mg/m 2 /d d 1, 8, 15 / 4 wk 50 mg/d d1-21 / 4 wk or 150 mg/m 2 /d d 1, 8, 15 / 4 wk 50 mg/d d1-21 / 4 wk or 75 mg/m 2 /d d 1, 8, 15 / 4 wk

Two Patients with Relapsed Multiple Myeloma 74 yo man with relapsed multiple myeloma and early signs of dementia (Ms Gleason) 64 yo man with relapsed mutliple myeloma who is experiencing corticosteroid-related symptoms (Ms Richards)

Case 4 (from the practice of Ms Gleason) A 74-year-old man diagnosed with MM in 2007 received RVD followed by ASCT and lenalidomide maintenance, which was discontinued due to cognitive changes and early signs of dementia He was observed off therapy and experienced disease progression, at which time carfilzomib was initiated

Evaluation and workup of patients with MM and altered mental status Discussion Point

Single-agent versus combination therapy in the relapsed setting; selection and sequencing of agents Discussion Point

Shah JJ et al. Proc ASH 2013;Abstract 690 Carfilzomib + Pomalidomide + Dexamethasone Phase I/II Dose Expansion Of a Multi-Center Trial Of Carfilzomib and Pomalidomide With Dexamethasone (Car-Pom- d) In Patients With Relapsed/Refractory Multiple Myeloma (RRMM) Target accrual (n = 82) Patients with RRMM Prior Len with ≤25% response/progression during Tx or ≤60 d after completion of regimen containing Len at full dose or MTD for ≥2 cycles Overall response rate: 55/79 (70%) Median PFS: 9.7 months Median OS: Not yet reached.

IMiDs Thalidomide Lenalidomide Pomalidomide Teratogenicity, peripheral neuropathy, constipation, sedation, rash, VTE Oral mg/d Myelosuppression VTE Oral mg/d Myelosuppression VTE Oral 1-4 mg/d

Phase III MM-003 Trial Design Eligibility (n = 455) Primary refractory or relapsed and refractory MM At least 2 prior therapies Failed LEN and BORT Dimopoulos MA et al. Proc ASH 2013;Abstract 408. PFS: 50% reduction in risk of disease progression OS: 28% reduction in risk of death POM + LoDEX (n = 302) POM: 4 mg/d, d1-21 LoDEX: 40 mg (≤75 y) 20 mg (>75 y) d1, 8,15, 22 (28-d cycle) HiDEX (n = 153) 40 mg (≤75 y) 20 mg (>75 y) d1-4, 9-12, (28-d cycle) R

Select Adverse Events (AEs) Grade 3/4 AEs POM + LoDEX (n = 300) HiDEX (n = 149) Hematologic Neutropenia Febrile neutropenia Anemia Thrombocytopenia 49% 9% 33% 22% 17% 0% 39% 26% Nonhematologic Infections DVT/PE Peripheral neuropathy 33%1% 25% 0% 1% San Miguel JF et al. Proc ASH 2013;Abstract 686.

Management of MM bone disease: Role of kyphoplasty, radiation therapy and/or bisphosphonates Discussion Point

Case 5 (from the practice of Ms Richards) A 64-year-old engineer and active runner developed chronic foot pain that led to an MRI, which demonstrated a lytic lesion in the foot. Bone survey revealed multiple lytic lesions, and bone marrow biopsy confirmed the diagnosis of MM The patient received CyBorD (with subcutaneous bortezomib) followed by ASCT but preferred not to receive maintenance therapy Eighteen months later he developed sternal pain, and a PET-CT showed uptake in the sternum, which was proven to be nonsecretory MM He was restarted on CyBorD and is responding again He has become hyperactive and unable to sleep due to corticosteroids and sends multiple s at night to the clinical staff

Bisphosphonates in patients without documented bone disease; duration of treatment Discussion Point

Other agents and strategies under investigation in relapsed/refractory MM: Monoclonal antibodies alone or with IMiDs Discussion Point

Accessed April Other Agents Under Investigation in Relapsed/Refractory MM Proteasome inhibitors Marizomib Ixazomib Oprozomib Histone deacetylase (HDAC) inhibitors Panobinostat Vorinostat ACY-1215 Monoclonal antibodies Elotuzumab Siltuximab Indatuximab ravtansine (BT062) Daratumumab Pidilizumab Tabalumab Signal transduction modulators/ protein kinase inhibitors Masitinib mesylate Ibrutinib Palbociclib Ganetespib Trametinib Kinesin spindle protein inhibitor ARRY-520