FINAL MM SLIDES-general-SK edits Tampa-2 · 8/15/16& 5 Kumar SK, et al. (2009). Mayo Clinic Proc....

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Collabora've Prac'ce in the Management of Pa'ents With Cancer

August 20, 2016, in Tampa, Florida

APSHO Regional Lecture Series: Hematologic Malignancies

Faculty Members

Program Chair Sandra Kurtin, RN, MS, AOCN®, ANP-C The University of Arizona Cancer Center Clinical Assistant Professor of Medicine

Adjunct Clinical Assistant Professor of Nursing

The University of Arizona

Faculty

Diane Cope, PhD, ARNP-BC, AOCNP®

Florida Cancer Specialists & Research Institute

R. Denise McAllister, MS,

ARNP, AOCNP® Florida Cancer Specialists &

Research Institute

Leslie Lauersdorf, ARNP, AOCNP® Moffitt Cancer Center

Lisa Nodzon, PhD, ARNP, AOCNP®

Moffitt Cancer Center

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Disclosures

Faculty Ms. Kur'n has served as consultant for Amgen, BMS, Celgene, Genentech, Incyte, Janssen, NovarHs, Takeda, and Pharmacyclics. Dr. Cope has nothing to disclose. Ms. McAllister has served on the speakers bureau for Celgene. Ms. Lauersdorf has served on the speakers bureau for Amgen. Dr. Nodzon has received consulHng fees/honoraria and served on speakers bureaus for ARIAD, Gilead, NovarHs, Genentech, Pfizer, and Bristol-‐Myers Squibb.

Planning Commi;ee Alana Brody, Terry Logan, Lynn Rubin, and Wendy Smith (MEI) have nothing to disclose. Sandy Leatherman, Annamarie Luccarelli, and Jessica Tamasi (APSHO) have nothing to disclose. Claudine Kiffer and Annie Yueh (Harborside Press) have nothing to disclose.

Learning Objec'ves

•  Describe the various mechanisms of acHon of agents used to treat mulHple myeloma (MM)

•  Apply the principles of risk-‐adapted treatment using case-‐based scenarios to illustrate the impact of paHent a]ributes and disease-‐specific a]ributes in MM

•  Manage toxiciHes associated with newer agents used to treat MM

•  Apply the principles of adjuncHve supporHve care in the treatment of paHents with MM

•  Demonstrate a general understanding of how to perform a bone marrow biopsy

Measuring Ac'vity Outcomes

During today’s session, you will likely noHce that several quesHons are repeated.

This is done to measure the effecHveness of today’s educaHon.

Meniscus EducaHonal InsHtute also uses this data in order to study ongoing educaHonal need, ensuring that we are well posiHoned to offer Hmely educaHon on topics of greatest need.

Your parHcipaHon is greatly appreciated!

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MULTIPLE MYELOMA OVERVIEW

Mul'ple Myeloma Epidemiology

•  Risk factors –  Unknown in the majority of cases

–  Increased with age, male sex, obesity, and black race

•  Survival –  In 2012, there were an esHmated

89,568 people living with MM (survivors) in the United States

–  5-‐year OS has increased from 24.7% (1975-‐1977) to 48.5% (2005-‐2011) (p<.05)

•  Variable response to treatment and variaHon in survival

–  From a few months to > 10 yr –  High-‐risk a]ributes are thought to

play a primary role –  20% of paHents survive >10 yr,

regardless of therapy –  Novel agents may neutralize the

effects of some high-‐risk features –  Achievement of minimal residual

disease negaHve (MRD-‐) status early in the course of disease is key

Badros. J Natl Compr Canc Netw. 2010;8(suppl 1):S28-‐S34; Siegel L, et al. (2016). Cancer staHsHcs, 2016. CA Cancer J Clin 66(1), 7-‐30; Kumar SK, et al. Presented at ASH. 2012. Abstract 3972; Kumar SK, et al. Blood. 2008;111:2516-‐2520; h]p://seer.cancer.gov/stanacts/html/mulmy.html

New Cases (US, 2015)

Deaths (US, 2015)

Mean Age at Diagnosis, Yrs

5-‐Yr Overall Survival 1975 – 2011 (p<0.5)

30,330 12,650 69 Increased by 23.8%

RRMM

MGUS SMM

MM = mulHple myeloma; MGUS = monoclonal gammopathy of uncertain significance; SMM =aAsymptomaHc MM; NDMM = newly diagnosed MM; MRD0 = minimal residual disease negaHve; RRMM = relapsed and/or refractory MM

MRD -‐

Disease Plateau of variable length

Disease Plateau of variable length

Diminished depth and dura'on of response

AMM NDMM

Natural History of Mul'ple Myeloma •  Ini'a'on of the

best available treatment to induce an early and deep response

•  Limit end-‐organ damage

•  Op'mizing each treatment op'on to achieve and maintain MRD-‐ status

•  Use of AHSCT consolida'on and/or maintenance

Salvage therapy considering disease and personal factors

Early idenHficaHon of lack/loss of response

Rajkumar et al., 2014 et al., 2013; Ludwig et al., 2014; Mikael et al., 2013; NCCN, 2016; Palumbo et al., 2015; Palumbo et al., 2014; Adapted from KurHn, S. 2016.

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Common Presen'ng Signs and Symptoms •  Most common complaint at presentaHon is bone pain and

faHgue •  Signs and symptoms result from an overproducHon of

immunoglobulins with secondary processes

Disease Process Symptoms Clinical Findings

Plasma cell invasion of the bone

•  Bone pain (58%)

•  Hypercalcemia

•  Lytic lesions (66%)* •  Compression fractures or

other skeletal fractures •  Hypercalcemia (13%)* •  Osteoporosis, osteopenia •  Cord compression

Bone marrow involvement

•  Fatigue (32%) •  Infections •  Bleeding

•  Anemia (73%)* •  Neutropenia •  Thrombocytopenia

Kyle RA, et al. (2003). Mayo Clin Proc 78(1):21-33.

* Part of the CRAB Criteria

Common Presen'ng Signs and Symptoms (cont.)

Disease Process Symptoms Clinical Findings

Renal injury •  Fatigue •  Oliguria (late

finding) •  Hematuria

•  Elevated creatinine (19%)* •  Acute renal failure (ARF) •  Chronic renal insufficiency (CRI) •  Chronic renal failure •  Anemia •  Hypercalcemia •  Hyperviscosity •  Urate nephropathy

Abnormal immunoglobulin function

•  Fever •  Infections

•  Hypogammaglobulinemia •  Infections •  Neurologic disease

Hyperviscosity •  Pain •  Paresthesia •  Immobility

•  Peripheral neuropathy (5%) •  Strokes

* Part of the CRAB Criteria

Kyle RA, et al. (2003). Mayo Clin Proc 78(1):21-33.

Overproduc'on of Abnormal Plasma Cells and Associated Serum Proteins

Abnormal Plasma Cells

Hematopoietic stem cell

MM Bone Marrow

Myeloid progenitor cell

Natural killer (NK) cells

T lymphocytes

Neutrophils

Basophils

Eosinophils

Monocytes/ macrophages

Platelets

Red blood cells

Lymphoid progenitor cell

Invasion of bone

Invasion of bone marrow

Cytopenias

Lytic Lesions Hypercalcemia

Renal impairment

↑ circulating abnormal serum proteins

B lymphocytes

Immunodeficiency

Genetic and Molecular Defects

Neurologic Disease

Stem cell basics. NIH Stem Cell Information. Available at: http://stemcells.nih.gov/info/basics/basics4.asp. Accessed June 4, 2013. Image created by Sandy Kurtin, The University of Arizona Cancer Center.

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Kumar SK, et al. (2009). Mayo Clinic Proc. 84:1095-1110; Schmidt-Hieber M, et al. (2013). Haematologica. 98:279-287.

Classifica'on of MM Heavy chain: • IgG, IgA, IgD, IgM, IgE

• 77% of myeloma cases

•  IgG and IgA most common

Nonsecretory: • No detectable immunoglobulin

• 1% to 2% of myeloma cases

Heavy chain

Light chain

Serum free light chain

Variable region

Constant

region

Light chain (Bence-‐Jones protein): § Kappa (κ) or lambda (λ)

§ 20% of myeloma cases

Disease Trajectory

§  < 10% BMPC §  <30g/L M-protein §  No MDE §  1%/yr risk of

progression to MM

Myeloma Defining Events (MDE)

Plasma Cell Leukemia

MGUS Smoldering Myeloma

§  10-60% BMPC §  ≥ 30g/L M-protein

(igG or IgA) OR •  ≥ 500 mg/24 hr

urinary protein §  No MDE or

amyloidosis §  10%/yr risk of

progression to MM in the first 5 yr

Nonmalignant Accumulation Malignant Transformation Aggressive and

Stromal Independent

Stroma angiogenesis

and IL-6 dependent

≥ 10% clonal BMPC or biopsy proven bony or extramedullary plasmacytoma AND 1 or more Myeloma Defining Events (MDE) including CRAB features. Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically

Rajkumar, et al., 2014; Kuehl WM, et al. (2002). Nat Rev Cancer. 2:175-187. Agarwal A, et al. (2013). Clin Cancer Res.19:985-994. Durie BG, et al. (2003). Hematol J. 4:379-398. Kurtin SE. (2010). J Adv Pract Oncol. 1:19-29.

Mul'ple Myeloma

Myeloma Defining Events (MDEs): CRAB Criteria Revised

C: Calcium elevaHon Serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than ULN or > 2.75 mmol/L (> 11 mg/dL)

R: Renal dysfuncHon CreaHnine clearance < 40 mL/min or serum creaHnine > 177 μmol/L (> 2 mg/dL)

A: Anemia Hemoglobin > 20 g/L below LLN or < 100 g/L

B: Bone disease One or more osteolyHc lesions on skeletal radiography, CT, or PET/CT

Any one or more biomarkers of malignancy •  BMPC > 60% •  Involved/uninvolved serum free light chain raHo ≥ 100 •  > 1 focal lesion > 5 mm on MRI studies

MGUS = myeloma of undetermined significance; SMM = smoldering mulHple myeloma; BMPC = bone marrow plasma cells; MDE = myeloma-‐defining events; ULN = upper limit of normal; LLN = lower limit of normal. From KurHn et al., 2016, J Adv Pract Oncol; Adapted from Rajkumar et al., 2014, Lancet Oncol, 15(2):e538-‐e54.

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Case Study 1 •  57-‐yr-‐old male presented to PCP with intractable back pain over

2-‐week period –  Prior discectomy treated with nonsteroidal pain medicaHon; no

improvement •  Presented to ED on weekend with severe pain

–  Plain films of spine and pelvis showed degeneraHve changes –  CT of spine (bone protocol) with osseous demineralizaHon and a

moth-‐eaten appearance of bones •  Labs

–  WBC 5.5 g/dL, hemoglobin 11.7 g/dL, hematocrit 34%, platelets 240,000/μL

–  CreaHnine 2.6 mg/dL, calcium 12.8 mg/dL, albumin 3.4 g/dL •  Admi]ed with acute renal failure and hypercalcemia •  Suspicion for mulHple myeloma: consult to hematology/

oncology

IniHal diagnosHc evaluaHon of suspected mulHple myeloma (NCCN, 2010). BUN = blood urea nitrogen; CBC = complete blood cell count; FISH = fluorescence in situ hybridizaHon; Ig = immunoglobulin; LDH = lactate dehydrogenase; MGUS = monoclonal gammopathy of undetermined significance; MM = mulHple myeloma; MRI = magneHc resonance imaging.

KurHn et. al. (2016) J Adv Pract Oncol, 7(S1), S59-‐S70. Adapted from: KurHn, 2010. Data from: NCCN, 2015, Ludwig et al., 2014; Rajkumar et al, 2014, Mikhael, et al., 2013

Ini'al Workup General

• H&P with parHcular a]enHon to bone health, faHgue, infecHons, neuropathy

• Co-‐morbidity evaluaHon • Fit vs. frail • Lifestyle and personal wishes • Financial consideraHons • Availability of a caregiver

Peripheral Blood

• CBC, differenHal, and platelet count

• CMPNL: Includes BUN, creaHnine, calcium, albumin

• Β2 microglobulin • LDH • FLC assay+ • SPEP with IFE • QuanHtaHve Immunoglobulins

• 24 hour urine: UPEP with IFE

Imaging Techniques for Assessing Bone Disease

Technique How it Works When to Use Limita'ons to Use WBXR/bone survey

•  Series of x-‐rays of axial and appendicular skeleton

• Baseline & relapse • Bone lesions only seen if >30% bone loss occurs

• More accurate for lesions in the ribs and skull than newer techniques

MRI •  Three sequence approach (T1,T2, STIR, post-‐gadolinium) detects MM acHvity in bone marrow

• Highly sensiHve

• Procedure of choice to evaluate a painful lesions

• Verify solitary plasmacytomas; non-‐secretory disease

• Assess spinal cord compression

•  Lack of specificity reflects marrow infiltraHon not specifically bone deterioraHon

•  Expense & Hme •  Excludes paHents with implanted metal

STIR = short time inversion recovery; FDG = 18-fluorine-fluoro-deoxyglucose ; MRD = minimal residual disease CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography; DEXA = dual-energy X-ray absorptiometry; MM = multiple myeloma. Dimopoulos, Hillengass et al. 2015; Regelink, Minnema et al. 2013, Dimopoulos, Kyle et al. 2011, NCCN, 2016

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Imaging Techniques for Assessing Bone Disease (cont’d)

Technique How it Works When to Use Limita'ons to Use CT • MulHple computerized x-‐

ray images from different angles


•  Early detecHon of bone lesions not detected by WBXR

• More sensiHve to detect small osteolyHc lesions

• Does not differenHate between acHve & inacHve lesions

• Higher levels of radiaHon exposure

PET •  FDG tracer illuminates metabolically acHve cells


• Assess extra-‐medullary disease; response; MRD

•  Lack of specificity of findings may result in false-‐posiHve results; expense

DEXA (bone densitometry)

• Measurement of osteopenia or osteoporosis

•  If comorbid condiHons exist for osteoporosis

• Does not measure osteolyHc disease

STIR = short time inversion recovery; FDG = 18-fluorine-fluoro-deoxyglucose ; MRD = minimal residual disease CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography; DEXA = dual-energy X-ray absorptiometry; MM = multiple myeloma. Dimopoulos, Hillengass et al. 2015; Regelink, Minnema et al. 2013, Dimopoulos, Kyle et al. 2011, NCCN, 2016)

Case Study (cont’d)

•  57-‐yr-‐old male, excellent performance status •  PMH/comorbidiHes

•  Bladder cancer, hyperlipidemia, hypertension, basal cell carcinoma, melanoma, shingles, anxiety, insomnia, colon polyp

•  Exposure to trichlorethylene in childhood •  MedicaHons

•  GabapenHn (post-‐herpeHc neuralgia), diazepam, hydrocodone, acyclovir

•  Social •  ReHred engineer, married, 2 sons •  No tobacco history, occasional alcohol

Case Study (cont’d) Imaging •  Skeletal survey

–  DegeneraHve changes of lumbar spine, otherwise normal exam (lesions noted on CT not apparent)

•  Renal ultrasound –  No renal parenchymal disease

•  PET/CT –  Subtle lyHc changes within thoracic and lumbar vertebral bodies; mildly hypermetabolic; max SUV 2.8

Bone marrow –  9.58% monotypic plasma cells –  FISH: del(13q); loss of 3-‐IGH of chromosome 14, trisomy 15; del(17p)

–  CytogeneHcs: normal male karyotype

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Case Study (cont’d)

Peripheral blood Serum free light chains

–  Kappa: 338 mg/dL (0.33-‐1.94 mg/dL)

–  Lambda: 0.21 mg dL (0.57-‐2.63 mg/dL)

–  RaHo: 1012.50 (0.26-‐1.65) –  β2M: 2.58 mg/L –  LDH: 249 IU/L –  C-‐reacHve protein: 12.30 mg/L

–  SPEP: no monoclonal protein

UPEP •  M-‐component: 606 mg/L

(normal = 0) •  ImmunofixaHon of urine

demonstrates mulHple oligoclonal bands in kappa lane

Audience Response Ques'on

You are seeing a newly diagnosed 57-‐year-‐old MM paHent with kappa light chain disease: Past medical history includes melanoma (resected), eczema, low-‐back pain. CytogeneHcs: 46 XY [20},FISH: del(13q); loss of 3-‐IGH of chromosome 14, trisomy 15; del(17p) Which of the following treatment opHons would you suggest for this paHent?

A.  A clinical trial using lenalidomide/bortezomib/dexamethasone followed by maintenance vs. autologous HSCT

B.  Melphalan and prednisone followed by HSCT C.  Carfilzomib/pomalidomide/dexamethasone followed by HSCT D.  A clinical trial using daratumumab/lenalidomide/dexamethasone E.  Unsure

Updated MM Staging Stage Interna'onal Staging System (ISS) Revised-‐ISS (R-‐ISS)

I Serum beta 2 microglobulin < 3.5 mg/dL Serum albumin > 3.5 g/dL Median survival: 62 months

ISS stage I and standard risk chromosomal abnormaliHes by iFISH – AND Serum LDH < ULN (varied by insHtuHon) 5 year OS rate: 82%; PFS at 46 months 55%

II Not ISS stage I or II Median survival: 44 months

Not R-‐ISS stage I or III 5 year OS rate: 62%; PFS at 46 months 36%

III Serum beta-‐2 macroglobulin greater than or equal to 5.5 mg/L Median survival: 29 months

ISS stage III and either high risk chromosomal abnormaliHes by iFISH OR Serum LDH > ULN (varied by insHtuHon) 5 year OS rate: 40%; PFS at 46 months 24%

Greipp et al. (2005). J Clin Oncol. 23:3412-‐3420; Palumbo, A., et al. (2015). J Clin Oncol. 33:2863–2869

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Minimal Residual Disease: The Path to a Cure

25 Brian Durie, Best of ASH 2014. Available at h]p://myeloma.org/ArHclePage.acHon?arHcleId=4492

More sensi've

Less sensi've

•  A paHent negaHve for MRD by less-‐sensiHve assay may truly be posiHve for MRD

•  Next-‐generaHon sequencing (NGS) and next-‐generaHon flow (NGF) are becoming standard tools for assessing MRD

•  MRD is becoming a standard endpoint for assessing outcome

•  Next generaHon flow (NGF) is part of the new response criteria

•  MRD status does not tell us whether to change therapy, conHnue therapy, or stop therapy

•  It can be used as a prognosHc marker more than a tool for treatment decisions

General Approach to Treatment of NDMM

Continued Treatment Salvage therapy Maintenance therapy

Confirmed Diagnosis of Multiple Myeloma: MDE and CRAB Criteria Determination of

transplant eligibility Immediate interventions

for serious adverse events

Individualized Treatment Selection for Induction Therapy Transplant Eligible

Works rapidly (CR, nCR, VGPR) Well tolerated

Spares stem cells Level of evidence 1 or 2A

Transplant Ineligible Achieving a CR or nCR

Level of evidence 1 or 2A Tolerability and QOL

Fit vs. frail and comorbidities

NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.3.2016.

Kyle RA, et al. N Engl J Med. 2007;356:2582-‐2590; Jagannath S, et al. Clin Lymphoma Myeloma Leuk. 2010;10(1):28-‐43; Kyle RA, et al. Curr Hematol Malig Rep. 2010 ;5(2):62-‐69; Rajkumar et al., 2014, Lancet Oncol 15(12), e538-‐e548.

Disease Progression in SMM and MGUS Pa'ents

Smoldering Mul'ple Myeloma Pa'ents Have a High Risk of Progression

•  First year: screen every 3 to 6 months

•  A�er first year: screen at least every 1 to 2 years

•  3% of people over 50 years old •  5% of people over 70 years old

10% risk of progression per year*

•  Screen every 4 to 6 weeks *For first 5 years, ~3% per year for next 5 years, ~1% per year therea�er

1% risk of progression per year MGUS

Smoldering Multiple Myeloma

SMM = smoldering mulHple myeloma MGUS = monoclonal gammopathy of undetermined significance

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Paraprotein markers M-‐protein > 3g/dL

IgA subtype Decreased levels of > 1 uninvolved Ig

FLC ra'o > 8

Imaging markers MRI: > 1 Focal lesion, bone

marrow infiltra'on PET/CT: Diffuse uptake or focal

lesions

Gene'c markers t(4;14), 1q gain, and

dele'on 17p GEP 70 score > 0.26 GEP 4 score > 9.28

Others Age > 65

Bone marrow plasma cells > 20% > 95% of PC aberrant

Increased circula'ng plasma cells

High-‐Risk Smoldering Myeloma

Factors Associated With High-‐Risk Smoldering MM

Sundararajan et al., 2016, published online Curr Hematol Malig Rep, DOI10.1007/s11899-‐016-‐0305-‐6

Cytogene'c Classifica'on

•  mSMART 2.0: classificaHon of acHve MM

High Risk 20%

Intermediate Risk 20%

Standard Risk 60%

§  FISH −  Del17p −  t(14;16) −  t(14;20)

§  GEP −  High-‐risk

signature

§  FISH −  t(4;14)

§  CytogeneHc deleHon 13 or hypodiploidy

§  PCLI ≥ 3%

All others including:

§  Hyperdiploid §  t(11;14) §  t(6;14)

OS 3 Years OS 4-5 Years OS 8-10 Years

Mikhael JR, et al. Mayo Clinic Proc. 2013;88:360-376.

Other Biomarkers Associated With High-‐Risk MM

*Increase in serum monoclonal protein by ≥10% on each of two successive evaluations within a 6-month period

Biomarker 2-‐yr probability of progression

High levels of circulaHng plasma cells 80% Abnormal plasma cell immunophenotype ≥95% plus immunoparesis

50%

EvoluHon of smoldering mulHple myeloma 65% CytogeneHc subtypes: t (4;14), 1q amp, or del 17p 50% High bone marrow plasma cell proliferaHve rate 80% Unexplained decrease in creaHnine clearance by ≥25% accompanied by a rise in urinary monoclonal protein or serum free light-‐chain concentraHons

Not known

Rajkumar, S. V., et al. (2014) The Lancet Oncology 15(12): e538-‐e548

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NOTE: Clinical trial par'cipa'on should be encouraged.

Standard Risk

VRD for 4 cycles*

ASCT in eligible paHents; if ineligible, conHnue VRD for 12 cycles; if frail or

aged ≥75 yr, conHnue Rd

Lenalidomide maintenance if not in CR or VGPR following ASCT

Intermediate Risk

VRD for 4 cycles*

ASCT in eligible paHents; if ineligible, conHnue VRD for 12 cycles; if frail or aged ≥75 yr, consider

low-‐dose VCD

Bortezomib or bortezomib-‐based

maintenance for 2 yr

High Risk

KRD for 4 cycles

ASCT in eligible paHents; if ineligible, conHnue VRD for 12 cycles; if frail or aged ≥75 yr, consider

lower doses

Carfilzomib or bortezomib-‐based

maintenance for 2 yr

Mayo Clinic Approach to Newly Diagnosed MM

Mikhael JR, et al. Mayo Clinic Proc. 2013;88:360-376.

Factors Affec'ng Transplant Eligibility

•  Age –  Older than 70 yrs of age may not be eligible –  Older pts more sensiHve to toxicity; less physical reserve

•  Fit vs. frail •  ComorbidiHes: heart disease, lung disease

–  Increased risk of infecHon –  Decreased tolerability for high-‐dose therapy

•  Renal and hepaHc funcHon •  Personal preference •  Insurance coverage •  Eligibility of a caregiver

NCCN. Clinical practice guidelines in Oncology: Multiple Myeloma. v.3.2016.; Miceli et al., 2013, Clin J Oncol Nurs 17 Suppl, 13-24

Case Study: Transplant Eligibility

•  Individual paHent consideraHons –  Prior history of cancer

•  Bladder; resected (cure) •  Basal cell; resected (cure) •  Melanoma; resected (cure) •  Polyp; hyperplasHc

–  TCE exposure in childhood –  Anxiety –  Married –  ReHred engineer

•  MM-‐specific consideraHons –  Risk-‐straHficaHon is criHcal

to early treatment decisions

–  MulHple treatment opHons –  High-‐risk disease (del17p)

•  ConsideraHon of HSCT –  Excellent performance

status –  Availability of caregiver;

supporHve family and friends

–  Good organ funcHon

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FDA Approved Drugs to Treat MM Drug Abbreviation Drug Class Brand

Bortezomib btz Proteasome inhibitor Velcade

Carfilzomib car Proteasome inhibitor Kyprolis

Daratumumab dara Monoclonal antibody Darzalex

Elotuzumab elo Monoclonal Antibody Emplicit

Lenalidomide len Immunomodulatory agent Revlimid

Ixazomib Ixa Proteasome inhibitor Ninlaro

Thalidomide thal Immunomodulatory agent Thalomid

Pomalidomide pom Immunomodulatory agent Pomalyst

Panobinostat pan Histone deacetylase inhibitor Farydak

Melphalan mel Alkylating agent Alkeran, Alphalan

Cyclophosphamide CTX Alkylating agent Cytoxan

Prednisone P, pred Corticosteroid Deltasone

Dexamethasone D, d, dex, DXM Corticosteroid Decadron

Pamidronate pmd Bisphosphonate Aredia

Zoledronic acid zol Bisphosphonate Zometa

Myeloma Preferred Induc'on Regimens* CombinaHon AbbreviaHon(s) Bortezomib/dexamethasone (dex)† VD or Vd Bortezomib/cyclophosphamide/dex CyBorD Bortezomib/doxorubicin/dex† Bortezomib/lenalidomide/dex VRD or VRd Bortezomib/thalidomide/dex† VTD or VTd Lenalidomide/dexamethasone† RD or Rd Bortezomib/dex VD or Vd Lenalidomide/low-‐dose dex† Rd Bortezomib/cyclophosphamide/dex Bortezomib/lenalidomide/dex Bortezomib/thalidomide/dex† VMP or MPB Lenalidomide/dexamethasone† MPR or MPL Melphalan/prednisone/thalidomide† MPT

NCCN Preferred Regimens -‐ Category 1

Combina'on therapies have demonstrated improved response rates, progression-‐free survival, and/or overall survival compared to single agents

*NCCN Guidelines MulHple Myeloma Version 3.2016 †Category 1

Tran

splant

Non

-‐transp.

Suppor've and pallia've care should be provided concurrently with disease modifying treatment bisphosphonates, an'bio'cs, and reduced doses of steroids

Improving quality of life and survival has become an important goal of treatment

Immunomodulatory Agents

Agent/Class Dosing and Route of Administra'on

Lenalidomide1 Immunomodulatory agent

§  25 mg/day by mouth for inducHon §  Variable dosing in combinaHon regimens §  Dose modificaHon based on renal funcHon, cytopenias

Pomalidomide2 Immunomodulatory agent

§  4 mg/day on days 1-‐21 using a 28-‐day cycle §  Dose modificaHons for cytopenias

Thalidomide3 Immunomodulatory agent

§  50-‐200 mg/day by mouth at bedHme §  Variable dosing in combinaHon regimens §  Dose modificaHon for neuropathy, cytopenias

1. Lenalidomide [package insert]. 2. Pomalidomide [package insert]. 3. Thalidomide [package insert].

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Proteasome Inhibitors Agent Dosing and Route of Administra'on Bortezomib1 § 1.3 mg/m2 IV or SC on days 1, 4, 8, 11, every 21 days

x 2 cycles, then weekly dosing 3 wks on/1 wk off § Variable dosing as a single agent and in combinaHon regimens

§ Dose modificaHon for neuropathy, cytopenias Carfilzomib2 § 20 mg/m2 IV (cycle 1), 27 mg/m2 (cycles 2-‐12) on

Days 1, 2, 8, 9, 15, 16, every 28 days § Dose modificaHons for cytopenias, cardiopulmonary symptoms

Ixazomib3

§ Recommended starHng dose of 4 mg taken orally on days 1, 8, and 15 of a 28-‐day cycle

§ Dose should be taken at least 1 hour before or at least 2 hours a�er food

§ Dose modificaHon for moderate or severe hepaHc impairment, or renal impairment

1. Bortezomib [package insert]. 2. Carfilzomib [package insert]. 3. Ixazomib [package insert]

Clinical Considera'ons in Induc'on Therapy

•  High tumor burden –  Pulse dexamethasone –  CombinaHon therapies with alkylators

and IMiDS and bortezomib

•  Renal failure –  Pulse dexamethasone –  Proteasome Inhibitor +/-‐ alkylator –  Renal dosing required for selected

agents -‐ may benefit from graduated inducHon

•  Hypercalcemia –  Pulse dexamethasone –  Bisphosphonates –  Risk-‐adapted inducHon

•  Frail –  Avoid high-‐dose dexamethasone –  Dose modificaHons may be indicated

for selected agents

•  Clonng or bleeding history –  Assess risk of use of IMIDs –  Evaluate platelet funcHon with

concurrent use of anHcoagulaHon/ anH-‐platelet agents

•  Preexis'ng neuropathy –  Assess use of bortezomib/

thalidomide

Niesvizky R, et al. Oncology (Williston Park). 2010;24:14-21; NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.3.2016. ; Stadtmauer EA. Oncology (Williston Park). 2010;24:7-13.

For inducHon therapy in transplant eligible paHents, triple therapy is recommended with VRd as the recommended iniHal regimen

Expected Side Effects of Front-Line Therapies: IMiDs

Side effect Thalidomide Lenalidomide Pomalidomide

Peripheral neuropathy

√

Deep vein thrombosis

√ More with dex

√ More with dex

√ More with dex

Myelosuppression √ Neutropenia

√ Neutropenia,

thrombocytopenia, anemia

√ Neutropenia,


Fatigue, weakness √ √ √

Sedation √

Rash √ √ √

Gastrointestinal disturbance

√ Constipation

√ Constipation, diarrhea

√ Constipation, diarrhea

Renal/Hepatic √ Reduce dose for decreased CrCL

CrCL, creatinine clearance; dex, dexamethasone; len, lenalidomide. Velcade prescribing information; Revlimid prescribing information; Thalomid prescribing information; Pomalyst prescribing information; Kyprolis prescribing information.

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Expected Side Effects of Front-Line Therapies: Proteasome Inhibitors

Side effect Bortezomib Carfilzomib Ixazomib

Peripheral neuropathy √ Myelosuppression √

Thrombocytopenia √

Neutropenia, thrombocytopenia,

anemia

√ Neutropenia,


Hypotension √

Cardio/Pulmonary √ √ √ ECG abnormalities

Fatigue, weakness √ √ Viral reactivation of herpes zoster

√ √ √

Gastrointestinal disturbance

√ Nausea and vomiting,

diarrhea

√ Nausea and vomiting, diarrhea, constipation,

mucositis/stomatitis

√ Diarrhea

Renal/Hepatic √ Hepatic

CrCL = creatinine clearance; dex = dexamethasone Velcade prescribing information; Revlimid prescribing information; Kyprolis prescribing information.

SWOG S0777: Newly Diagnosed MM Study Design Randomized phase III trial of VRd vs. Rd in previously untreated ac've MM –  VRd x eight 21-‐day cycles

•  Len 25 mg/d; dex 40 mg weekly •  n = 230

–  Rd x six 28-‐day cycles •  Len 25 mg, dex 20 mg 2 consecu've days each week

•  n = 243 –  Followed by: Rd maintenance

un'l PD, unacceptable toxicity, or withdrawal of consent

Outcomes • Primary end point: PFS • Secondary end points: ORR, OS, safety

Timeline: • Median follow-‐up: 55 mo; median 'me on maintenance: 385 days Prophylaxis • All pts received aspirin 325 mg/day; bortezomib pts received HSV prophylaxis

Durie B, et al. ASH 2015. Abstract 25.

SWOG S0777: Key Takeaways

Durie B, et al. ASH 2015; Abstract 25.

PFS

Safety

OS

Survival (mo) VRd

(n = 242) Rd

(n = 229) HR P Value

Median PFS 43 30 0.712 (0.560 - 0.906) .0018*

Median OS 75 64 0.709 (0.516 - 0.973) .025†

Adverse Event,* % VRd

(n = 241†) Rd

(n = 226†) P Value Grade ≥ 3 AE § Neurologic § Pain § Sensory § Gastrointestinal

33 12 23 22

11 4 3 8

< .0001 .0002 .004 NR

Secondary primary malignancies 4 4

VRd induc'on followed by con'nuous Rd maintenance represents poten'al new standard of care for newly diagnosed MM

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IFM/DFCI 2009: Phase III, Randomized Symptoma'c, Newly Diagnosed

MM Pa'ents (N = 700) Study design •  Pts 65 yrs of age or younger

with symptomaHc, measurable NDMM

•  RVd x 8 followed by Rd maintenance –  RVd: bortezomib 1.3 mg/m2

IV on days 1, 4, 8, 11 + lenalidomide 25 mg on days 1-‐14 + dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, 12

VS –  RVd x 3 -‐> cyclophosphamide

mobilizaHon -‐> MEL200 + HSCT -‐> R maintenance

Outcomes •  Primary objecHve: PFS •  Secondary objecHves: ORR,

MRD, TTP, OS, safety

Attal M, et al. ASH 2015. Abstract 391.

IFM/DFCI 2009: Phase III, Randomized Symptoma'c, Newly Diagnosed MM Pa'ents

(N = 700): Key Takeaways

PFS

OS

Despite a very effec've regimen such as VRd, adding transplanta'on as a part of the con'nuum of therapies certainly seems to increase the depth of response, and these pa'ents do well

Parameter RVd

(n = 350) Transplanta'on

(n = 350) P Value

Median follow-‐up, mo 41 41

Progression or death, n 204 158

Median PFS, mo 34 43

4-‐yr PFS, % 35 47

HR (95% CI) 1 0.69 (0.56-‐0.84) < .001

4-‐yr survival, % 83 81

HR (95% CI); P value 1.2 (0.7-‐1.8); NS


IFM/DFCI 2009: Phase III, Randomized Symptoma'c, Newly Diagnosed MM Pa'ents

(N = 700): Key Takeaways

Safety

Despite a very effec've regimen such as VRd, adding transplanta'on as a part of the con'nuum of therapies certainly seems to increase the depth of response, and these pa'ents do well.


Event, % RVd

(n = 350) Transplanta'on

(n = 350) Neutropenia 31 89 Thrombocytopenia 9 78 InfecHon 10 18

Thromboembolic events 4 5

Peripheral neuropathy 11 11 Secondary primary malignancies 3 5

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IFM/DCFI 2009: Overall Conclusions

•  ASCT vs. RVD in pts with NDMM is associated with: – 31% reduced risk of progression or death (P < .001)

–  Improved TTP and rate of MRD negaHvity – Similar, low rate of mortality

•  Longer follow-‐up required to make any conclusions about OS

•  ASCT should remain a standard of care for eligible pts with myeloma

•  Similar, confirmatory trial ongoing in US Attal M, et al. ASH 2015. Abstract 391.

MRD Sub-‐studies of IFM/DFCI 2009

MRD Assessment •  Bone marrow MRD

evaluaHon planned before and a�er maintenance for pts achieving ≥ VGPR in either arm

•  Primary objecHve: assess MRD by FCM

•  Secondary objecHve: assess MRD by NGS (n = 289)

Imaging (IMAJEM) Sub-‐study

EvaluaHon of Imaging, MRD and survival based on imaging •  MRI or PET/CT at

diagnosis •  MRI or PET/CT a�er 3

cycles of RVD •  MRI or PET/CT before

maintenance

NGS = next generaHon sequencing; MRD = minimal residual disease

Avet-Loiseau H, et al. ASH 2015. Abstract 191; Moreau P, et al. ASH 2015. Abstract 395.

MRD Sub-‐studies of IFM/DFCI 2009

MRD Assessment •  MRD-‐negaHve status

significantly predicHve of 3-‐yr PFS

•  NGS offers improved MRD sensiHvity (< 10-‐6) over FCM and is feasible in most pts

•  MRD negaHvity at 10-‐6 level strongly predicHve of 3-‐yr PFS, including pts who achieve CR and those with t(4;14) and in both treatment arms

•  InvesHgators concluded: •  SensiHve MRD evaluaHon may

idenHfy pts cured of myeloma •  Warrants further evaluaHon in

clinical trials

Imaging (IMAJEM) Sub-‐study •  PET/CT and MRI both effecHve in

detecHng bone lesions at diagnosis

•  MRI negaHvity was not prognosHc for PFS, OS during follow-‐up

•  PET/CT negaHvity a�er 3 cycles of chemotherapy and before maintenance is prognosHc for PFS

•  PET/CT negaHvity before maintenance is prognosHc for OS

•  PET/CT and flow cytometry can be complementary when evaluaHng MRD status

Avet-Loiseau H, et al. ASH 2015. Abstract 191; Moreau P, et al. ASH 2015. Abstract 395.

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Audience Response Ques'on

You are seeing a newly diagnosed 57-‐year-‐old MM paHent with kappa light chain disease: Past medical history includes melanoma (resected), eczema, low-‐back pain. CytogeneHcs: 46 XY [20},FISH: del(13q); loss of 3-‐IGH of chromosome 14, trisomy 15; del(17p) Which of the following treatment opHons would you suggest for this paHent?

A.  A clinical trial using lenalidomide/bortezomib/dexamethasone followed by maintenance vs. autologous HSCT

B.  Melphalan and prednisone followed by HSCT C.  Carfilzomib/pomalidomide/dexamethasone followed by HSCT D.  A clinical trial using daratumumab/lenalidomide/dexamethasone E.  Unsure

NON-‐TRANSPLANT ELIGIBLE AND RELAPSED OR REFRACTORY DISEASE

General Approach to Therapy in the Older Adult

Pa'ent Characteris'cs Approach to Treatment

FuncHonally independent without co-‐morbidiHes

Candidates for most forms of therapy with consideraHon of goals of treatment/expected outcomes.

Intermediate funcHonal impairment unable to tolerate intensive life-‐prolonging curaHve therapy

ApplicaHon of individualized pharmacological approach

Major funcHonal impairments or complex co-‐morbidiHes

PalliaHve therapies with supporHve care

Poor prognosis and limited funcHonal status

Symptom management and supporHve care

NCCN Senior Adult Oncology, 2016, v1; KurHn, S. J Adv Pract Oncol 2010;1:19–29

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Func'onal Status, Co-‐morbidi'es, Frailty, and Vulnerability

•  Func'onal Status: Measures by ECOG and KPS –  ADLs: ability to bathe, dress, toilet and maintain conHnence, transfer, and eat

independently –  IADLs: finances, shopping, housekeeping, transportaHon, and self-‐medicaHon

•  Co-‐morbidi'es –  Cardiovascular, renal, hepaHc, pulmonary, endocrine, rheumatologic disease and

other cancers –  Number, severity, controlled or uncontrolled

•  Frailty –  Weight loss, weakness, poor nutriHonal intake, cogniHve impairment and poor

endurance –  Cardiovascular Health Study (n=5317): frailty associated with hospitalizaHon, falls,

declining ADLs including diminished mobility, and death (P<.001) •  Vulnerability

–  A complex of comorbidity (presence of chronic diseases or condiHons), disability (physical or mental impairment), and frailty (faHgue, low acHvity) that could prevent adequate therapy.

Palumbo et al, Blood 2011; 118:4519-‐29; Kumar et al, CA Cancer J Clin. 2010. doi:10.3322/caac.20059; Balducci & Extermann, Oncologist. 2000;5:224–237

Suggested Dose Modifica'ons for ≥ 1 Risk Factor: Age ≥ 75 yr, Presence of Comorbidi'es, Frailty or Disability

Drug Ini'al/standard dose Reduced dose Further reduc'on if needed

Dexamethasone 40 mg/d 1,8,15,22 every 4 weeks

20 mg/d 1,8,15,22 every 4 weeks

10 mg/d 1,8,15,22 every 4 weeks

Melphalan 0.25 mg/kg or 9 mg/m2 d 1–4 every 4–6 weeks

0.18 mg/kg or 7.5 mg/m2 d 1–4 every 4–6 weeks

0.13 mg/kg or 5 mg/m2

d 1–4 every 4–6 weeks

Thalidomide Thalidomide 100 mg/d

Thalidomide 50 mg/d Thalidomide 50 mg qod

Lenalidomide (plus dexamethasone)

25 mg/d days 1–21 every 4 weeks



Bortezomib

1.3 mg/m2 twice weekly days 1,4,8,11 every 3 weeks

1.3 mg/m2 once weekly days 1,8,15,22 every 5 weeks

1.0 mg/m2 once weekly days 1,8,15,22 every 5 weeks

Palumbo A, et al. (2013). Blood Rev 27(3):133-‐142.

Case Study 2: 75-‐year-‐old Female

Ini'al Presenta'on to PCP: August 2011 •  75-‐year-‐old female •  Hypertension, A. fib •  Performance status 1 •  Symptoms: faHgue, consHpaHon, increased forgenulness, back and leg pain

•  x-‐ray revealed lyHc lesions •  Referred to heme/onc

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•  Hg: 8.6 g/dL •  B2M: 4.13 mg/dL •  Albumin: 2.8 g/dL •  Calcium: 9.8 g/dL •  Cr: 1.4 mg/dL •  M-‐protein: 12 g/dL •  IgA: 3724 mg/dL •  Lambda FLC: 9.35 mg/L •  LDH: 340 (180=ULN)

•  BMPC: 70% •  CytogeneHcs: Normal

Female 46xx[20] •  FISH: gain of 1q21 along

with a t(11;14).

Diagnosis: IgA Lambda Myeloma, ISS Stage II


•  IniHal treatment with VRd –  Achieved a VGPR a�er 8 cycles of treatment

–  PaHent relocated to live near children and decided to stop therapy a�er 8 cycles

•  Concurrent supporHve care –  Pamidronate for 2 yr –  DVT prophylaxis –  InfecHon prophylaxis

•  Re-‐established care with a local oncologist

•  Off treatment for a total of 10 months

•  Three incremental increases in IgA and lambda measures over a 5-‐month period

•  IgA: 309 -‐> 427 -‐> 525 g/dL •  Lambda FLC:

1.86 -‐> 2.08 -‐> 4.63 mg/dL

RELAPSED AND RELAPSED REFRACTORY MM

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Audience Response Ques'on You are seeing a 68-‐year-‐old widower with relapsed IgA lambda MM following iniHal treatment with cyclophosphamide/bortezomib/dexamethasone (CyBorD) with a very good parHal response. The paHent does not want to have a stem cell transplant and disconHnued therapy due to difficulty with travel. He has been off treatment for 6 months. Over the last three surveillance visits, you have noHced the IgA and lambda light chain levels rising incrementally. The paHent reports a recent hospitalizaHon for CHF exacerbaHon. He has residual grade 1 peripheral neuropathy. Which of the following treatment opHons would you consider as the best opHon for this paHent?

A.  ConHnue CyBorD and monitor for three addiHonal months B.  Start carfilzomib/pomalidomide/dexamethasone with a plan for

autologous HSCT C.  Start ixazomib/lenalidomide/dexamethasone and treat to progression

or unacceptable toxicity D.  Start daratumumab E.  Unsure

Natural History of Mul'ple Myeloma

MGUS or smoldering myeloma

Asymptomatic Symptomatic

ACTIVE MYELOMA

M P

rote

in (g

/L)

20

50

100

RELAPSE

2. RELAPSE

REFRACTORY RELAPSE

First-line therapy

Plateau remission

Second-line therapy

Third-line therapy

Adapted with permission from Durie B @ www.myeloma.org.

Evalua'on of treatment response un'l best response Surveillance

Monitoring for Response and Surveillance

KurHn et. al. (2016) J Adv Pract Oncol, 7(S1), S59-‐S70.

• Heavy/light chain monthly with iniHaHon of therapy, unHl best response

• CMPNL, CBC, diff, plts and other labs as indicated based on treatment plan and individual profile

• Myeloma panel every 3 months

• Skeletal survey yearly • Other laboratory or diagnosHc tesHng as indicated by individual disease and personal a]ributes

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Suspected relapse or progression

Monitoring for Response and Surveillance

KurHn et. al. (2016) J Adv Pract Oncol, 7(S1), S59-‐S70.

•  Increase frequency of myeloma panel •  Repeat imaging as clinically indicated •  Repeat bone marrow biopsy to detect changes/clonal

evoluHon with progression •  ConHnued monitoring for organ damage •  EvaluaHon of any residual adverse events •  Re-‐assess co-‐morbidiHes and fit vs. frail •  InfecHous disease workup based on transplant history,

infecHous history, and treatment plan

Relapsed and Relapsed Refractory MM

•  Primary refractory: failure to achieve any response to specific MM treatments, o�en 2 or 3 novel agent combinaHon regimens

•  Relapse: development of clinically measurable disease or secondary organ effects a�er achieving a CR

•  Progression: development of clinically measurable signs of increase disease acHvity a�er achieving PR or disease plateau

–  Progression of disease is implied in the term “relapsed”

•  Relapsed and refractory: defined as a lack of response or disease progression on or within 60 days of the last therapy

–  The therapy in use at the Hme of progression is what the paHent is refractory to

KurHn, S. J Adv Pract Oncol 2013;4(suppl 1):5-‐14

Clonal Evolution in MM MM clones detected by FISH and cytogenetics can evolve At each relapse there is a change in the dominant clone It is critical to re-evaluate the patient at each point of relapse to characterize the disease and select the best treatment FISH = fluorescence in situ hybridization

Keats JJ, Chesi M, Egan JB, et al. Blood. 2012;120:1067-‐1076.

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Considera'ons in Selec'ng Salvage Therapy Time from previous therapy to relapse or progression

§  > 6 mo may use similar agents §  Agents based on:

−  Time from previous therapy to relapse/progression −  Any residual clinical condiHons (neuropathy, renal funcHon, etc.) −  Newly FDA-‐approved agents for second line: carfilzomib,

pomalidomide, ixazomib, panobinostat, elotuzumab §  < 6 mo consider alternaHve agents in combinaHon

Refractory disease §  Clinical trial enrollment §  Newly FDA-‐approved agents

Reassess transplant opHons including allogeneic stem cell transplant on a clinical trial

§  Previous ASCT: second ASCT if Hme to progression (TTP) > 2 yr §  Allogeneic SCT: clinical trial enrollment is recommended

Previous thalidomide §  Bortezomib or bortezomib/pegylated liposomal doxorubicin §  Lenalidomide/dexamethasone §  High-‐dose dexamethasone/carfilzomib/pomalidomide

Previous bortezomib §  Lenalidomide §  Bortezomib §  Carfilzomib/pomalidomide

Previous lenalidomide §  Bortezomib §  Ixazomib §  Carfilzomib/pomalidomide

Richardson PG, et al. Oncology. 2010;24(3 suppl):22-29. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.3.2016.

Retreatment With Bortezomib: RETRIEVE Trial

Clinical Trial Design •  Single arm, open-‐label phase II •  PaHents who achieved ≥ PR on btz

regimen and who relapsed >/= 6 months a�er prior bortezomib treatment

•  n = 130 Results •  PaHents treated with bortezomib +

dex •  40% overall response rate (PR or

be]er) •  DuraHon of response 6.5 months •  Safety profile consistent with

bortezomib

FDA approved bortezomib retreatment August 2014

Type of previous non-‐bortezomib therapy

Pa'ents receiving this therapy, N

Steroids 115

AlkylaHng agents 100

Anthracyclines 75

Thalidomide 40

Other

Previous high-‐dose therapy/stem-‐cell transplant

39

Previous bortezomib treatment

Bortezomib single agent 48

Bortezomib plus other agents

82

Petrucci MT, et al. Br J Haematol. 2013;160:649-‐659.

Case Study 1: Ac've Surveillance

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Clinical Decision Making

What addiHonal tesHng or invesHgaHons would you consider at this point and why?

Clinical Decision Making: What Addi'onal Tes'ng Would You Consider at This Point

and Why?

The kappa light chains and the kappa/lambda ra'o have increased on three consecu've visits •  Bone marrow biopsy: no evidence of disease, normal cytogeneHcs and normal FISH results

•  PET/CT The pa'ent describes a sense of pressure radia'ng from the sub-‐sternal region to the back, most notable when flat in bed •  Echocardiogram: EF 64%, no pericardial effusion, normal wall moHon

•  EKG unremarkable

Case Study Con'nued…

2-‐16-‐2016

PET/CT: 2/16/16 compared to baseline scan on 1/19/15 1. Interval progression of disease in the form of an enlarging, increasingly FDG avid (SUV 29.5) para-‐aorHc mass consistent with known mulFple myeloma 2. Previously idenHfied FDG avid mixed lyHc/scleroHc osseous lesions involving the axial skeleton demonstrate no significant interval change

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Clinical Decision Making/Discussion

What addiHonal tesHng or invesHgaHons would you consider at this point and why?

Relapsed MM

2-‐16-‐2016 2-‐18-‐2016

MRI: 2/18/16 MulHple levels of involvement of the thoracic spine with myeloma, most significantly at T8 where there is a pathologic fracture Large prevertebral mass extends from T6 to T10

The paHent has a history of malignant melanoma on the right shoulder. SenHnel nodes were negaHve and margins were clear on wide excision. What would you recommend at this point?

Clinical Decision Making: What Addi'onal Tes'ng Would You Consider at This Point

and Why?

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CT-‐guided biopsy ordered – confirmed MM Referred to Radia'on Oncology

Relapsed MM

2-‐16-‐2015 2-‐22-‐2016 2-‐18-‐2015

Pomalidomide

FDA approval: February 8, 2013 Class: IMiD Administra'on: oral •  REMS program

–  Discuss administraHon with paHent: 4 mg once daily on days 1-‐21 of 28-‐day cycle

–  Take without food •  At least 2 hr before/a�er meals

•  Do not break, chew, or open the capsules

–  Adherence: consistent schedule (AM or PM)

Educate paHents on •  DVT prophylaxis •  InfecHon risk/blood counts •  FaHgue •  Should not cause peripheral

neuropathy

Pomalidomide Common AEs (in > 30%)

AE, all grades %

FaHgue and asthenia 55

Neutropenia 52

ConsHpaHon 38

Nausea 36

Diarrhea 34

Dyspnea 34

Upper resp. tract infecHon 32

Back pain 32

Pyrexia (pom + dex) 30

Pomalidomide [package insert].

Carfilzomib

FDA approval: July 20, 2012 Class: proteasome inhibitor Administra'on: •  Premedicate: 4 mg

dexamethasone before carfilzomib –  All doses cycle 1; 1st dose cycle 2

–  AddiHonal doses/cycles if infusion reacHons

•  Hydrate: 250 to 500 mL IV saline –  Before carfilzomib; a�er (opHonal)

–  Monitor for overhydraHon

•  Administer carfilzomib IV –  Over ~ 10 min (longer if needed)

–  Rinse IV with saline before and a�er

•  Monitor AEs, which may include cardiopulmonary

•  The drug may require dose adjustment for toxiciHes; diureHcs, inhalers; minimal peripheral neuropathy

Carfilzomib AEs (All Grades) >30%

AE %

FaHgue 56

Anemia 47

Nausea 45

Thrombocytopenia 36

Dyspnea 35

Diarrhea 33

Pyrexia 30

Carfilzomib [package insert].

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Carfilzomib/Pomalidomide/Dexamethasone (CPD; Car/Pom/Dex)

•  Open-‐label, mulHcenter, phase 1, dose-‐escalaHon study

•  PaHents with RRMM, including lenalidomide (n=32)

–  Heavily pretreated paHent populaHon (median of 6 lines of prior therapy)

•  Primary objecHve: Evaluate safety, determine MTD

www.clinicaltrials.gov as #NCT01464034

MTD of CPD (28-‐day cycle) Carfilzomib 20/27 mg/m2

Pomalidomide 4 mg Dexamethasone 40 mg

Safety •  Hematologic adverse events (AEs) occurred in ≥ 60%

of all paHents, including 11 paHents with grade ≥ 3 anemia

•  Dyspnea was limited to grade 1/2 in 10 paHents •  Peripheral neuropathy was uncommon and limited

to grade 1/2 •  Eight paHents had dose reducHons during therapy,

and 7 paHents disconHnued treatment due to AEs •  Two deaths were noted on study due to pneumonia

and pulmonary embolism (n = 1 each)

RRMM=relapsed/refractory mulHple myeloma

Newly Approved Agents: Immunotherapy, HDAC

Inhibitors, and Oral Proteasome Inhibitors

Panobinostat

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Panobinostat in Combination With Bortezomib and Dexamethasone (Pan/Btz/Dex)

Registra'on trial: Phase III PANORAMA1 trial Primary objec've: PFS with PAN-‐BTZ-‐Dex vs. Pbo-‐BTZ-‐Dex in RMM or RRMM Efficacy •  PFS benefit of 7.8 months with PAN-‐BTZ-‐Dex

among paHents who received >2 prior regimens including bortezomib and an IMiD

•  Prior IMiD (12.3 vs. 7.4 months; hazard raHo [HR], 0.54; 95% CI, 0.43-‐0.68)

•  Prior bortezomib plus IMiD (10.6 vs. 5.8 months; HR, 0.52;95%CI, 0.36-‐0.76),

•  >2 prior regimens including bortezomib and an IMiD (12.5 vs. 4.7 months; HR, 0.47; 95% CI, 0.31-‐0.72)

Safety

Common grade 3/4 adverse events:

•  Thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/faHgue

•  Minimal peripheral neuropathy

•  Incidence of on-‐treatment deaths among paHents who received prior bortezomib and an IMiD (regardless of number of prior regimens) was similar between treatment arms.

Class: Histone deacetylase inhibitor

FDA-‐Approved Indica'on (2/25/2015):

In combinaHon with bortezomib and dexamethasone for the treatment of MM in paHents who have received at least two prior chemotherapy regimens

dex = dexamethasone; len = lenalidomide; PR = partial response; VGPR = very good partial response; IMID = immumodulatory agent; HR = hazard ratio; CI = confidence interval. Richardson, Hungria et al, Blood. 2016;127(6):713-721; www.clinicaltrials.gov #NCT01023308

PAN-BTZ-Dex: Clinical Management

Pa'ent management •  Severe diarrhea in 25% of paHents •  At first sign of abdominal cramping, loose

stools, or onset of diarrhea, paHents should be treated with anH-‐diarrheal medicaHon (e.g., loperamide)

•  Consider and administer prophylacHc anH-‐emeHcs as clinically indicated

•  Cardiac toxiciHes, including ischemic events and severe arrhythmias

•  Hematologic toxiciHes: thrombocytopenia and myelosuppression

•  Hepatotoxicity •  Embryo-‐fetal toxicity •  Management of adverse drug reacHons may

require treatment interrupHon and/or dose reducHons

Dosing Considera'ons •  HepaHc impairment

–  Mild: starHng dose 15 mg –  Moderate: starHng dose 10 mg –  Severe: avoid panobinostat use

•  Renal impairment –  Mild to severe renal impairment did

not impact plasma exposure of panobinostat; not studied in paHents on dialysis

•  Co-‐administraHon with CYP3A inhibitors: starHng dose 10 mg

•  Dose modificaHons for the following toxiciHes detailed in package insert:

–  Thrombocytopenia –  Neutropenia –  Anemia –  Diarrhea

dex = dexamethasone; len = lenalidomide; PR = partial response; VGPR = very good partial response. Richardson, Hungria et al, Blood. 2016;127(6):713-721

NovarHs PharmaceuHcals, 2015; Noonan et al. (2016). J Adv Pract Oncol. 7(Suppl).

•  Capsules should not be opened, broken, or chewed •  ConHnue up to 8 cycles for paHents with clinical benefit who do not experience

unacceptable toxicity •  Advise paHents to avoid star fruit, pomegranate, grapefruit or their juices because

they can affect panobinostat pharmacology •  If dose reducHon is required, dose of panobinostat should be reduced in increments

of 5 mg (i.e., from 20 to 15 mg, or from 15 to 10 mg)

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Molecular Targets of Proteasome Inhibitors

20S proteasome

Proteins for degrada'on

Pep'de fragments

Bortezomib Carfilzomib Chymotrypsin-‐like

Trypsin-‐like

(Bortezomib)

Ac've enzyma'c sites and proteasome inhibitor targets

Caspase-‐like

7 1

2

3 6

5 4

(Ixazomib)

Marizomib

Oprozomib

Ixazomib

Adapted from McBride A, Ryan PY. Expert Rev AnFcancer Ther 2013;13:339-‐358

Ixazomib Citrate Class: Proteasome inhibitor Registra'on Trial: TOURMALINE-‐MM1 ClinicalTrials.gov Iden'fier: NCT01850524 •  InternaHonal, randomized, double-‐blind,

placebo-‐controlled clinical trial of 722 paHents

–  Ixazomib, lenalidomide and dexamethasone compared to placebo, lenalidomide and dexamethasone in relapsed and/or refractory mulHple myeloma

•  Approval based on a 6 month improvement in median PFS: 20.6 months vs. 14.7 months (placebo regimen) HR = 0.74 (95% CI, 0.587, 0.939); P=0.012.

•  Median Hme to response 1.1 mo in the ixazomib arm and 1.9 mo in the placebo arm

FDA Approved Indica'on (11/20/2015): In combinaHon with Lenalidomide + Dexamethasone in paHents who have received at least 1 prior therapy

Adverse events (AEs) •  No grade 4 non-‐hematological toxicity •  Grade 3 occurring in > 5% of pts with a

> 5% difference in the two arms: o  Thrombocytopenia: 3% of paHents

on Ixazomib and 1% on the placebo arm had a platelet count of < 10,000 during treatment

o  Diarrhea (42% vs. 36%), consHpaHon (34% vs. 25%)

Other AEs •  Neutropenia, peripheral edema,

backache •  Disorder of the eye •  Rash: generally self-‐limiHng •  Neuropathy: majority were grade 1/2

with incidence similar in both arms

dex = dexamethasone; len = lenalidomide Ninlaro prescribing information, 2016

Ixazomib Citrate: Clinical Management Pa'ent Management •  Baseline CBC

–  ANC > 1,000/mm3

–  Platelet count > 75,000/mm3

•  Monitor CBC at least monthly or more frequently if indicated

–  Platelet nadir, days 14-‐21 of each cycle

•  All paHents should receive shingles prophylaxis (Acyclovir)

•  Treatment should be conHnued unHl disease progression or unacceptable toxicity

•  Oral adherence

Dosing Considera'ons •  Avoid concomitant use with strong

CYP3A inducers •  A�er oral administraHon median Hme

to peak plasma concentraHon = 1 hour •  Should be taken at least 1 hour before

or at least 2 hours a�er food •  HepaHc impairment

–  reduce the starHng dose to 3 mg in paHents with moderate or severe hepaHc impairment

•  Renal impairment –  reduce the starHng dose to 3 mg

in paHents with severe renal impairment or end-‐stage renal disease requiring dialysis

•  Dose modificaHon must be balanced for all drugs in the regimen

Ninlaro prescribing information, 2016.

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•  Should be taken at least 1 hour before or at least 2 hours after food •  Missed doses or emesis:

•  Missed dose should not be taken with 72 hours of the next scheduled dose

•  Do not repeat the dose if vomiting occurs •  Swallow pill whole, do not crush or chew

Ninalro prescribing information, 2016.

Dosing Schedule for Ixazomib

Week 1 Week 2 Week 3 Week 4 Day

1 Days 2-‐7

Day 8

Days 9-‐14

Day 15

Days 16-‐21

Day 22

Days 23-‐28

Ixazomib √ √ √ Lenalidomide √ √ daily √ √ daily √ √ daily √

Dexamethasone √ √ √ √

Ixazomib Citrate: Dosing

Mechanisms of Action of Monoclonal Antibodies Targeting Surface Antigens on MM Cells

Niels WC, et al. Blood 2016;127:681-695

©2016 by American Society of Hematology

Tai YT, et al. Bone Marrow Res. 2011;2011:924058; Balasa B, et al. Cancer Immunol Immunother. 2015;64:61-73

MAb-‐Based Targe'ng of Myeloma

Antibody-dependent cellular cytotoxicity (ADCC)

ADCC

Effector cells

MM

FcR

Complement-dependent cytotoxicity (CDC)

CDC

MM

C1q

C1q

Apoptosis/growth arrest via targeting signaling pathways

MM

Daratumumab (CD38)

SAR650984 (CD38)

huN901-‐DM1* (CD56) nBT062-‐maytansinoid/ DM4* (CD138) 1339 (IL-‐6) BHQ880 (DKK) RAP-‐011 (Ac'vin A) Daratumumab (CD38) SAR650984 (CD38) J6M0-‐MMAF* (BCMA)

Lucatumumab or Dacetuzumab (CD40) Elotuzumab (SLAMF7) Daratumumab (CD38) XmAb 5592 (HM1.24) SAR650984 (CD38)

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Daratumumab •  Humanized monoclonal

anHbody •  Target: CD38

–  Responsible for receptor mediated adhesion, signal transducHon, and regulaHon of intracellular calcium

•  Dara eliminates tumor cells expressing the CD38 anHgen

•  Mechanism: AnHbody-‐dependent cellular cytotoxicity (ADCC)

–  Major mechanism of cell death –  Complement-‐dependent

cytotoxicity (CDC) –  Apoptosis

•  Results in decline in M protein and bone marrow plasma cells

dex = dexamethasone; len = lenalidomide.

Daratumumab FDA Approval: November 16, 2015 Registra'on Trial: MMY2002 (SIRIUS) study ClinicalTrials.gov Iden'fier: NCT01985126 •  Approval was based on a mulH-‐center,

open-‐label study evaluaHng response rates in 106 paHents with relapsed or refractory mulHple myeloma treated with daratumumab monotherapy.

•  Median of 5 prior lines of therapy •  The objecHve response rate was 29%

(95% CI: 21-‐39%) with a median response duraHon of 7.4 mo (range: 1.2 to 13.1+ mo)

FDA Approved Indica'on (11/16/15) Treatment of paHents with mulHple myeloma who have received at least 3 lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double-‐refractory to a proteasome inhibitor and an immunomodulatory agent

•  Updated approval: 7/26/16 The FDA granted daratumumab (Darzalex) a breakthrough therapy designaHon for use in combinaHon with len/dex or Vel/dex as a treatment for paHents with mulHple myeloma following at least 1 prior therapy -‐

Adverse events •  The most frequently reported

adverse reacHons (incidence ≥20%) were infusion reacHons, faHgue, nausea, back pain, pyrexia, cough, and upper respiratory tract infecHon

•  Interference with cross-‐matching and red blood cell anHbody screening

FDA News Release, 2015; Darzalex prescribing information, 2015.

Daratumumab Administra'on: IV The recommended dose for daratumumab is 16 mg/kg Pre-‐medicate with corHcosteroids, anHpyreHcs, and anHhistamines

FDA News Release, 2015; Darzalex prescribing information, 2015.

Schedule Weeks

Weekly Weeks 1-‐8

Every 2 weeks Weeks 9-‐24

Every 4 weeks Weeks 25 unHl disease progression

Dilu'on volume

Ini'al rate (first hour)

Rate increment

Maximum rate

First infusion 1000 mL 50 mL/hr 50 mL/hr every hour

200 mL/hr

Second infusion 500 mL 50 mL/hr 50 mL/hr every hour

200 mL/hr

Subsequent infusions

500 mL

100 mL/hr 50 mL/hr every hour

200 mL/hr

Infusion rates for daratumumab administra'on

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Special Considera'ons for Daratumumab

For paHents treated with CD38-‐targeHng anHbodies with higher risk of respiratory complicaHons (e.g., FEV1, 80%), post-‐infusion medicaHon should be considered (e.g., anHhistamines, b-‐2 adrenergic receptor agonist by inhalaHon, or control medicaHon for paHents with asthma and COPD such as inhalaHon corHcosteroids. ProphylacHc treatment with the oral leukotriene antagonist montelukast 10 mg the day before and again on the morning of infusion may be considered prior to daratumumab.

For daratumumab: PaHents with known COPD with a FEV1, 50% of the predicted normal value, with moderate or severe persistent asthma within the past 2 years, or with uncontrolled asthma, were excluded from trials with daratumumab. Recommenda'ons FEV1 tesHng for paHents with suspicion of having COPD, and it should be considered to exclude paHents from daratumumab treatment if FEV1, 50% of predicted.

van de Donk, NW, et al. (2016). Blood 127(6): 681-695.

Thal/Dex VTD CVDD

Auto-‐PBSCT Rev/Dex

Velcade/Pom/Dex

Auto-‐PBSCT

Car/Pom/Dex

Velcade/Pom/Dex

Daratumumab

IgD levels 2010-‐2016 (normal: < 15.3 mg/dL)

Daratumumab in a Pa'ent With Mul'ple Relapses, Refractory to IMIDs and Proteasome Inhibitors

Courtesy of Sandra KurHn, University of Arizona Cancer Center

Elotuzumab

Elotuzumab exerts a dual effect:

Induces NK-‐mediated myeloma cell death with minimal effect on normal cells MediaHng anHbody-‐dependent cell-‐mediated cytotoxicity through the CD16 pathway

ORR = overall response rate; PFS = progression-‐free survival. Lonial S, et al. J Clin Oncol. 2013;31(suppl):abstract 8542; Facon T, et al. Haematologica 2013;98(s1):319.

Humanized monoclonal anHbody Target: myeloma cells expressing signaling lymphocyte acHvaHon family 7 (SLAMF-‐7, also called CS1)

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Elotuzumab

Registra'on Trial: Phase III ELOQUENT-‐2 trial combining ELO, lenalidomide, and low-‐dose dexamethasone (ERd) Clinical Trials.gov Iden'fier: NCT01239797 •  Randomized paHents with RRMM (1-‐3

prior therapies) who were not refractory to lenalidomide to receive ERd or standard lenalidomide-‐dexamethasone (Rd) in 28-‐day cycles

•  Treatment was conHnued unHl disease progression or unacceptable toxicity

•  The primary endpoints were progression-‐free survival (PFS) and ORR

•  At interim analysis, 646 paHents had been enrolled (321 ERd, 325 Rd)

•  A number of paHents in this trial had adverse disease a]ributes, including del(17p) in 32% and t(4;14) in 9%

•  At 24 months of follow-‐up, paHents in the ERd arm demonstrated a 30% reducHon in the risk of disease progression or death compared to the Rd alone arm (HR 0.70 (95% CI = 0.57–0.85); p = .0004

•  PFS favored ERd over Rd, with a median of 19.4 (16.6–22.2) months vs 14.9 (12.1–17.2) months and HR of 0.70 (95% CI = 0.57–0.85; p = .0004)

•  At 2 years of follow-‐up, 35% (ERd) and 21% (Ld) of paHents remained on therapy; disconHnuaHon was mainly for disease progression (42% ERd, 47% Rd)

FDA Approved Indica'on (11/30/2015): Indicated in combinaHon with lenalidomide and

dexamethasone for the treatment of paHents with mulHple myeloma who have received one to three prior therapies

EMPLICITI [package insert]. Princeton, NJ: Bristol-‐Myers Squibb Company.

Elotuzumab: Clinical Management FDA Approval November 30, 2015

Interference with determina'on of complete response •  Elotuzumab is a humanized IgG kappa

monoclonal anHbody that can be detected on both the serum protein electrophoresis and immunofixaHon assays used for the clinical monitoring of endogenous M-‐protein

•  This interference can impact the determinaHon of complete response and possibly relapse from complete response in paHents with IgG kappa myeloma protein

•  CorrelaHon with clinical findings is recommended

Second primary malignancies (SPM) –  9.1% (ERd) and 5.7% (Rd) –  No difference in hematologic SPM –  Slightly higher incidence for solid tumors

(3.5% vs. 2.2%) and skin cancers (4.4% vs. 2.8%) in the ELO arm.

–  Monitor paHents for SPM Hepatotoxicity

–  Monitor liver enzymes periodically –  Stop elotuzumab upon grade 3 or higher

elevaHon of liver enzymes –  A�er return to baseline values,

conHnuaHon of treatment may be considered

EMPLICITI [package insert]. Princeton, NJ: Bristol-‐Myers Squibb Company; Lonial S, et al. N Engl J Med. 2015;373(7):1-‐11. h]p://www.nejm.org/doi/full/10.1056/NEJMoa1505654; Cheng M, et al. Cell Mol Immunol.2013;10(3):230-‐252; Lonial S, et al. N Engl J Med.2015;373(suppl):1-‐18.

Infec'ons •  Grade 3/4 infecHons were 28% (ERd) and 24.3%

(Rd) •  Monitor paHents for development of infecHons

and treat promptly •  Implement infecHon prophylaxis as indicated

Elotuzumab: Administra'on and Dosing

Infusion reac'ons •  70% of infusion reacHons occurred during the first dose •  The most common symptoms of an infusion reacHon included fever, chills,

and hypertension •  Bradycardia and hypotension also developed during infusions •  5% of paHents required interrupHon of the administraHon of elotuzumab for

a median of 25 minutes due to infusion reacHon

Start of infusion 30 min 60 min or more Cycle 1 dose 1 0.5 mL/min 1 mL/min 2 mL/min Cycle 1 dose 2 1 mL/min 2 mL/min Cycle 1 dose 3 & 4 and all subsequent cycles

2 mL/min

Premedica'on •  Dexamethsaone 28 mg orally 3-‐24 hours prior to infusion •  H1 and H2 blocker, dexamethasone 8 mg IV and acetaminophen 45-‐90

minutes prior to infusion Dosing: 10 mg/kg intravenously

EMPLICITI [package insert]. Princeton, NJ: Bristol-‐Myers Squibb Company; Lonial S, et al. N Engl J Med. 2015;373(7):1-‐11. h]p://www.nejm.org/doi/full/10.1056/NEJMoa1505654; Cheng M, et al. Cell Mol Immunol.2013;10(3):230-‐252; Lonial S, et al. N Engl J Med.2015;373(suppl):1-‐18.

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The recommended dosage of elotuzumab is 10 mg/kg administered IV

Pa'ents must be premedicated prior to each dose of elotuzumab

Treatment should continue until disease progression or unacceptable toxicity

EMPLICITI [package insert]. Princeton, NJ: Bristol-‐Myers Squibb Company.

Infusion Reac'ons vs. Hypersensi'vity Reac'ons

•  Hypersensitivity reactions are antibody-mediated and can occur only after repeated exposure to an antigen

•  Anaphylactoid infusion reactions are nonantibody-mediated and often occur on the initial exposure to a drug

•  Cytokine-release syndrome comprises a subset of nonantibody-mediated infusion reactions associated with the use of monoclonal antibodies and immune therapies

•  Clinical symptoms of hypersensitivity reactions and nonantibody-mediated infusion reactions heavily overlap and can be difficult to distinguish in practice

•  Pre-medication and having an established protocol for management is the key!

Asselin, B. (2016). Future Oncol. Apr 16. E-‐pub ahead of print. doi:10.2217/fon-‐2016-‐0005

Signs and Symptoms of Hypersensi'vity Reac'ons

System Clinical Findings

General Fever, chills, flushing, rigors, sweaHng, faHgue, agitaHon, metallic taste

Cutaneous Rash, urHcaria (hives, welts, wheals) pruritus, angioedema (including face, lips or eyelids)

Respiratory Dyspnea, wheezing, stridor, rhiniHs, repeHHve cough, chest Hghtness, throat Hghtness, change in voice quality (from laryngeal edema)

Cardiovascular Tachycardia, hypotension/hypertension

GastrointesHnal Nausea, vomiHng, diarrhea, abdominal cramping

Renal Flank pain, back pain, hematuria

Neurological Headache, dizziness, tunnel vision, ‘feeling of impending doom’

Asselin, B. (2016). Future Oncol. Apr 16. E-‐pub ahead of print. doi:10.2217/fon-‐2016-‐0005

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Preven'on and Treatment of Infusion Reac'ons in Mul'ple Myeloma

Preven'on •  PremedicaHon, consisHng of steroids, anHhistamines, and acetaminophen,

30-‐60 minutes prior to infusion. •  Both daratumumab and elotuzumab have specific recommendaHons for

pre-‐medicaHon, administraHon an post-‐infusion management Treatment •  Interrupt infusion •  AcHvate rapid response team if available •  AcHvate standing orders/protocol

–  Administer anHhistamines, corHcosteroids, IV fluid, b-‐2 adrenergic receptor agonist by inhalaHon, oxygen if needed

•  A�er infusion reacHon is resolved, restart infusion at lower rate as described in the administraHon guidelines for the specific drug

van de Donk, N. W., et al. (2016). Blood 127(6):681-‐695.

Audience Response Ques'on You are seeing a 68-‐year-‐old widower with relapsed IgA lambda MM following iniHal treatment with cyclophosphamide/bortezomib/dexamethasone (CyBorD) with a very good parHal response. The paHent does not want to have a stem cell transplant and disconHnued therapy due to difficulty with travel. He has been off treatment for 6 months. Over the last three surveillance visits, you have noHced the IgA and lambda light chain levels rising incrementally. The paHent reports a recent hospitalizaHon for CHF exacerbaHon. He has residual grade 1 peripheral neuropathy. Which of the following treatment opHons would you consider as the best opHon for this paHent?

A.  ConHnue CyBorD and monitor for three addiHonal months B.  Start carfilzomib/pomalidomide/dexamethasone with a plan for

autologous HSCT C.  Start ixazomib/lenalidomide/dexamethasone and treat to progression

or unacceptable toxicity D.  Start daratumumab E.  Unsure

ADJUNCTIVE AND SUPPORTIVE CARE IN MM

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NCCN Recommenda'ons for Adjunc've Treatment

•  Infection –  IVIG for recurrent infections –  Pneumovax and influenza vaccine –  PCP, herpes and antifungal

prophylaxis for high-dose or long-term steroids

–  Herpes zoster prophylaxis with bortezomib

•  Bone disease

–  Bisphosphonates –  Radiation therapy –  Orthopedic consultation –  Vertebroplasty or kyphoplasty

•  Renal dysfunction

–  Avoid aggravating factors: contrast, NSAIDs, dehydration

–  Not a contraindication to HCT –  Monitor bisphosphonates closely

•  Coagulation/thrombosis –  Prophylactic anticoagulation with IMiDs

•  Hypercalcemia –  Hydration, steroids, furosemide –  Zoledronic acid preferred

•  Hyperviscosity –  Plasmapheresis

•  Anemia –  Consider erythropoietin –  Transfusion –  Type and screen patients prior to

daratumumab administration

NCCN Clinical PracHce Guidelines in Oncology: MulHple Myeloma—v.3.2016.

Prevention and Treatment of Neutropenia and Infections

•  Establish a plan for close monitoring of blood counts in initial phase of treatment where risk is greatest

•  Review reportable signs and symptoms with patient and caregivers, including who to contact and how

•  IVIG for serum IgG < 500 •  Immunizations:

–  Poor response to pneumococcal and influenza vaccines (STILL GIVE)

–  DO NOT GIVE herpes zoster vaccine

•  Shingles prophylaxis: –  Acyclovir is recommend for all

proteasome inhibitor therapy

•  Prompt identification of symptoms and institution of treatment

•  Subsequent treatment may require dose modification, dose delay, or administration of G-CSF agents as secondary prophylaxis

•  Treatment for fungal infections using azoles based on response and tolerance

IVIG = intravenous immunoglobulin NCCN v3, 2016; Anderson et al., J Natl Compr Canc Netw 2015;13:1398–1435; Colson K, Support Care Cancer 2015:23(5):1431-1445

Bone Disease

o  Malignant plasma cells produce cytokines

o  Increase osteoclast differenHaHon

o  Suppress osteoblast maturaHon o  Inhibit new bone o  Results

–  Infiltrate and destroy bone –  Secondary effects

•  Osteolysis •  Bone pain •  Pathological fractures •  Hypercalcemia

Images courtesy of Sandra Kurtin, RN, MS, AOCN®, ANP-C.

Common presenting symptoms

NCCN v3, 2016; Anderson et al., J Natl Compr Canc Netw 2015;13:1398–1435; Colson, 2015; Support Care Cancer 23(5):1431-1445; Zangari, M. et al (2016). The effects of proteasome inhibitors on bone remodeling in multiple myeloma. Bone.

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Management of Bone Disease

o  Treat the myeloma o  Novel therapies have benefit:

–  Direct effect on inflammatory cytokines –  InhibiHon of bone resorpHon –  Osteoblast sHmulaHon

o  Radiotherapy (low dose) –  Impending fracture –  Cord compression –  Plasmacytomas

o  Orthopedic consultaHon –  Impending or actual long-‐bone fractures –  Bony compression of spinal cord –  Vertebral column instability

TreaHng the underlying disease and managing any symptoms of clinical findings that require immediate intervenHon are the goals for managing MM bone disease

Anderson et al., J Natl Compr Canc Netw 2015;13:1398–1435; Colson, 2015, Support Care Cancer 23(5): 1431-‐1445; Zangari, M. and L. J. Suva (2016). "The effects of proteasome inhibitors on bone remodeling in mulHple myeloma." Bone.

Management of Bone Disease: Suppor've Care

•  Bisphosphonates (category 1) –  Pamidronate –  Zoledronic acid –  Both require monitoring

•  Renal funcHon •  Osteonecrosis of jaw

•  Kyphoplasty/vertebroplasty •  Home safety evaluaHon •  Pain management •  Use of spinal support (braces) may be

indicated •  Ongoing evaluaHon of bone health

Image: Medtronic, Kyphon Products Division NCCN Guidelines for MulHple Myeloma V3, 2016; Terpos E., et al. (2013). J Clin Oncol 31(18): 2347-‐2357.

Kyphoplasty uses a “balloon” to create a cavity for bone cement to reduce vertebral fracture and pain

IMWG Recommenda'ons for Use of Bisphosphonates in MM

Factor 2013 Recommendation Patient population Newly diagnosed patients with MM who require

antimyeloma treatment (regardless of bone status)

Administration IV Duration/frequency Monthly during initial therapy and ongoing in

patients who are not in remission

After 2 years, discontinue if CR/VGPR; continue if ≤ PR

Monitoring Monthly creatinine clearance Choice Zoledronic acid (first option)

Pamidronate (second option)

CR = complete response; IV = intravenous; MM = multiple myeloma; PR = partial response; VGPR = very good partial response.

Terpos, E., et al. (2013). J Clin Oncol 31(18):2347-‐2357.

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Bisphosphonate Use in MM: Adverse Events

•  Flu-‐like symptoms •  Fever, myalgias, arthralgias •  Occurs usually 12-‐48 hours following infusion; lasts 6-‐24 hours •  Occurs in minority of paHents (10%-‐20%) •  Generally reduced with conHnued dosing •  Slow rate of infusion and use of steroids and anHhistamines may help reduce

intensity

Zoledronic Acid: Use in Renal Patients

Creatinine clearance (mL/min)

Dosing (mg)

>60 4.0 50-60 3.5 40-49 3.3 30-39 3.0 <30 Not recommended

NS = normal saline; IV = intravenous. NCCN, 2016 v3 ; Terpos et al, 2013, Blood 121(17): 3325-‐3328; Aredia prescribing informaHon, 2012; Zometa prescribing informaHon, 2014.

Pamidronate: Use in Renal Patients

Creatinine clearance (mL/

min)

Dosing (mg) 90 mg/500 mL NS

IV

>30 2-4 hours

<30 Not recommended

Osteonecrosis of the Jaw (ONJ)

•  Baseline dental exam prior to starHng bisphosphonate treatment –  Dental procedures (below the gum

line/extensive) should be done prior to starHng IV BPs if possible

–  If below the gum line procedures are necessary – hold bisphosphonates 2 months prior to and a�er procedures

•  Avoid unnecessary dental procedures once IV BPs start

•  There is no standard treatment: prevenHon is key –  Excellent oral hygiene is best prophylaxis –  Limit alcohol and tobacco use –  Consider supplementaHon with calcium

1,000 mg/day and vitamin D 400 IU/day

Long-‐term use of bisphosphonates (> 2.5 years) increases the risk for development of ONJ

Boonyapakorn T, et al. (2008). Oral Oncol 44(9):857-‐869; Jackson GH, et al. (2014). Br J Haematol 166(1):109-‐117.

Renal Disease in Mul'ple Myeloma

MM Factors 2%-‐40% of paHents Cast nephropathy Hypercalcemia Hyperviscosity Light chain deposiHon Amyloidosis

Contribu'ng Factors DehydraHon Hyperuricemia MedicaHons Loop diureHcs NSAIDs Contrast media AcHve therapies for MM Bisphosphonates

Measure of Renal Disease in MM Serum creaHnine > 2 mg/dL Calcium levels > 12 mg/dL Elevated free light chains Uric acid

Treatment of the mul'ple myeloma is oxen the best strategy to improve renal

func'on

NSAIDs = nonsteroidal anH-‐inflammatory drug Palumbo et al, 2014. J Clin Oncol 32(6):587-‐600.

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Renal Considera'ons in MM •  Treatment of hypercalcemia

–  HydraHon –  Dexamethasone –  DiureHcs –  Bisphosphonates

•  Treatment of hyperviscosity –  MM therapy –  Plasmapheresis

•  CoordinaHon with dialysis schedule –  All agents are administered

a�er dialysis with the excepHon of ixazomib, which is not dialyzable

•  Avoidance of aggravaHng factors –  DehydraHon –  Diabetes –  Hypertension –  MedicaHons

(NSAIDs, loop diureHcs) –  IV contrast

;

Palumbo A, et al. (2014). J Clin Oncol 32(6): 587-‐600; Gonsalves WI, et al. (2015). Blood Cancer Journal. 5, e296; doi:10.1038/bcj.2015.20; published online 20 March 2015

Renal Considera'ons in MM: Novel Therapies

Thalidomide •  No dose adjustment required •  May be associated with

hyperkalemia •  Administer a�er dialysis Lenalidomide •  Excreted substanHally by the

kidney •  Dose adjustments required •  Adverse events may be increased

with renal impairment •  Administer a�er dialysis Pomalidomide •  Dose adjustment required in

severe renal impairment •  Administer a�er dialysis

Bortezomib •  No dose adjustment required •  Dialysis may reduce

concentraHons, administer a�er dialysis

Carfilzomib •  No dose adjustment required •  Dialyzability unknown, administer

a�er dialysis Ixazomib •  No dose adjustment required •  Not dialyzable

Panobinostat •  No dose adjustments required •  Dialyzability unknown, administer

a�er dialysis ;

Risk Factors for Thromboembolism Individual Factors •  General

–  Age –  Obesity or diabetes –  Cardiovascular or renal disease –  Acute infecHon

•  Inherited thrombophilic abnormaliHes –  Protein C deficiency, protein S

deficiency, factor V Leiden mutaHon

–  Elevated homocysteine levels •  Central venous catheter use •  Prior DVT, PE, or superficial vein

thrombosis

Disease-‐Related Factors • Diagnosis of MM • Anesthesia, surgery, trauma, or hospitalizaHon

•  ImmobilizaHon, sedentary lifestyle, extremity paresis

• Other malignant neoplasm • Hyperviscosity

DVT = deep venous thrombosis; PE = pulmonary embolism; MM = mulHple myeloma; ESA = erythropoieHn. Palumbo et al, 2014; Palumbo et al, 2008. Leukemia 22(2):414-‐423

Treatment-‐Related Factors •  High-‐dose dexamethasone •  Thalidomide, lenalidomide, pomalidomide

•  Adjuvant doxorubicin for other cancer

•  MulHagent chemotherapy •  ESA use

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Preven'on of Thrombosis

•  Low risk –  0 or 1 risk factor –  Thromboprophylaxis

•  Low-‐dose aspirin (81-‐100 mg/d) is effecHve if used consistently

•  High risk –  ≥ 2 risk factors –  Thromboprophylaxis

•  LMWH or warfarin with therapeuHc dosing (INR 2-‐3)

LMWH = low-‐molecular-‐weight heparin; INR = internaHonal normalized raHo. NCCN Treatment Guidelines for MulHple Myeloma, V3, 2016.

Evaluating VTE risk and implementing risk-adapted VTE prophylaxis is a critical prevention strategy in MM

Thromboembolic Events: Prophylaxis

o  Mechanical –  AmbulaHon, exercise is the most effecHve prophylacHc strategy

–  SequenHal compression devices –  AnH-‐embolism stockings: quesHonable

o  Steroid dose reducHon –  Decreased risk of venous thromboembolism in ECOG trial –  Dexamethasone reduced dosing 40 mg weekly

•  Deep vein thrombosis: 26% high-‐dose vs. 12% low-‐dose (P = 0.0003)

•  InfecHon/pneumonia: 16% high-‐dose vs. 9% low-‐dose (P = 0.04)

ECOG = Eastern CooperaHve Oncology Group. Rajkumar SV et al. (2010). Lancet Oncology, 11:29-‐37; Palumbo, 2014.

Neuropathy General Considera'ons •  Neuropathy may be due to the

disease itself due to the overproducHon of myeloma proteins

•  PaHent specific factors may also contribute to neuropathy

•  Treatment related neuropathy, most o�en sensory in nature, is drug specific

Most Common Symptoms •  Sensory deficits •  Neuropathic pain

Pa'ent-‐Related Factors •  Endocrine disorders

•  Hypothyroidism •  Diabetes

•  NutriHonal disease •  ConnecHve Hssue disease •  Vascular disease •  MedicaHons •  Herpes zoster Disease-‐ and Treatment-‐Related Factors •  Hyperviscosity syndrome •  Hypergammaglobulinemia •  Incidence of peripheral

neuropathy in untreated paHents: 39%

Gleason C, et al (2010). J Natl Compr Canc Netw 7(9):971-‐979; Velcade prescribing informaHon, 2012; Thalomid prescribing informaHon, 2013; Kyprolis prescribing informaHon, 2012.

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Neuropathy Incidence of grade 3/4 CIPN with novel agents: Bortezomib

–  Untreated MM: grade 3 = 12%; grade 4 = 1% –  Relapsed/refractory MM: grade 3 = 7%; grade 4 = <1% –  Relapsed/refractory MM (SC vs. IV): grade 3 = 5% SC, 14% IV; grade 4 = 1% SC,

1% IV –  ↓ with weekly vs. twice weekly dosing –  ↓ with SC administra'on

Thalidomide –  Study 1: neuropathy-‐sensory grade 3/4 = 4%; neuropathy-‐motor

grade 3/4 = 8% –  Study 2: peripheral neuropathy NOS grade 3/4 = 3% –  ↑ with higher doses and prolonged therapy

Carfilzomib –  All events of peripheral sensory neuropathy and peripheral motor

neuropathy = 14%; grade 3 = 1% Ixazomib

-‐ All events of peripheral neuropathy = 18%; grade 3 = 2%

CIPN = chemotherapy-induced peripheral neuropathy; SC = subcutaneous; IV = intravenous; NOS = not otherwise specified. Kurtin & Billotti, 2013; Colson, 2015; Gleason et al, 2010; Velcade prescribing information, 2012; Thalomid prescribing information, 2013; Kyprolis prescribing information, 2012.

Management of Neurotoxicity Symptoms

•  Baseline and ongoing evaluaHon –  Include high-‐risk comorbidiHes

•  Dose reducHon, delay, or omission of drug –  Agent-‐specific guidelines –  Administer bortezomib SC

•  Use of various supplements –  Avoid green tea or vitamin C with bortezomib administraHon –  Daily doses of B6 should not exceed 100 mg

•  Emollient creams (e.g., cocoa bu]er, menthol, and eucalyptus-‐based)

•  Physical therapy •  Stress reducHon •  CogniHve behavioral therapy •  Acupuncture •  Pain also may be treated with gabapenHn, tricyclic anHdepressants,

or other agents helpful in relieving neuropathic pain

Hausheer et al, 2006; Agafitei et al, 2004; Saif, 2004; Tariman et al, 2008.

Tools for Management of Fa'gue

•  Individualized assessment –  Sleep, nutriHon, depression, medicaHons, acHvity, comorbidiHes

•  Individualized intervenHons –  Balance between acHvity and energy conservaHon –  Psychosocial intervenHons –  NutriHon consultaHon –  Sleep evaluaHon –  Pharmacologic intervenHons

•  PsychosHmulants, sleep medicaHons

NCCN, Guidelines for Fatigue, V1, 2016

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Strategies for Staying Well

•  Eat a balanced diet •  Get daily acHvity/exercise •  Avoid infecHon •  Avoid bleeding or clo�ng •  ConHnue to enjoy things you love…

in other words, LIVE •  Get enough rest •  Take advantage of available resources •  Ask for help when needed

Summary •  Although currently not curable, the median overall

survival for mulHple myeloma has improved dramaHcally over the last decade –  Understanding of the pathobiology of the disease will improve the raHonale of supporHve care requirements

•  Improved long-‐term survival is the goal –  Early depth of response → sustained response with an acceptable level of toxicity

•  Many new agents are on the way, many will be oral •  CollaboraHve clinical management together with paHent

and caregiver empowerment will promote the best outcomes and preserve future treatment opHons

FINAL MM SLIDES-general-SK edits Tampa-2 · 8/15/16& 5 Kumar SK, et al. (2009). Mayo Clinic Proc....

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