Multiple Myeloma Objectives and MGUS of hematopoietic … - PDF of Slide… · · 2010-07-20gamma beta alpha-2 alpha-1 albumin ... XP et al. Increased incidence of disease transformation

1

Multiple Myelomaand MGUS

Craig Hofmeister, M.D.Assistant Professor of Medicine

OSU Comprehensive Cancer Center

• Review epidemiology and pathophysiology of multiple myeloma.

• Obtain familiarity with International Myeloma Working Group criteria to diagnose plasma cell dyscrasias.

• Be able to describe the most active drugs for myeloma: IMiDs and proteasome inhibitors.

Objectives

• Understand the eligibility and purpose of hematopoietic stem cell transplantation for myeloma.

• Understand who will benefit from intravenous bisphosphonates and the most common complications.

Objectives

• PrevalenceAnnual incidence about 4 per 100,00019,900 new diagnoses in the United States in 200710,790 expected deathsThe average age at diagnosis is 68 years1% diagnosed in individuals aged <40 years

Epidemiology

1. Multiple Myeloma Research Foundation. Causes & incidence. http://www.multiplemyeloma.org/about_myeloma/2.03/php. Accessed May 2, 2007. 3. Multiple Myeloma Research Foundation. Multiple myeloma: disease overview. 2006. http://www.multiplemyeloma.org/downloads/about_myeloma/

Disease_Overview.pdf. Accessed April 30, 2007.4. American Cancer Society. Detailed guide: multiple myeloma - what are the risk factors for multiple myeloma?

http://www.cancer.org/docroot/CRI/content//CRI_2_4_2X_What_are_the_risk_factors_for_multiple_myeloma_30.asp?sitearea=. Accessed April 30, 2007.

2

• Population subgroupsIncidence of multiple myeloma (MM) is twice as common in African AmericansSlightly more frequent in men than women• 10,960 men; 8940 women (estimated new

cases in 2007)

• Remains incurable

Epidemiology

1. Multiple Myeloma Research Foundation. Causes & incidence. http://www.multiplemyeloma.org/about_myeloma/2.03/php. Accessed May 2, 2007. 3. Multiple Myeloma Research Foundation. Multiple myeloma: disease overview. 2006. http://www.multiplemyeloma.org/downloads/about_myeloma/

Disease_Overview.pdf. Accessed April 30, 2007.4. American Cancer Society. Detailed guide: multiple myeloma - what are the risk factors for multiple myeloma?

http://www.cancer.org/docroot/CRI/content//CRI_2_4_2X_What_are_the_risk_factors_for_multiple_myeloma_30.asp?sitearea=. Accessed April 30, 2007.

EpidemiologyAge-specific Incidence Rates for Myeloma, 2000–2003

*<25 cases for this age group.

Source: SEER Cancer Statistics Review 1975-2003, National Cancer Institute, 2006.

50

40

30

20

10

0

Inci

denc

e (p

er 1

00,0

00)

85+80-8475-7965-69 70-7460-6455-5950-5440-44 45-4935-3930-340-24*

Age in Years

25-29

• Common clinical features includeBone pain, fractures, osteolytic lesionsAnemia, hypercalcemiaRenal insufficiencyBleeding tendencyPeripheral neuropathy

Epidemiology

1. American Cancer Society. Cancer facts & figures. 2002. 2003. 2004. 2005. 2006. 2007. http://www.cancer.org. Accessed April 30, 2007.2. International Myeloma Foundation. Concise review of the disease and treatment options. 2006.

http://www.myeloma.org/pdfs/ConciseReview2006.pdf. Accessed April 30, 2007.

10,90014,600

2003

10,80014,600

2002 2007200620052004

10,79011,31011,30011,070Deaths19,90016,57015,98015,270New Cases

Estimated Annual Cases in the United States

Clinical Presentation• Bone pain• Bone marrow

Easy bruisingInfectionAnemia

• Headaches• Blurry vision• Renal insufficiency• Hypercalcemia

SomnolenceNausea and vomiting

1. International Myeloma Foundation. Concise review of the disease and treatment options. 2006. http://www.myeloma.org/pdfs/ConciseReview2006.pdf. Accessed April 30, 2007.

2. Multiple Myeloma Research Foundation. Multiple myeloma: disease overview. 2006. http://www.multiplemyeloma.org/downloads/about_myeloma/Disease_Overview.pdf. Accessed April 30, 2007.

3

• Hematologic

73% of patients will have anemia secondary to

• Marrow infiltration with plasma cells

• Decreased levels of erythropoietin

• Decreased erythrocyte survival

Systems Affected

Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.

• SkeletalBone pain is the most common symptom• Osteolytic lesions, generalized

osteoporosis, or osteopeniaAssociated oncologic emergencies• Spinal cord compression• Hypercalcemia (Not a true emergency)

• RenalM proteins may lead to renal failure

Systems Affected

Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.

Renal Manifestations• 55%: Myeloma kidney = Cast

nephropathy, i.e. tubular casts in the distal nephron

• 20% AL amyloidosis in glomeruli and blood vessels

• 20% Monoclonal Ig deposition disease, most commonly light-chain deposition disease

• 5% Cryoglobulinemic glomerulonephritis & proliferative glomerulonephritis (rare)

Congo red birefringence of a glomerulus when viewed

through crossed Polaroid filters

In MM, there is overproduction of one subtype of immunoglobulin, called the M protein (monoclonal protein)

“M-spike”

Adapted from International Myeloma Foundation. Concise review of the disease and treatment options. 2006. http://www.myeloma.org/pdfs/ConciseReview2006.pdf. Accessed April 30, 2007.

4

Serum Protein Electropheresis

+

Control

Patient

albuminalpha-1alpha-2betagamma

Monoclonal “spike”

_

Urine

Serum

Hypogammaglobulinemia

albuminalpha-1

alpha-2beta

gamma

Monoclonal Light Chain Proteinuria

Urine Protein Electropheresis

Bone Marrow in Myeloma

• BM involvement can be patchy• Aspirates can give false negatives• Discrepancies between core biopsy and

aspirate not uncommon

5

• Multiple Myeloma• Non-secretory myeloma• Smoldering myeloma• Plasmacytoma (single or

multiple)• Plasma cell leukemia• Monoclonal gammopathy…

IMWG Diagnostic Criteria. Br J Haematol. 2003;121:749-757; Leukemia 2006 w/ erratum 2007

• M-protein in serum and/or urine OR abnormal FLC ratio

• Κ or λ restricted plasmacytoma or marrow plasma cells

• Related organ or tissue impairment

Buy – Lytic bone lesionsC – Hypercalcemia (Ca > 11 mg/dL)A – Anemia (Hb < 10)V – HyperviscosityI – Bacterial infections (>2)A – AmyloidosisR – Renal (Crt > 1.96 mg/dL)

Related organ or tissue dysfunction

Update on diagnosis

• Non-secretory myeloma• Smoldering myeloma• Plasmacytoma (single or



• No M-component and normal FLC ratio

• BmBx clonal PCs ≥ 10% or plasmacytoma




Update on diagnosis

6

• Smoldering myeloma• Plasmacytoma (single or



• M-protein in serum ≥ 3 g/dLand/or clonal PCs on BmBx ≥10%

• NO related organ or tissue impairment



Update on diagnosis

• Plasmacytoma (single or multiple)

• Plasma cell leukemia• Monoclonal gammopathy…


• Small M-protein in serum and/or urine if at all

• Κ or λ restricted plasmacytoma(s)• Single area of bone destruction• No clonal PCs on BmBx• NO related organ or tissue

impairment except for adjacent bone if affected



Update on diagnosis

• Plasma cell leukemia• Monoclonal gammopathy…


• 20+% circulating monoclonal plasma cells, ≥ 2000 PCs




Update on diagnosis

Update on diagnosis

• Monoclonal gammopathy…


• M-protein in serum < 3 g/dL• < 10% clonal PCs on BmBx• No evidence of other B-cell

lymphoproliferative disorder• No related organ or tissue

impairment



7

• Primary amyloidosis (AL) – clonal plasma cell disorder in which monoclonal light chains are deposited in kidney, liver, heart, or peripheral nervous system. Treatment somewhat similar to myeloma. Less than 30% PCs on BmBx.

• Waldenstrom’s macroglobulinemia (a.k.a. lymphoplasmacytic lymphoma) – a B-cell non-Hodgkin’s lymphoma that secretes IgM monoclonal protein (> 3 gm/dL) into the serum. IgM antibodies are viscous d/t their structure and patients often present with symptoms of hyperviscosity.

• Other non-Hodgkin’s lymphomas can produce monoclonal proteins (e.g. CLL) –Monoclonal protein is an incidental finding.

DDx

• B-NHL secreting IgM

• Gene expression profiling suggests closer to CLL than myeloma

• Responses may be best for agents that work for both: Velcade, Thal/Rituxan, Campath; standard of care is fludarabinebased, despite concerns for transformation to DLBCL, MDS/AML

Waldenstrom’s

Leleu, XP et al. Increased incidence of disease transformation and development of MDS/AML in Waldenstrom’smacroglobulinemia (WM) patients treated with nucleoside analogues. JCO 25(18S) 2007: 8018.

MGUS Myeloma

Serum m-spike value

Rel

ativ

e ris

k of

full

prog

ress

ion

Prob

abili

ty o

f ful

l pro

gres

sion

at 2

0 ye

ars

(%)

0.5 1.0 1.5 2.0 2.5 3.0

13.6

25

50

65

3

9

5

7

1 13.6

15.6

41.248.8

24.6

64

Kyle, et al., New Engl J Med, 346:564, 2002

MGUS Myeloma

Rajkumar, V et al. Blood . 2005

58%20.8All 3 factors abnormal

37%10.1Any 2 factors abnormal

21%5.4Any 1 factor abnormal

5%1

Lowest risk: 1. M protein < 1.5 g/dL2. IgG subtype3. Normal FLC ratio

Risk @ 20 yrs

RelativeRiskRisk group

8

SMM MM

3

2

1

PCs < 10%, M protein ≥ 3 g/dL

PCs ≥ 10%, M protein < 3 g/dL

PCs ≥ 10%, M protein ≥ 3 g/dL

Risk group

Kyle RA et al. NEJM . 356: 2582-90, 2007

Stage Criteria Median Survival (mo)

I β2m < 3.5 mg/L 62albumin > 3.5 g/dL

II* Not stage I or III 44

III β2m > 5.5 mg/L 29

Greipp et al. J Clin Oncol 2005; 23: 3412-20

*β2m < 3.5 mg/L and albumin < 3.5 g/dL or β2m 3.5 - < 5.5 mg/dL, any albumin

Staging for Myeloma

Future Staging…

Initial Studies• Laboratory studies

CBC/d/p, BMP (incl. Ca), LFTs

B12, 25-OH-Vit D

B2Microglobulin

M-protein assessment – SPEP/IFE, UPEP/IFE, serum immunoglobulins

Serum free light chains

9

Initial Studies• Bone marrow biopsy, CD138-

selected myeloma FISH panel & karyotype

• Skeletal survey

• If back pain present, MRI entire spine

Treatment History

Bergsagel, P.L. Molecular principles underlying myeloma pathogenesis. Accessed at the International Myeloma Foundation website’s webcast of the XIth International Myeloma Workshop. http://www.myeloma.org/pdfs/Kos2007_Bergsagel.pdf.

Bortezomib (Velcade™)

Chymo-tryptic

Site

Post-glutamyl

SiteTryptic

Site

β1 β2

β3

β4

β5

β6

β7

VELCADE

• Chymotryptic site is rate limiting in protein degradation

1. Adams J, et al. Bioorg Med Chem Lett. 1998;8:333-338.2. DeMartino GN, Slaughter CA. J Biol Chem. 1999;274:22123-22126.3. Seemuller E, et al. Science. 1995;268:579-582.

α β

19SCap

20SSubunit

26S Proteasome

• Degrades ubiquitinated proteins• Proteolysis is adenosine triphosphate

(ATP) dependent

19SCap

Lenalidomide (Revlimid™)

Bartlett JB et al. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nature Reviews. 4: 314-322, 2004.

10

Hig

h ris

kSt

anda

rd ri

sk

17p- [p53] ort(4,14) ort(14;16) or13q- w/ 11q32 orTetraploidy

All others

1. Rev/Dex: Revlimid 25 mg days 1-21 + 40 mg decadron weekly2. Vel/Dex: Velcade 1.3 mg/m2 1, 4, 8, 11 + 40 mg decadron

weekly3. MPT: Melphalan 4 mg/m2 d1-7, Pred 40 mg/m2 d1-7,

Thalidomide 100 mg PO qHS continuous q 42 days f/bthalidomide maintenance

4. VMP: Melphalan 9 mg/m2 d1-4, prednisone 60 mg/m2 d1-4, Velcade d1,4,8,11 & 22, 25, 29, 32 q42 days x 4 cycles f/b 5 cycles with Velcade d 1, 8, 15, 22 q35 days

5. Thal/Dex: Thalidomide 100 mg qHS + 40 mg decadron weekly

Risk stratification Preferred treatments (prioritized)

OSU Algorithm1. Vel/Dex: Velcade 1.3 mg/m2 days 1, 4, 8, 11 + 40 mg decadron

weekly2. Rev/Dex: Revlimid 25 mg days 1-21 + 40 mg decadron weekly

• Mateos M, et al. Bortezomib plus melphalan and prednisone in elederly untreated patients with multiple myeloma: results of a multicenter phase ½ study. Blood. 108: 2165-2172, 2007.

• Palumbo A, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 367: 825-831, 2006.

OSU Treatment

Responseafter 2-4 cycles

Upfront treatment

Relapsed/refractoryOSU clinical trials

Progression

Any Response

Stem cell transplantOSU clinical trials

CR/VGPR Observe until relapse

Maintenance 1. Revlimid 10 daily, or2. Thalidomide 100 qHS

Less than

VGPR

Progression

Protocol ineligible

Melphalan conditionedAutologous transplant

Relapsed/refractoryOSU clinical trials

Progression

Progression

Progression

Autologous Transplant

Updated 7-year EFS= 16% vs 8% (P=0.01) and 7-year OS=43% vs 25% (P=0.03)

Attal M. N Engl J Med 1996; 335:97; Child J. N Engl J Med 2003; 348:1875

• Melphalan 200 mg/m2 autologous transplant improves survival over standard cytotoxic chemotherapy1-4

• Who can be transplanted safely?Age < 75 y.o.Functionally able to work at a “desk job”Normal functioning liver by enzymes and PT/PTT, low risk PFTs, LVEF > 50%No other interfering comorbidity

Auto transplant in standard risk patients

1. Attal M et al, New England Journal of Medicine, 1996.2. Child JA et al, New England Journal of Medicine, 2003.3. Fermand et al, Journal of Clinical Oncology, 2005.4. Barlogie B. et al, Journal of Clinical Oncology, 2006.

11

Allogeneic Transplant

Bruno B et al. A comparison of allografting with autografting for newly diagnosed myeloma. NEJM 356: 1110-1120, 2007.

Bisphosphonates

Bisphosphonates

*Patients with both normal and abnormal baseline renal function.†Renal deterioration was defined as an increase of 0.5 mg/dL for patients with normal baseline serum creatinine(<1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine (>1.4 mg/dL).

Renal safety profile of ZOMETA compared with pamidronate and placebo*

ZOMETA Prescribing Information.

Breast and multiple myeloma(N=540)P=NS

Lung and other solid tumors

(N=328)P=NS

Prostate(N=170)P=NS

Patie

nts

with

det

erio

ratio

n in

re

nal f

unct

ion

vs b

asel

ine†

50%

40%

30%

20%

10%

0%

11%9%

11%

7%

17%13%

ZOMETAPamidronatePlacebo

Bisphosphonates

12

• Calculate baseline creatinine clearance (CrCl) to determine patient-specific starting dose

• For patients with CrCl >60 mL/min, the recommended starting dose is 4 mg infused over no less than 15 minutes Q 3 to 4 weeks

• For patients with reduced CrCl the following schedule is recommended

Calculate CrCl using the Cockcroft-Gault formula.*Doses calculated assuming target AUC of 0.66 (mg.hr/L) (CrCl=75 mL/min)..

• Starting Dose Recommendations for Patients With Reduced Creatinine Clearance

• 50-60 3.5 mg• 40-49 3.3 mg• 30-39 3.0 mg• <30 Not recommended

Baseline Creatinine Clearance (mL/min) Recommended Dose*

ZOMETA Prescribing Information.

Zometa Dosing

Osteonecrosisof the Jaw

Clinical Features of Suspected ONJ

• Exposed bone in maxillofacial area that occurs in association with dental surgery or occurs spontaneously, with no evidence of healing*

Working Diagnosis of ONJ

• No evidence of healing after 6 weeks of appropriate evaluation and dental care

• No evidence of metastatic disease in the jaw or osteoradionecrosis


• Precipitating dental events: extraction(n = 16), periodontal disease (n = 12),bone exostosis (n = 10), and trauma(dentures, implants, intubation; n = 5)

• In patients with multiple myeloma,periodontal disease and osteoporosiswere significant risk factors

Hoff AO, et al. Poster presented at: ASCO 2006. Abstract 8528.


• Compared to patients without ONJ,patients with ONJ had

– Longer duration of disease

– Longer duration of follow-up

– Longer duration of IV bisphosphonatetreatment

– Higher cumulative doses of IVbisphosphonates

Hoff AO, et al. Poster presented at: ASCO 2006. Abstract 8528.

13


• Before initiation of bisphosphonate therapyA dental examination with appropriate preventive dentistry should be considered in patients with concomitant risk factors (eg, cancer, chemotherapy, corticosteroids, poor oral hygiene)

• During bisphosphonate therapyPatients should avoid invasive dental procedures if possible


Bottom line:

Risk of osteonecrosis of the jaw:

Zometa: 4%Pamidronate: 0.4%

• N = 597 after tandem and without progressive disease randomized to three arms: observation, pamidronate, or pamidronate + thalidomide (avg. dose 200 mg daily)

• Skeletal related events in 24%, 21%, and 18% (p=0.4).

• Take home: Without the use of bone turnover markers, stop bisphosphonate when you stop myeloma treatment

Using Bisphosphonates

Attal M, Facon T, et al. Maintenance therapy with thalidomide improves survival …. Blood. 108: 3289-3294, 2006. Lacy, MQ, …Kyle RA. Mayo clinic consensus statement …. Mayo Clinic Proc. 81(8): 1047-1053, 2006.

• Joyce AT, et al. Risk of renal failure associated with IV bisphosphonate use …. JCO 25(18S): 8104, 2007. • Berenson, JR et al. Zometa may improve survival compared to pamidronate in pts w/ high BALP. Blood. 108: 3589,

2006.

• Given only to patients with lytic lesions seen on skeletal survey and relatively good kidney function –doubles the risk of renal insufficiency

• Zometa 4 mg IV over 30 mins q28 days preferred for patients with elevated bone alkaline phosphatase(>150), otherwise pamidronate 90 mg IV over 2 hrs q28 days

• No bisphosphonates for patients with VGPR, CR, or sCR after transplant

Using Bisphosphonates

14

Ohio State MyelomaDon Benson, MD Craig Hofmeister, MD

Nurse practitionerMegan Smith

Transplant coordinatorMichelle Johnson

http://www.jamesline.com

Spine disease:Ehud Mendel MD

Pain management: Steve Severyn MD

Documents

Multiple Myeloma Objectives and MGUS of hematopoietic … - PDF of Slide… · · 2010-07-20gamma beta alpha-2 alpha-1 albumin ... XP et al. Increased incidence of disease transformation