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Diagnosing and Treating Multiple Myeloma in 2008. Craig Hofmeister, M.D. Assistant professor of medicine OSU Comprehensive Cancer Center Craig.Hofmeister@osumc.edu. Objectives. Review epidemiology and pathophysiology of multiple myeloma.

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diagnosing and treating multiple myeloma in 2008

Diagnosing and Treating Multiple Myeloma in 2008

Craig Hofmeister, M.D.

Assistant professor of medicine

OSU Comprehensive Cancer Center

Craig.Hofmeister@osumc.edu

objectives
Objectives
  • 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.
  • Understand the eligibility and purpose of hematopoietic stem cell transplantation for myeloma.
  • Understand who will benefit from intravenous bisphosphonates and the most common complications.
epidemiology
Epidemiology
  • Prevalence1,3,4
    • Annual incidence about 4 per 100,000
    • 19,900 new diagnoses in the United States in 2007
    • 10,790 expected deaths
    • Usually occurs in individuals aged >60 years
    • The average age at diagnosis is 68 years
    • 1% diagnosed in individuals aged <40 years
  • Population subgroups4
    • Incidence of multiple myeloma (MM) is twice as common in African Americans
    • Slightly more frequent in men than women
      • 10,960 men; 8940 women (estimated new cases in 2007)
  • Remains incurable

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.

epidemiology1
Epidemiology
  • Second most common hematologic cancer
  • Common clinical features include
    • Bone pain, fractures, osteolytic lesions
    • Anemia, hypercalcemia
    • Renal insufficiency
    • Bleeding tendency
    • Peripheral neuropathy

Estimated Annual Cases in the United States

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.

myeloma is a plasma cell cancer
Myeloma is a plasma cell cancer
  • Plasma cells are normally present in the bone marrow and are responsible for immunoglobulin production in response to infection/other immune system-triggering events
  • In MM, monoclonal plasma cells infiltrate the bone marrow and replace normal cells, leading to
    • Tumor formation
    • Monoclonal immunoglobulin (M protein) production
    • Reduced immune response
    • Bone resorption and bone lesions

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

clinical presentation
Bone pain

Cord compression

Osteoporosis

Bone marrow

Infection

Anemia (73%)

Clinical presentation
  • Headaches
  • Blurry vision
  • Renal insufficiency (25-50%)
  • Hypercalcemia
    • Somnolence
    • Nausea 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.

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

renal manifestations
Renal manifestations
  • Myeloma kidney = Cast nephropathy (40%), i.e. tubular casts in the distal nephron
  • AL amyloidosis (15%) in glomeruli and blood vessels
  • Monoclonal Ig deposition disease, most commonly light-chain deposition disease (15%)
  • Cryoglobulinemic glomerulonephritis & proliferative glomerulonephritis (rare)

Congo red birefringence of a glomerulus when viewed through crossed Polaroid filters

m spike
“M-spike”

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

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.

dx myeloma
Dx: Myeloma
  • M-protein in serum and/or urine
  • Κ or λ restricted plasmacytoma or marrow plasma cells; clonality is often defined as the presence of only kappa or lambda light chains in these plasma cells (a.k.a. “light chain restriction”)
  • Related organ or tissue impairment (see next slide)

IMWG Diagnostic Criteria. Br J Haematol. 2003;121:749-757

related organ or tissue impairment
Related organ or tissue impairment

Buy – Lytic bone lesions – visible on x-ray in 85% of patients. Hint – Osteoclasts activated, not osteoblasts.

C – Hypercalcemia (Ca > 11 mg/dL)

A – Anemia (Hb < 10)

V – Hyperviscosity – especially common in the rare IgM secreting myeloma

I – Bacterial infections (>2)

A – Amyloidosis

R – Renal (Crt > 1.96 mg/dL): HINT – occurs 50% of the time because most often the light chains are toxic to the tubules.

These are the end organ manifestations of myeloma

dx monoclonal gammopathy of undetermined significance
Dx: Monoclonal gammopathy of undetermined significance
  • 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

IMWG Diagnostic Criteria. Br J Haematol. 2003;121:749-757

dx smoldering myeloma
Dx: Smoldering myeloma
  • M-protein in serum ≥ 3 g/dL and/or clonal plasma cells on BmBx ≥ 10%;
  • NO related organ or tissue impairment

IMWG Diagnostic Criteria. Br J Haematol. 2003;121:749-757

dx non secretory myeloma
Dx: Non-secretory myeloma
  • No M-component  many would say this means a negative serum and urine immunofixation
  • Bone marrow biopsy shows clonal plasma cells ≥ 10% or there is a plasmacytoma
  • Related organ or tissue impairment

IMWG Diagnostic Criteria. Br J Haematol. 2003;121:749-757

dx plasmacytoma
Dx: Plasmacytoma
  • Small M-protein in serum and/or urine (if at all)
  • Κ or λ restricted plasmacytoma(s)
  • Single area of bone destruction if plasmacytoma is next to bone
  • No clonal plasma cells on bone marrow biopsy
  • NO related organ or tissue impairment except for adjacent bone if affected

IMWG Diagnostic Criteria. Br J Haematol. 2003;121:749-757

differential diagnosis
Differential diagnosis
  • 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. Treatment similar to that for CLL. 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) – The circulating serum monoclonal protein is generally asymptomatic and is an incidental finding.
waldenstrom s macroglobulinemia
Waldenstrom’s Macroglobulinemia
  • B-NHL secreting IgM
  • Gene expression profiling suggest more similar to CLL than myeloma
  • Responses may be best for agents that work for both: Velcade, Thal/Rituxan, Campath; standard of care is fludarabine based, despite concerns for transformation to DLBCL, MDS/AML

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

risk of mgus myeloma
Risk of MGUS  Myeloma

Rajkumar, V et al. Blood . 2005

smoldering myeloma active myeloma
Smoldering myeloma  Active myeloma

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

update on current staging for myeloma
Update on current staging for myeloma

Stage Criteria Median Survival (mo)

I β2m < 3.5 mg/L 62

albumin > 3.5 g/dL

II* Not stage I or III 44

III β2m > 5.5 mg/L 29

*β2m < 3.5 mg/L and albumin < 3.5 g/dL or

β2m 3.5 - < 5.5 mg/dL, any albumin

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

slide21

1.00

0.75

0.50

0.25

0.00

0

100

200

300

400

500

600

700

Future staging…

No t(4;14), no del(17p), low 2m

Other

Overall Survival

T(4;14) or del(17p), and high 2m

Time (d)

Avet-Loiseau H, et al, IMW 2007, Abstract S1.5.

slide22

OSU initial diagnostic studies

  • Laboratory studies
    • CBC/d/p, Creatinine
    • Ca, 25-OH-Vit D, testosterone
    • B2Microglobulin, LDH
    • M-protein assessment – SPEP/IFE, UPEP/IFE, serum immunoglobulins
    • Serum free light chains
  • Bone marrow biopsy, CD138-selected myeloma FISH panel & karyotype
  • Skeletal survey
  • If back pain present, MRI entire spine
bortezomib velcade

VELCADE

Bortezomib (Velcade)

26S Proteasome

b1

b2

Post-

glutamylSite

TrypticSite

19SCap

b7

b3

20SSubunit

b6

b4

19SCap

Chymo-

trypticSite

b5

  • Degrades ubiquitinated proteins
  • Proteolysis is adenosine triphosphate (ATP) dependent
  • 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.

lenalidomide revlimid
Lenalidomide (Revlimid)

Anti-neoplastic

Immunomodulatory Anti-angiogenic

osu upfront treatment algorithm
OSU upfront treatment algorithm

Velcade

Melphalan

Prednisone

  • 17p- [p53] or
  • t(4,14) or
  • t(14;16) or
  • 13q- w/ 14q32
  • Tetraploidy
  • 1p/1q karyotype

(VMP)

Velcade

Dexamethasone

Phase I

clinical trial

At

relapse

High risk

Melphalan

Prednisone

Revlimid

(MPR)

Velcade

Dexamethasone

Autologous

hematopoietic

stem cell

transplant

or

All others

Standard risk

Revlimid

Dexamethasone

We believe that all myeloma patients should be treated on a clinical trial for all phases of their care.

The above algorithm applies only to patients ineligible or unwilling to be treated on a clinical protocol.

what is a stem cell transplant
What is a stem cell transplant?
  • Autologous transplant (1% transplant-related mortality)
    • Essentially just high dose chemotherapy done safely
    • Melphalan 200 mg/m2 autologous transplant improves survival over standard cytotoxic chemotherapy
    • Goal is to find myeloma that is sensitive to melphalan
    • Eligibility: Age < 75 y.o., kidneys optional
  • Allogeneic (20% 1-year all-cause mortality)
    • Graft-versus-myeloma effect;
    • Chemo just prevents rejection
    • Graft-versus-host disease is significant detriment
osu post autologous transplant care

Progression

OSU post autologous transplant care

Stem cell transplant

OSU clinical trials

CR

VGPR

Observe until relapse

  • Maintenance
  • Revlimid 10 daily, or
  • Thalidomide 100 qHS
  • Velcade weekly

Protocol ineligible

Less than

VGPR

Melphalan conditioned

Autologous transplant

Progression

Relapsed/refractory

OSU clinical trials

Progression

what is the hope for allo transplant
What is the hope for allo transplant?

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

probability of survival after transplant 1998 2004

100

80

60

40

20

0

Probability of survival after transplant 1998-2004

Auto (N=12,565)

Probability, %

HLA-id sib (N=763)

Unrelated (N=103)

1

3

0

2

4

5

6

Years

bisphosphonates1
Bisphosphonates

Renal safety profile of ZOMETA compared with pamidronate and placebo*

50%

40%

30%

20%

10%

0%

ZOMETA

Pamidronate

Placebo

Patients with deterioration in renal function vs baseline†

17%

13%

11%

11%

9%

7%

Breast and multiple

myeloma

(N=540)P=NS

Prostate

(N=170)

P=NS

Lung and other solid tumors (N=328)

P=NS

*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).

ZOMETA Prescribing Information.

osteonecrosis of the jaw
Osteonecrosis of 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