Multiple Myeloma Something Old, Something New, Something Borrowed

(1)

Nicolas Novitzky Dip Med, PhD, FCP(SA)

H a e m a t o l o g y

C l i n i c a l & L a b o r a t o r y S c i e n c e , D e p a r t m e n t o f M e d i c i n e U n i v e r s i t y o f C a p e T o w n

Multiple Myeloma

Something Old, Something New, Something

Borrowed…

(2)

Plasma Cell Dyscrasias

1. Monoclonal gammopathy

2. Smouldering or indolent myeloma. 3. Solitary plasmacytoma

i) bone ii) soft tissue

3.Multiple plasmacytoma or myeloma i) medullary

ii) extramedullary

4. Plasma cell leukaemia

7. Amyloidosis

5. Macroglobulinaemia

(3)

(4)

Pathophysiology

Plasma cell homeostasis



Antigen dependent increase in

proliferation of B-cells

–

Cell cycle regulation

 Cycline dependent kynases  Cytokine signals

−

Upregulation of survival signals

• IL-6 • IGF • SDF-1 • VEGF 

Reduction in apoptosis

–

FAS

–

TRAIL/Apo

Karyotypic abnormalities

common



Inherent genetic instability

 VDJ recombination  Somatic hypermutation  Isotype switching 

Chromosomal translocations

 14q32 (75% of myeloma cells) 

Karyotypic abnormalities in MM

& MGUS

 Numeric abnormalities Hypo/hyper diploid Chromosome gains/losses  Structural abnormalities Translocations

(5)

(6)

Incidence of Chromosomal Abnormalities in MM

Genomic Aberrations

Incidence of aberration

Del (13)

48%

Del (17p)

11%

t(4;14) (p16;q32)

14%

Hyperdiploidy

39%

t(11;14) (q13;q32)

21%

• N= 1064 patients

(7)

From MGUS to Myeloma



Definitions *



MGUS (1-3% annual

progression)



IgG < 30g/L



Plasma cells in BM < 10%



No CRAB



Smoldering myeloma (10%

annual progression)



IgG > 30 g/L



Plasma cells > 10%



No CRAB



Multiple myeloma



IgG > 30 g/L



Plasma cells > 10%



CRAB

(8)

MGUS



MGUS



In 3% of > 55 years

• Asymptomatic



Higher incidence among Africans



Family history



Precedes plasma cell disorder in

all cases

 Myeloma  Amyloidosis  Waldestrom MG



Progression (21, 37 & 58%)

o

M protein concentration > 15 g/L

o

Aberrant plasma cell population by

flowcytometry

(CD38+, CD56+, lack of CD19, CD45)

o

DNA aneuploidy



All patients need evaluation

o Marrow morphology,

o

Cytogenetics or FISH



Bone imaging

o Skeletal survey

(9)

Multiple Myeloma

Accumulation of clonal plasma

cells



Impaired haematopoiesis



Secrete paraprotein



Bone disease



2% of cancers



20% of deaths from haematological

malignancies



Presentation age depends on clinical

variant

 MGUS 62 yr. (3% of >50 years)  Myeloma 69 yr.

(10)

Multiple Myeloma



Abnormal proliferation of

clonal plasma cells



IgG



IgA



Light chain only (BJP)



IgD, IgE



IgM very rare in myeloma



Common in Lymphoma esp.

Waldenstrom’s



Non-secretory



M protein found in serum or

urine or both at time of

diagnosis: 97%



Serum M spike by protein

electrophoresis: 80%



Abnormal serum immunofixation:

93%



Abnormal urine immunofixation:

75%

(11)

Diagnostic Criteria

•

Plasma cells >10% in marrow

• Or (in any quantity) in a biopsy from other

tissues (plasmacytoma)

•

Monoclonal protein (paraprotein)

in serum / urine

• except in non-secretory myeloma

•

Evidence of end-organ damage

• Calcium >2.75 mmol/L)

• Renal failure attributable to myeloma • Hb < 10gm/dl

• Lytic bone lesions

Monoclonal gammopathy of undetermined significance (MGUS):

 Serum paraprotein <30 g/L AND

 Clonal plasma cells <10% on bone marrow

biopsy AND

 NO myeloma-related organ or tissue

impairment



Asymptomatic (smouldering)

myeloma:

 Serum paraprotein >30 g/L AND/OR  Clonal plasma cells >10% on bone

marrow biopsy AND

 NO myeloma-related organ or tissue

impairment



Multiple myeloma

 IgG > 30 g/L

 Plasma cells > 10%

(12)

(13)

No anemia, bone lesions

normal calcium and

kidney function

Criteria for Diagnosis

MGUS <3 g M spike <10% PC AND Smoldering MM ε 3 g M spike OR ε 10% PC

Active MM

•ε 10% PC

•M spike +

AND

Kyle RA. N Engl J Med 2002; 346: 564

Anemia, bone lesions,

high calcium or

abnormal kidney function

(14)

Signs & Symptoms in 1027 Newly Diagnosed

Myeloma Patients

0 10 20 30 40 50 60 70 80 Bone lesions Fatigue Cr >2 mg/dL Ca >11 mg/dL Wt loss (>9 kg) % pat ient s 79 Hb<12 g/dL 73 Bone pain 66 32 13 19 12

(15)

Bone Imaging in MM



Skeletal radiography is the

primary diagnostic test to detect

destructive bony lesions in

multiple myeloma



MRI is useful in assessing spinal

compression fractures, focal mass

or from osteopenia due to

increased osteolysis



PET scans can be used to detect

soft tissue or bone metastases

(16)

(17)

Myeloma Bone Disease

Post-treatment appearance of multiple myeloma at FDG PET. Appearance of multiple myeloma at

(18)

(19)

Salmon & Durie

Prognostic factors



Stage III: one or more of

Hb < 8.5g/dL

Serum calcium > 3mmol/l

Skeletal survey: 3 or> lytic bone lesions Serum paraprotein

• > 70g/L IgG, > 50g/L IgA



Urinary light chain excretion >

12g/24h



Stage I: all of

Hb > 10g/dL Normal calcium

Skeletal survey: normal or single

plasmacytoma or osteoporosis

Serum PP < 50 g/L IgG, < 3o g/L IgA Urinary light chain excretion < 4 g/24h



Stage II: fulfilling the criteria of

(20)

International Staging System (ISS)

for Symptomatic Myeloma

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

Stage

Criteria

Median

_{Survival (mo)}

I

β2m < 3.5 mg/L

albumin ≥ 3.5 g/dL

62 II*

Not stage I or III

44 III

β2m ≥ 5.5 mg/L

29

(21)

Multiple Myeloma



Treatment



Smoldering or Stage I myeloma

 Counseling and observation  Follow up

CBC, SPEP, chemistry every 3 mo

Bone survey ± Bone marrow biospy every 6

mo



Clinical trial of thalidomide or other

biological therapy



Progression to Stage II, III disease



Treat accordingly



Solitary plasmacytoma



Radiation therapy 45 to 50 Gy



Follow up



CBC,

SPEP

, UPEP, chemistry

every 3 months



Bone Survey ± CT scan or

MRI every 6 mo



Yearly evaluation after one

(22)

Therapy

Melphalan & Prednisone

(NCI; MY-2, n= 460)

• Objective response 46%

o (50% reduction in tumour bulk)

o CR: 2% • Unchanged 10% • Progressive disease 44% • Increase in paraprotein • Hypercalcemia • Increase in plasmacytosis/omas • Increase in number/size lytic lesions 

Duration of response: 18 month



Overall survival: 24-36 months



Cycle is repeated every 4-6 weeks

(23)

High Dose Therapy in Myeloma

Autologous stem cell

transplantation



MRC Myeloma Working Party

– OR: 90% – CR: 25-80%



Intergroupe Francais du Mye’lome

• VCMP/VBAP vs. ABMT • Nº= 100 + 100 • OR : 74 vs. 42% • EFS @ 5 yr. : 28 vs. 10% • OS @ 5 yr. : 52 vs. 12% •

Prognosis:

(24)

(25)

Biological Cell Modifiers in Myeloma



Immuno-modulating agents



Thalidomide



Lenolidomide



Pomalidomide



Proteasome inhibitors



Bortezomib



Carfilzomib



Histone deacetylases



Vorinostat



Panobinostat



Mammalian target or

rapamicin complex (mTOR)



Temsirolimus



Everolimus



Heat shock protein 90



Perifostine



Tanepsimycin



Monoclonal antibodies

(26)

Thalidomide



Thalidomide



Old drug (1958)

 Sedative, anti emetic  Teratogenic !!!

 Withdrawn from market in 1962



Anti inflammatory

 Immunomodulating

 Inhibits TNF and IL-1

 Anti-angiogenesis 

Side effects

 Somnolence, tiredness  Peripheral neuropathy  Thrombophilia  Constipation

(27)

(28)

Lenolidomide



Synthetic immuno-modulatory

agent



Lower side effect profile



No Peripheral neuropathy



No constipation



No sedation



Not teratogenic



Associated with



Thombosis



Marrow suppression



Inhibits angiogenesis



Reduced VEGF levels



Decreased vascular density



Immuno-stimulatory



2000 x more potent than

thalidomide



NK cells



CD4+



IL-2 & IF- production



Inhibits apoptosis & IL-6

production

(29)

(30)

Treatment Decision Tree

Transplant candidate



Initial therapy

 Thalidomide based  CTD  Bortezomib based  VCD



Auto SCT (single / double)



Maintenance

 Thalidomide

 Pamidronate / zeledronic

acid



Salvage

 Bortezomib or lenolidomide  With anthacyclines (Doxyl)

Non- transplant candidate



Initial Therapy



MPT



VMP



Maintenance



Thalidomide



Pamidronate / zeledronic acid



Salvage



Bortezomib based

(31)

Multiple Myeloma Treatment Lines

a

Induction Consolidation Front-line treatment Maintenance Maintenance Rescue Relapsed Bor/Dex Bor/Dex/Dox Bor/Thal/Dex Len/Dex

SCT

Observation Thal Thal/Pred Bor Bor/Liposomal Dox Len/Dex

a_{Transplant eligible patients.}

Bor/Dex = bortezomib, dexamethasone; Bor/Dex/Dox = bortezomib, dexamethasone, doxorubicin; Bor/Thal/Dex = bortezomib, thalidomide, dexamethasone; Len/Dex = lenalidomide, dexamethasone; SCT = stem-cell transplant; Thal/pred = thalidomide, prednsione; Bor/Liposomal/Dox = bortezomib, liposomal doxorubicin.

(32)

(33)

Survival Benefits of New Agents

43mo

Median not yet reached

P = 0.001

73.9 mo 16mo

P < 0.001

Overall _{From relapse}

(34)

Treatment of Bone Disease



Bisphosphonates



Surgical procedures



Vertebroplasty



Balloon Kyphoplasty



Radiotherapy



Treatment of myeloma

MM patients with lytic disease or osteopenia on plain radiographs or imaging studies

Intravenous pamidronate 90 mg deliver over at least 2 hrs or zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks.

Continue therapy for 2 yrs & consider stopping in patients w/ responsive or stable disease; further use at physician’s discretion

(35)

Blade et al, Arch Int Med 1999; Leung et al, Kidney Int 2008

Clinical Problems: Renal Failure



Incidence in myeloma



Renal dysfunction in 20-40%



Dialysis required in 5-10%

 1-1.5% of all renal failure

2 year mortality 58 vs. 31%



Mechanisms:



Interstitial nephritis



Ca++, uric acid, drugs, etc.



Tubular necrosis



Cast nephropathy



Light chain deposition, tubular

atrophy (MIDD)



Amyloidosis



Reversible 20-70%

 Creatinine< 500 mmol/L  Proteinuria < 1 gr/ day  Ca++ > 3 mmol/L

(36)

Clinical Problems: Renal Failure



Management

 Supportive

 Hydration, alkalynisation of urine,

biphosphonates (CrCl > 30 mL)

 Omit nephrotoxins, radiological contrast

media, furosemide

 Prognosis related to response to therapy



Plasmapheresis

 Useful to clear light chains (for MIDD

only)

If > 50% reduction response in 80%



Renal replacement



High cut-off dialyser to remove

light chains



Chronic haemodialysis

 Median survival 2 years



Specific therapy



VAD 40% CR; 20% PR



Bortezomib based 75% CR

(37)

(38)

Myeloma Drugs

(39)

Monthly and Median Costs of Cancer Drugs at the

Time of Approval by the FDA from 1965 through 2008

(40)

Risk Adapted Therapy

Age Renal

function

Co morbid conditions

Geography Access _Patient Preference

Risk Profile

(41)

Conclusions



Multiple myeloma is a heterogeneous malignancy



Adverse factors include high ISS, adverse cytogenetics and poor

response to initial therapy

