Multiple myeloma (MM)

Multiple myeloma (MM)

The second most common adult haematological malignancy. MM is a clonal malignancy of terminally

differentiated plasma cells.

Multiple myeloma: Epidemiology and incidence

• Annual incidence of approximately 30-50 per million.

• Median age at presentation of about 70 years. Approximately 15% of patients are aged <60 years and a further 15% are aged between 60 and 65 years. Fewer than 2% of myeloma patients are under 40.

• Myeloma has a higher incidence in Afro-Caribbean ethnic groups compared with Caucasians.

• Median survival: – From the diagnosis: 3-5 years– From the first relapse: 1-3 years– In case of refracter disease: 6-9 months

Myeloma: Clinical presentation• Symptoms of bone disease: tipically persistent,

unexplained backache• Impaired renal function• Anaemia: typically normochromic, normocytic. Less

frequently leukopenia and thrombocytopenia• Hypercalcaemia• Recurrent or persistent bacterial infections• Hyperviscosity• Symptoms suggestive of spinal cord/nerve root

compression• Features suggestive of amyloidosis• Raised erythrocyte sedimentation rate

The role of RANKL/RANK/OPG system in myeloma bone disease

Myeloma cells induce the RANKL expression

Myeloma cells decrease the OPG avaiability

Increased osteoclast activity, decerased osteoblast function

Lateral skull X-ray with typical findings of multiple myeloma: multiple "punched-out" holes. The arrow is pointing at one of the larger holes

Spinal radiograph showing generalized osteopenia

and multiple compression fractures.

Renal impairment in multiple myeloma

• Prevalence in up to 30% of patients at presentation and up to 50% of patients at some stage of disease.

• Light-chain component of the immunglobulin can cause proximal tubular damage. – Other factors: dehydration, hypercalcaemia,

hyperuricaemia, infection and use of nephrotoxic drugs, amyloid, plasma cell infiltration and use of NSAIDs

Anaemia and immundeficiency in MM

• Anaemia is present in two-thirds of patients at presentation and becomes more common in patients with progressive disease

• Myeloma patients have B-cell defects with hypogammaglobulinaemia.

• Disturbed T-cell function has also been demonstrated.

• During chemotherapy neutropenia may occur.• High-dose corticosteroid treatment also

compromise defences against fungal and viral infections.

Diagnostic criteria of multiple myeloma

• Demonstration of a monoclonal protein (M-protein/paraprotein) in the serum or urine and

• lytic lesions on X-ray together with• an increased number (>10%) of plasma

cells in the bone marrow.

Patients with multiple myeloma show a "spike" in special regions of the serum protein

electrophoresis

Bone marrow smear in multiple myeloma

Other conditions in which an M-protein may be present

• Monoclonal gammopathy of undetermined significance (MGUS; prevalence 3% in those over 70 years old)

• AL amyloidosis• Solitary plasmocytoma (skeletal or extra

medullary)• B-cell non-Hodgkin lymphoma • CLL

Diagnostic criteria for MGUS, asymptomatic and symptomatic myeloma

MGUS Asymptomatic myeloma

Symptomatic myeloma

M-protein in serum

<30 g/l >30 g/l No specific level required

Bone marrow clonal plasma cells

<10% >10% >10%

Myeloma-related organ or tissue impairment and/or symptoms

No No Yes (hypercalcemia, renal insuff., anaemia, bone lesions, symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections

Progression of MGUS and asymptomatic myeloma to active disease

• The average risk of progression from MGUS to active myeloma is about 1% per year– Only proven prognostic factor for progression

to myeloma is serum M-protein level. The risk of progression in 10 years equal with paraprotein level in g/l

• The median time to progression from asymptomatic to symptomatic myeloma is 12-32 months

Multiple Myeloma Disease Progression1

1. Adapted from International Myeloma Foundation; 2001. Reprinted with permission.2. International Agency for Research on Cancer, World Health Organisation; Ferlay J, Bray F, Pisani, P and Parkin DM. Globocan 2000

Asymptomatic

20

50

100

Refractory Relapse MGUS* or

SmolderingMyeloma

Active Myeloma

Plateau Remission

Symptomatic

Relapse

Therapy

~53,000~19,000 New cases

in EU2

~15,000 Annual

deaths in EUAnnual patients in the EU2

M P

rote

in (g

/l)

*Monoclonal gammopathy of uncertain significance

Therapy Therapy

Diagnostic Tests for Multiple Myeloma

• Blood and urine tests1

– Complete blood count (CBC) to detect if red blood cells, white blood cells, or platelets are outside of normal range

– Chemistry profiles including blood urea nitrogen (BUN)2, calcium, creatinine, and lactate dehydrogenase (LDH)

– 24-hour urine collection to measure levels of protein in the urine– Serum protein electrophoresis or urine electrophoresis to measure levels of

immunoglobulins– Immunoelectrophoresis or immunofixation to provide more specific information

about the type of abnormal immunoglobulins present– ESR

• Bone tests1

– Bone (skeletal) survey utilizing X-ray or magnetic resonance imaging (MRI) to assess bone involvement and number/size of lytic lesions

– Bone marrow aspiration/bone marrow biopsy to measure number of plasma cells in the marrow

1. The Washington Manual of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins; 2002. 2. The Merck Manual of Diagnosis and Therapy. Sec II, ch 140, plasma cell dyscrasias. Available at: http://www.merck.com/pubs/mmanual/sectionII/chapter 140/140d.htm. Accessed March 25, 2003.

The use of imaging techniques in myeloma

• Plain radiographs is the standard method for radiological screening at diagnosis

• CT scanning: higher sensitivity than plain X-ray at detecting small lesions

• MR imaging: is useful for the assessment of the extent and nature of soft tissue disease. For investigation of patients with neurological symptoms suggestive of cord compression. Essential investigation in the differential diagnosis of solitary plasmacytoma and myeloma.

• PET scanning: Useful in detecting occult sites of disease in myeloma and solitary plasmacytoma

The changes in the treatment of multiple myeloma

Melphalan From 1980sMyeloablation +

ASCT

2000sTandem

ASCT

1999 First report on

thalidomide

1962 Prednisone +

melphalan

Bortezomib US licence 2003, EU licence 2004

1990s Supportive care March/April 2005

Bortezomib approved for second-line

in USA & Europe

Treatment of hypercalcemia (occurs in up to 30% of myeloma patients, typically in active

disease)

• In mild hypercalcemia (se Ca:2,6-2,9 mmol/l) oral rehydration

• In moderate-severe hypercalcemia (se Ca ≥2,9 mmol/l) – rehydrate with intravenous fluids and give

loop-diuretic drug.– Start bisphosphonate immediately– Additional therapy in refractory patients

General recommendation for bisphosphonate therapy

• Bisphosphonate therapy is recommended for all patients with myeloma requiring chemotherapy, whether or not bone lesions are evident.

• Treatment should be continued at least 2 years.• Oral clodronate (1600 mg/day) and monthly iv.

pamidronate ( 90 mg) or zoledronic acid (4 mg) are equivalent in efficacy.

• Renal function should be monitored, in case of severe renal failure the dose should be reduced

• No proven indication of bisphosphonates in asympromatic patients.

Prevention and management of renal failure

• Maintenance of a high fluid intake (3l/d)• Nephrotoxic drugs should be avoided• Hypercalcaemia must be corrected• Infection must be treated• In case of progressive renal failure plasma

exchange (theoretically beneficial in cast nephropathy)

• Dialysis

Management of anaemia

• Anaemia usually improves with response to chemotherapy.

• The use of EPO may be considered in patients with symptomatic anaemia.

• Serum EPO concentration should be measured (high EPO concentration, high transfusion requirement and a low-platelet count are negative prognostic factor for a response to EPO)

Infections in myeloma

• Febrile myeloma patient should be treated promptly with broad-spectrum antibiotics that will cover S. pneumoniae, H. influenzae and E. coli, which are the most common causes of infections.

• Administration of immunglobulins should be reserved for patients with recurrent infections.

Other complications of multiple myeloma

• Cord compression– Occurs in 5% of patients. MRI, ther.: dexamethasone, local

radiotherapy• Peripheral neuropathy

– Paraproteinaemic neuropathy should be considered in any patients with monoclonal protein presenting with weakness, numbness, paraesthesiae and hyporeflexia. IVIG therapy may be effective.

• Hyperviscosity– In patients with high paraprotein levels. Symptomatic patients

should be treated by plasma exchange. Chemotherapy should be started promptly

• Amyloidosis– Complications: cardiac failure, renal impairment and neuropathy,

lead to increased toxicity with various threpautic options (anthracyclins, thalidomide, streoids)



ASCT

2000sTandem

ASCT


thalidomide

1962 Prednisone +

melphalan




in USA & Europe

Measuring the response to therapy

Complete remission No M-protein detected in serum or urine. Fewer than 5% plasma cells in bone marrow, no hypercalcemia

Partial remission >50% reduction in serum paraprotein level and/or 90% reduction in urine free light chain excretion. In non-secretory disease at least 75% reduction in bone marrow plasma cells number

Minimal response 25-49% reduction in serum M-protein or <90% reduction in urinary light chain excretion.

Plateau No evidence of continuing myeloma-related organ damage, less than 25% change in serum M-protein levels for 3 months

Progressive disease Organ damage continuing despite therapy or its re-appearance in plateau-phase

Relapse Reappearance of disease in patients previously in CR

Treatment algorithms for patients with multiple myeloma

1. The early intervention in asymptomatic patients has shown no benefit

2. Transplant candidate or not a transplant candidate

Thaldex2. Line VelDex, VTD

MPTMPV

Criteria to decide which patient is eligible for high dose chemotherapy followed by

stem cell rescue • Age

– Initial studies tended to enroll patients younger than 65 years of age

– Recent studies indicate that transplant is safe in at least same who are over the age of 70

• Co-morbid medical conditions• Risk stratification

– Poor-risk chromosomal features have a short time to progression after auotologous transplantation

Risk stratification:International Staging System

Stage Criteria Median survival (months

I Se β2 microglobulin <3,5 mg/l and se albumin >35 g/l

62

II Se β2 microglobulin between 3,5-5,5 mg/l or Se β2 microglobulin <3,5 mg/l but se albumin <35 g/l

45

III Se β2 microglobulin >5,5 mg/l 29

Greipp et al 2003.

For individual patients the best staging systems can predict survival outcome with around 70% sensitivity and specificity.

Cytogenetics-based prognostic grouping

Risk group Cytogenetics Median Overall Survival

Poor t(4;14)t(14;16)p13-

24,7 months

Intermediate -13q14 42,3 months

Good All others 50,5 months

The significance of cytogenetic information:-Decision of possibility of stem cell transplantation

- indication of molecularly targeted approach of patients

Median survival time after transplantation according to the presence or absence of risk

factors

Risk factor combinations at diagnosis

Median survival time

Low β2-microglobulin level and absence of Δ13

> 111 months

High β2-microglobulin level and absence of Δ13 orLow β2-microglobulin and presence of Δ13

47 months

High β2-microglobulin level together with Δ13

25 months

Moreau P et al, Blood 2006;107:397-403.

Approach to newly diagnosed symptomatic myeloma

Low risk High risk

Not a transplant candidate

Transplant candidate

Dex or Thal-Dex or VAD x 4 cycles

Stem Cell Harvest for 2 transplants

Early Tx1; Tx2 in relapse Conventional chemother (HDC, melphalan 200 mg/m2) to plateau phase. Tx1 at relapse

Rajkumar SV 2004.

Induction therapy in transplant candidate patients

• VAD (repeated monthly)– Vincristin 0.4 mg 1-4. days.– Adriamycin 9 mg/m2 1-4. days– Dexamethason 40 mg 1-4., 9-12., 17-20. days

• Dex (repeated monthly)– 40 mg/day on day 1 trough 4, 9 through 12, and 17

through 20• Thal-Dex (repeated monthly)

– Thal 200 mg/d p.o. with Dex on day 1 trough 4, 9 through 12, and 17 through 20



ASCT

2000sTandem

ASCT


thalidomide

1962 Prednisone +

melphalan




in USA & Europe

Melphalan + prednisone is the standard of care for induction therapy in not transplant candidate elderly

patients with multiple myeloma

Melphalan+ prednisone

Melphalan+ Dex

Dex Dex+ Interferon

Partial response 41% 70% 40% 42%

Complete response

1% 3% 1% 1%

Median progression-free survival

21.1 mos 22.9 mos. 12.2 mos.

15.2 mos

Severe pyogenic infection

11% 20% 13% 11%

Any severe toxicity 18% 33% 31% 31%

Facon T et al. Blood 2006;107:1292-1298.

Induction therapy of multiple myeloma in patients who are not candidate for stem

cell transplantation• The dose of Melphalan = 7-12 mg/m2/day,

4-7 days, given on an every 4-6 weeks schedule until plateau phase.– Side effects: nephrotoxicity, myelotoxicity.

• Combined chemotherapy can improve the remission rate together with higher prevalance of side effects.

The story of thalidomide

• First marketed in the 1950s for the treatment of pregnancy-related morning sickness and later as a sedative.

• It was withdrawn because of serious adverse events in pregnant women including teratogenicity and dysmelia.

• Interest in the drug resurfaced in the 1990s because of its antiangiogenic and immunmodulatory effects

Thalidomide in multiple myeloma: mechanisms of action

• Antiangiogenic effects, mediated via inhibition of VEGF (vascular endothelial growth factor) and βFGF(fibrobalst growth factor)

• Inhibition of multiple myeloma growth factors, including IL-6, TNFα, and VEGF

• Down-regulation of binding of myeloma cells to bone marrow stromal cells

• Immunmodulatory effects, evidenced by upregulation of natural killer cells (through the release of interferon gamma and IL-2), producing MM cell lysis

• Direct proapoptotic effects, arrests G1 growth phase of myeloma cells

Richardson et al.: J Clin Oncology 2006;24(3):1-2., San Miguel JF, Haemat Rep, 2005;1(11):2-6

Comparison of results of MP and MPT treatment in older patients with newly

diagnosed multiple myelomaResponse quality Melphalan+

Prednisone (MP)Melphalan+Prednisone+ Thalidomide (MPT)

Complete response 2% 16%

At least a partial response

40% 81%

Response durability - Progression-free survival- Overall survival

17.1 mos.32.2 mos.

27.6 mos53.6 mos

More than 50% of patients reaching a PR within the first 2 months of therapyFa

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Regimens not based on MP

• Thal/dex 200-400 mg thalidomide/day + dexamethasone 40 mg/day on 1-4., 9-12. and 17-20. days. (remission rate: 64%) as first-line therapy.

• Thalidomide+pegylated liposomal doxorubicin+dexamethasone. Comparable response rates (84%) in untreated patients as well as those with relapsed/refractery disease.

Thalidomide toxicity

• Thromboembolic episodes (involving venous or arterial events)

• Neutropenia, thrombocytopenia• Constipation• Infections (pneumonia, herpes zoster)• Peripheral neuropathy• Psychiatrical problems (letargy, fatigue)• Skin reactions and cardiac events

Lenalinomid: more potent thalidomide, and has a more favorable toxicity profile than thalidomide

Proteasome inhibition is a new second- or third-line treatment possibility in multiple myeloma

Bortezomib seems able to enhance chemosensitivity and

overcome chemoresistance

Summary: Mechanism of Action of Bortezomib (VELCADE)

The 26S proteasome is alarge protein complex thatdegrades tagged proteins

Bortezomibis a reversibleinhibitor of the chymotrypsin-likeactivity of the 26S proteasome

Inhibition of the 26Sproteasome preventsproteolysis of taggedproteins which can affect multiple signaling cascades with the cellNonclinical studies

showed bortezomib to be cytotoxic to a variety of cancer cell types

1

2

3

4

Millennium Pharmaceuticals, Inc., 2003.Adams J. Drug Discov Today. 2003;8:307-315.

BortezomibBortezomib (VELCADE (VELCADE))

B/NFB

Apoptosis Inhibitors(IAP, FLICE)

Caspases 8,3

FAS

MAPKPI3K

Decreased Decreased ProliferationProliferation

antiapoptotic

Intracellular level

X Xproliferation

Increased Increased ApoptosisApoptosis

IL-6, VEGF

BlockBlock activationactivation

InhibitionInhibitionDNA-repair effectorsDNA-repair effectors

Adhesion Cytokine Angiogenesis

BMSCBMSC

MM cells

VEGF

IGF-ITNF

IL-6 BM VesselsX

Disruption of Disruption of unfolded protein unfolded protein

responseresponse

San Miguel J. Hematol J. 2003;4(suppl 3):201-207.

Normal Cells Survive Effects of VELCADE™

• Normal cells can recover from transient proteasome inhibition– 72 hour rest period

• Cancer cells are more susceptible– Pre-existing dysregulation of cell cycle, growth,

differentiation and apoptotic mechanisms– Myeloma cells are 100-1000 times more sensitive to

effects of VELCADE™ • Absence of side-effects such as mucositis and

alopecia– Common with other cytotoxic agents that target all dividing cells

• 1.3 mg/m2 as a 3- to 5-second bolus IV injection via peripheral or central IV catheter– Follow with a standard saline flush

• At least a 72-hr rest period between doses is required– Allows for restoration of proteasome function towards

baseline

Day 1

Bortezomib1.3 mg/m2

Day 4

Bortezomib 1.3 mg/m2

Day 8


Day 11


REPEAT CYCLE

10-day RESTPERIOD

Velcade: Dosing and schedule

Alkalmazási előirat Janssen-Cilag 2005

Clinical studiesSUMMIT CREST APEX

Study design Phase II, open-label, multicenter

Phase II, open-label, multicenter, randomized; two dose levels bortezomib ± dexamethasone

Phase III, international, open-label, randomized to bortezomib or dexamethasone

Patients Relapsed or refractory MM; n=202

Relapse during/following front-line therapy for MM;n=54

Relapsed MM; n=669

Endpoints Primary: overall response rate (CR + PR + MR) Secondary: safety, quality of life, clinical benefit

Overall response rate (CR + PR + MR)

Primary: time to progression (TTP) Secondary: overall/1-year survival, response rate, duration, time to response, safety

Richardson et al. N Engl J Med 2003;348:2609; Jagannath et al. Br J Hematol 2004;127:165;Richardson et al. ASH 2004 (abstract 336.5)

– Bortezomib continues to demonstrate superior survival despite > 62% of HD dex pts crossing over to bortezomib

– Median OS: 29.8 months (95% CI: 23.2, not estimable) vs 23.7 months (95% CI: 18.7, 29.1); hazard ratio = 0.77; P = 0.0272 1-year survival rate: 80% vs 67%; P = 0.0002

Updated Results of APEX Trial

Richardson P, et al. ASH 2005, abstract #2547

►SURVIVAL

Overall and 1-Year Survival

P=.0272

Pretreatment After 4 Cycles

Plasmacytomas

Jagannath et al. ASH 2004; Abstract 333

Velcade + DexamethasoneThe evidence of remission: PET Scan

Past and current treatment algorithms for not transplant candidate patients with

multiple myeloma

Orlowski RZ. Multiple Myeloma. Hematology 2006:338-347.

A hypothetical future treatment algorithm for patients with multiple myeloma

BP=: bendamustine+prednisone; MDT= Melphalan+Prednisone+Thalidomide; MP=melphalan+prednisone; R-MP=melphalan+prednisone+lenalidomide; ThaDD=thalidomide+pegylated liposomal doxorubicin+dexamethasone; VMP=melphalan+prednisone+bortezomib O

rlow

ski R

Z. M

ultip

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ma.

Hem

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2006

:338

-347

.

Waldenström’s macroglobulinaemia

• Malignancy of lymphoplasmacytoid cells that secrete IgM.

• Rare disease, 2% of hematological malignancies • The disease associates with lymphadenopathy

and hepatosplenomegaly, but the major clinical manifestation is the hyperviscosity syndrome.

• Slightly more common in men and occuring with increased incidence with age (median age at presentation is 63 year).

• The disease involves bone marrow, but unlike myeloma, it does not cause bone lesion or hypercalcaemia.

Waldenström’s macroglobulinaemia

• Malignant lymphocytes are present in the peripheral blood.

• Like myeloma, a serum M component is present in the serum in excess of 30 g/l, but inlike myeloma, the size of the IgM paraprotein result in little renal excretion. Therefore, renal disease is not common.

• Median survival is about 5 years (in appr. 10% of patients is more than 15 years).

The differential diagnosis of WM from other B-lymphoproliferative disorders

Ghobrial I, Witzig T: Waldenström Macroglobulinemia. Current Treatment Options in Oncology. 5(3):239-247.

Clinical symptoms and physical abnormalities in patients with WM

Tarkovács G: Waldenström macroglobulinaemia. in Fókuszban az onkológia és az onkohematológia, ed.: Dank M, Demeter J, 2006. Melinda Kiadó

Symptom Frequency Physical abnormality Frequency

Weakness 66% Hepatomegaly 20%

Loss of apetite 25% Splenomegaly 19%

Peripheral neuropathy

24% Lymphadenopathy 15%

Weight loss 17% Purpura 9%

Fever 15% Other bleedings (retinal hemorrhages)

7%

Raynaud’s phenomenon

11%

Characteristic features of WM

Retinal hemorrhage from hyperviscosity

BM showing increased numbers of lymphoid and plasmacytoid cells

BM showing IgM in cytoplasm of lymphoid cells with immunofluorescence

The serum protein electrophoretic pattern is characterized by a tall, narrow peak (bottom center) or dense band

Frequency of laboratory abnormalities at the presentation of WM

Parameter Frequency

Anaemia (Hb<120 g/l) 63%

Leukopenia (<3x109/l) 4%

Throbocytopenia (<100x109/l) 16%

IgM (monoclonal)-kappa/lambda ratio- >30 g/l-Cryoglobulins

80/2035%10% of macroglobulins

Serum béta2-microglobulin >3 mg/l 62%

Serum viscosity >4 17%

Indications of the therapy in patients with WM

• Appearence of general symptoms (fever, fatigue caused by anaemia, loss of body weight)

• Progressive hepatosplenomegaly, symptoms related to lymphadenomegaly

• Severe anaemia and/or thrombocytopenia• Hyperviscosity (plasmapheresis)• Amyloidosis (cardiomyopathy, nephrotic

syndrome, peripheral neuropathy)• Cryoglobulinaemia with symptoms ( Raynaud’s

phenomenon)

Treatment of WMMajor response rate (>50% reduction of IgM concentration)

Median duration of response

Chlorambucil 75% 46 months

Fludarabine-first-line treatment-Salvage-treatment

75.5%33.7%

40-60 months30-32 months

BM depression, opportunic infections, Coombs + hemolysis

Cladribine-first-line treatment-Salvage-treatment

56.6%42.6%

20-39 months8-12 months

Rituximab 44-48% 16-29 months In patients with cytopenia. Temporary IgM

Thalidomide ? ?

Corticosteroid Mostly in patients with cryoglobulinaemia and iimmune vasculitis

Documents

Multiple myeloma (MM)