Multiple Myeloma and Related Disorders · Multiple Myeloma Smolderimg Multiple Myeloma Plasma cell ... (SPEP/UPEP) – Gamma-globulins • Polyclonal gammopathy: ...

Multiple

Myeloma and

Related

Disorders

Zsolt Nagy

Outline

• Biology

• Plasma Cell Dyscrasia

– MGUS

– Plasmacytoma

• Multiple myeloma

– Smoldering

– POEMS

• Waldenstrom’s Macroglobulinemia

• Amyloidosis

Classification of Monoclonal Gammopathies

• Monoclonal Gammopathy of Undetermined Significance "Benign"/idiopathic

Associated with other diseases (autoimmune, infectious, non-heme cancer, etc)

• Plasma cell or lymphoid malignancy Waldenstrom's macroglobulinemia

Other lymphoproliferative disorders

Multiple Myeloma

Smolderimg Multiple Myeloma

Plasma cell leukemia

IgD myeloma

POEMS

• Plasmacytoma

• Heavy Chain disease

• Amyloidosis

The Continuum of Plasma Cell Disorders

Normal MGUS Indolent Multiple

Myeloma Myeloma

Myeloma, Malpas et al. 2004

• The hallmark of plasma cell disorders is the

presence of a paraprotein in the serum

and/or urine.

Paraproteinemias

• Normal immunoglobulin pattern

– Polyclonal reflects progeny of different

plasma cells

• Paraproteinemia

– Monoclonal immunoglobulin band in sera

reflects synthesis from single plasma cell

clone

SPEP

Polyclonal

Gammopathy

Monoclonal

Gammopathy

Normal Immunoelectrophoresis

Presentation of Plasma Cell Disorders

• Increased protein on a routine chemistry

panel

• Anemia

• Bone pain

• Renal dysfunction

• Hypercalcemia

Pathophysiology: Monoclonal B-

Cells/Plasma Cell Dyscrasia• Marrow replacement

– Cytopenias

– Constitutional symptoms

• Decreased quantitative immunoglobulins

– Infections

• Lytic bone lesions

– Fractures

– Hypercalcemia

• Extramedullary involvement

– Plasmacytomas

– Organomegaly

Pathophysiology: Monoclonal

Immunoglobulin Proteins• Heavy chains or Light chains in serum, urine,

kidney or other tissues

– Renal insufficiency

– Neurologic disease

– Hyperviscosity

– Cold Agglutinin disease

– AL Amyloidosis

– POEMS: Polyneuropathy, Organomegaly, Endocrine disturbances, M-protein, Skin changes

Solitary or extramedullary plasmacytoma

3% (27)

Chronic lymphocytic leukaemia 2% (21)

Waldenström’s macroglobulinaemia 2% (20)

MGUS 56% (578)

Multiple Myeloma 18%

(185)

Lymphoma 5% (50)

Amyloidosis (AL) 10%

(106)

Smouldering myeloma 4% (39)

RA Kyle in: Myeloma Biology & Management, 1995

M-protein at the Mayo Clinic

MGUS

• Diagnosis

– Serum M-protein

• Usually IgG or IgA, usually <3 g/dL

• Stable over time

– Marrow plasma cells <10%

– No lytic bone lesions, unexplained anemia, hypercalcemia, or renal insufficiency

• Incidence

– 1-2% of adults

– Increases with age

• 6% aged 62-79 y/o, 14% >90 y/o

Other diseases associated

with M-protein

• Autoimmune diseases (RA, SLE, scleroderma)

• Skin diseases (pyoderma gangraenosum)

• Liver disease (cirrhosis)

• Infectious diseases (m.tuberculosis, Hep C,HIV)

• …………..

NEJM 2002;346:564. Kyle ASH

2002 #384.

MGUS Progression

• 1384 patients at Mayo

• MGUS: 1% per year progression

– Relative risk 25x (myeloma), 46x (Waldenstrom’s),

8.4x (amyloid), 2.4x (lymphoma)

• IgM MGUS: 1.5% per year

• Predictors

– Size of M-spike (> 2.5 g/dL, 41% at 10 yr)

– Serum albumin

NEJM 2002;346:564

MGUS Progression: 1% per Year

Diagnostic work-up MGUS

LAB

• CBC

• Serum Ca/alb and creatinin

• Serum protein electrophoresis (EF) and immunofixation (IF)

• Quantification of immunoglobulins

• 24-hour urine albumin, EF +IF

Skeletal X rays

Bm aspirate/biopsy if– M-protein > 15 g/l

– IgA or IgM M-protein

– Abnormal free light chain ratio

CT thorax/abdomen if IgM paraprotein (m.Waldenstrom)

MGUS: Management

• Testing

– CBC, calcium, creatinine, SPEP with immunofixation, quantitative immunoglobulins, 24-hour urine protein (with UPEP and immunofixation if positive)

– If M-protein 2-3 g/dl, add bone marrow and skeletal survey

• F/U

– SPEP/H&P repeated in 6 months, then annually

Multiple Myeloma and

Related Disorders

• Definition:

A group of diseases that involve

malignant proliferation of Ig-secreting

cells of B-cell lineage that are usually

associated with paraproteinemia or

paraproteinuria.

Multiple Myeloma

• US Incidence: 15,000 new cases/year

– 1% of malignancies

• US Prevalence: 65,000 cases/year

• Double incidence rate in African Americans

• Median age 65

– 3% <40 years old

• Unknown cause

– Radiation, benzene, solvents, pesticides, insecticides

Etiology

• Etiology is not known.

• Risk factors: Race, sex.

• Increased risk with ionizing radiation and

exposure to pesticides like Dioxin.

• Recently viruses like HHV-8 and SV-40,

have been linked to myeloma development.

Pathogenesis

• Bone marrow microenvironment very important

for proliferation and chemotherapy resistance.

• BM stromal cells produce IL-6, responsible for

pathogenesis and progression.

• IL-6 inhibits apoptosis of plasma cells.

• IL-6 contributes to bone loss by stimulating

osteoclasts and inhibiting bone formation.

• Interaction with extracellular matrix proteins

protect cells from chemo and radiation.

MM: Clinical Features

• Disease of the elderly (7th decade)

• Bone pain

– most commonly vertebra and long bones

– lytic lesions

– fractures

Myeloma: Clinical Features

• Bone pain: often with loss of height

• Constitutional: weakness, fatigue, and weight loss

• Anemia

• Renal disease: renal tubular dysfunction

• Infections: neutropenia/hypogammaglobulinemia

• Hypercalcemia: myeloma cells secrete osteoclast-activating

factors

• Hyperviscosity: 2% with myeloma; 50% with

macroglobulinemia

• Neurologic dysfunction: spinal cord or nerve root compression

Major Symptoms at Diagnosis

• Bone pain: 58%

• Fatigue: 32%

• Weight loss: 24%

• Paresthesias: 5%

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

11% of patients are asymptomatic or have only mild symptoms at diagnosis

Multiple Myeloma

Typical “Punched Out” Lesions

Multiple Myeloma

Diagnostic Criteria for Myeloma

1. IMWG. Br J Haematol. 2003;121:749-757. 2. Kyle RA, et al. N Engl J Med. 2002;346:564-569.3. Durie BG, et al. Hematol J. 2003;4:379-398.

Patient Criteria MGUS[1,2] Smoldering

Myeloma[1]

Active Myeloma

M protein < 3 g/dL spike ≥ 3 g/dL spike

and/or

In serum

and/or urine[2]

Monoclonal

plasma cells in

bone marrow, %

< 10 ≥ 10 ≥ 10[2]

End-organ

damage

None None ≥ 1 CRAB*

feature[3]

*C: Calcium elevation (> 11.5 mg/L or ULN)R: Renal dysfunction (serum creatinine > 2 mg/dL)A: Anemia (Hb < 10 g/dL or 2 g < normal)B: Bone disease (lytic lesions or osteoporosis)

Only patients with symptomatic MM should be treated

Multiple Myeloma Diagnosis(1 major+1 minor or 3 minor)

• Major Criteria

– Plasmacytoma on

tissue biopsy

– 30% Marrow

plasmacytosis

– M-protein

• 3.5 g/dL IgG

• 2 g/dL IgA

• 1g/24 hr urine Bence

Jones

• Minor Criteria

– 10-29% Marrow

plasmacytosis

– M-protein

• Less than major

– Lytic bone lesions

– Low immunoglobuins

• IgM <50 mg/dL

• IgA <100 mg/dL

• IgG <600 mg/dL

Kyle, Mayo Clin Proc, 2003.

Newly Diagnosed Multiple

Myeloma: 1985-1998

• N=1027

• Median age: 66 years

• Median survival: 33 months

– Did not improve 1985 through 1998

• Multivariate analysis

– Age, plasma cell labeling index, thrombocytopenia, serum albumin, creatinine (log value)

Kyle, Mayo Clin Proc, 2003.

Newly Diagnosed Multiple

Myeloma: 1985-1998

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Ca Cr >2 Anemia Skel Surv UPEP SPEP

Myeloma Diagnostic Work-Up

• SPEP and UPEP (24 collection) with immunofixation

– 3% nonsecretory: check serum free light chains

• Skeletal survey (not a bone scan)

• Quantitative serum immunoglobulins (IgA, IgG, IgM)

• Bone Marrow Aspirate and Biopsy

• Other tests (calcium, creatinine, beta-2 microglobulin, CRP, albumin, plasma cell labeling index, etc, etc) are only for staging/prognosis

M-Protein Tests

• Urine Dipstick not sensitive to Bence Jones proteins, need sulfosalicylic acid (SSA)

• Screening (SPEP/UPEP)

– Gamma-globulins

• Polyclonal gammopathy: liver disease, connective tissue disease, chronic infection, others

• Hypogammaglobulinemia: Immunodeficiency, nephrotic syndrome (amyloidosis), myeloma/CLL

• Monoclonality

– Immunofixation with monospecific antibodies

– Immunoelectrophoresis

– Immunoassay for serum free light chains (Mayo Clinic)

Myeloma Prognostic Work-Up

• Hemoglobin

• Calcium

• Serum creatinine

• Beta-2 microglobulin

• Albumin

• Bone Marrow cytogenetics

– FISH chromosome 13 and 11?

• C-reactive protein??

• Plasma cell labeling index??

• Serum IL-6??

Myeloma Renal Disease

• “Myeloma kidney”

– Normal glomerular function

– Concentrated light chains precipitate in tubules

– Monoclonal light chains seen in UPEP with

immunofixation

• Glomerular lesions

– Deposits of amyloid or light chain deposition disease

– Nonselective leakage of all serum proteins

– UPEP preponderance of albumin

Renal Manifestations

Amyloidosis

Light chain Deposition

Pierre Ronco JNEPHROL 2000; 13 (suppl. 3):

Myeloma Kidney Cast Formation

Pathology

Myeloma: Durie-Salmon Staging

Stage I• Hemoglobin >10 g/dL

• Normal calcium

• No lytic bone lesions

• Low M-protein

– IgG <5 g/dL

– IgA <3 g/dL

– Bence Jones <4 g/24h

Stage II (not Stage I/III)

Stage III• Hemoglobin <8.5

• Calcium >12 (adjusted)

• >3 lytic bone lesions

• High M-protein

– IgG >7 g/dL

– IgA >5 g/dL

– Bence Jones >12 g/24h

A) Creatinine <2

B) Creatinine >2

Myeloma: Median Survival

Durie-Salmon stage

Stage I 60 months

Stage II 40 months

Stage III 15 months

International Myeloma Working

Group Staging System

Stage 2Microglobulin Albumin

I < 3.5 > 3.5

II <3.5

3.5 – 5.5

<3.5

any

III

> 5.5

any

Kyle, Mayo Clin Proc, 2003.

Therapy of Newly Diagnosed

Multiple Myeloma: 1985-1998

clinicaloptions.com/oncology

Multiple Myeloma in Session: Basics of Multiple Myeloma

No Improvement in Therapy for Patients

With Myeloma in 30 Yrs Until . . . Prospective, randomized study

of autologous bone marrow transplantation plus chemotherapy

74 patients in high-dose group received autologous transplantation

Attal M, et al. N Engl J Med. 1996;335:91-97.

Type of Response Patients, n

Conventional

Dose

(N = 100)

High

Dose

(N = 100)

CR 5 22

Very good PR 9 16

PR 43 43

MR 18 7

PD 25 12

100

75

50

25

0

OS

(%

)

0 15 30 45 60

Mos

Conventional

dose

High dose

Myeloma: Therapy Principles

• Observation for stage I

• Incurable despite conventional chemotherapy and high-dose therapy

• Bisphosphonates

• Chemotherapy

– Conventional

– High-dose with stem cell rescue

– New agents

• Graft-versus-myeloma

Myeloma: Therapy

• Alkylating agents

– Melphalan: low-dose oral to high-dose myeloablative

• Steroids

– Alone (pulse Dexamethasone) or combination (M&P, VAD, Thal/Dex)

• Cyclophosphamide

• Thalidomide and the IMiD’s

• Bortezomib (Velcade): proteosome inhibitor

• Graft-versus-myeloma effect

– Mini-allogeneic transplantation

• Interferon: maintenance

Therapy of Multiple Myeloma

• Chemotherapy

– pulse dexamethasone

– pulse dexamethasone+ thalidomide

– pulse dexamethasone +lenalidomide (revlimid)

– pulse dexamethasone + bortezimib (velcade)

– melphalan+prednisone + imid (not transplant candidate)

• Autologous stem cell transplant

• Radiation

Kyle, R. A. et al. N Engl J Med 2004;351:1860-1873

Major Classes of Drugs Used in the Treatment of Myeloma

NEJM 2003; 348: 1875.

Autologous Transplantation

Myeloma: Supportive Therapy

• Bisphosphonates

– Phase III: monthly pamidronate (JCO 1998;16:593)

• Skeletal-related events 38% versus 51%, p=0.015

• Median survival 21 versus 14 months

• Compression fractures: vertebroplasty

• DVT risk: steroids, steroids + thalidomide

• Hypercalcemia

• Renal insufficiency: ?Plasmapheresis

• Infections

• Anemia: Eyrthropoietins

Myeloma Bone Marrow

Microenvironment

• Interactions

– Myeloma cell adhesion molecules react with

stroma

– Release of osteoclast activating factors (IL-1B,

IL-6, TNFB)

– Vascular endothelial growth factor (VEGF)

secreted by myeloma cells

• Myeloma Bone Disease

New Agents

JCO 2002;20:1625.

Smoldering Myeloma

• Serum M-protein >3 g/dL

• Marrow plasma cells >10%

• No lytic bone lesions, unexplained anemia,

hypercalcemia, or renal insufficiency

• Evolve to overt multiple myeloma

– 3.3% per year

– Greatest for IgA

Plasmacytoma

Extramedullary Plasmacytoma

• ~3% of plasma cell neoplasms

• Isolated plasma cell tumors of soft tissues

– Upper respiratory tract common

• Uninvolved marrow, negative skeletal survey

• M-protein present ~25% cases

– Disappears following treatment

• Curable with local radiation therapy

Solitary Plasmacytoma of Bone

• ~3% of plasma cell neoplasms

• One isolated bony lesion of plasma cells

• Uninvolved marrow <5% plasma cells

• M-protein present ~25% cases

– Disappears following treatment

• Curable with local radiation therapy

– Median OS 10 years

– Multiple myeloma develops in 50-60%

Osteosclerotic Myeloma

(POEMS)• Polyneuropathy

– Sensorimotor peripheral neuropathy in 75%

• Organomegaly

– Lymphadenopathy, hepatomegaly, splenomegaly

• Endocrinopathy

– Adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic

• M-Protein

• Skin changes

– Hyperpigmentation, hypertrichosis, plethora, hemangiomata, white nails

Osteosclerotic Myeloma

Ghobrial et al, Lancet Oncol 2004, Treon et al, Blood 2009

• 30-50% of patients:

deletion 6q by FISH

Lymphoplasmacytic Lymphoma (Waldenstrom’s Macroglobulinemia)

• Malignant proliferation of plasmacytoid lymphocytes secreting IgM M-protein

• 1400 cases/year

• Organomegaly/Peripheral neuropathies

• Cryoglobulinemia

– Type I: Raynaud’s phenomenon, cold urticaria, etc.

– Type II: Purpura, arthralgias, renal failure, mononeuritis

• IgM tissue infiltration/AL amyloidosis

• Coagulation abnormalities

Consensus recommendations of the 4th

International WM meeting

• First Line therapy:

– Combination therapy

• (RCD or CPR; Cytoxan+nucleoside analogues+R; R-CHOP, R-CVP)

– Rituximab single agent

– Nucleoside analogues

– Alkylators

• Salvage therapy:

– Re-use therapies

– Bortezomib

– Thalidomide+steroids

– Alemtuzumab

– AHSCT

Dimopoulos, JCO 2009, Treon et al Clin

Lymph and Myeloma 2009

Hyperviscosity

• Usually IgM >5 g/dL, viscosity >4.0

• Eyes

– “Sausage link” conjunctival and retinal veins

– Retinal hemorrhages, Papilledema

• CNS

– Ataxia, nystagmus, vertigo, confusion, altered consciousness

• Increased intravascular volume

– Dilutional anemia

– Risk congestive heart failure with transfusion

• Therapy: plasmapheresis/chemotherapy

Waldenstrom’s

Macroglobulinemia: Therapy

• Plasmapheresis for hyperviscosity

• 2-Chlorodeoxyadenosine (2-CdA,

cladribine)

• Fludarabine

• Rituximab

• Other myeloma-like therapies

Monoclonal IgM: DDx

• MGUS

• Multiple myeloma

• Waldenstrom’s

• CLL

• Chronic cold agglutinin disease

– No evidence of neoplasia

– Hemolytic anemia aggravated by cold exposure

– 90% have kappa light chains

Amyloidosis

• Extracellular tissue deposition of low molecular weight fibrils

– Beta-pleated sheets, bind Congo red

• Precursor proteins involved

– Monoclonal immunoglobulin light chains: Primary (AL) Amyloidosis

– Serum amyloid A protein: Reactive or Secondary (AA) Amyloidosis

– Beta-2 microglobulin: Dialysis (DA) Amyloidosis

– Transthyretin, apolipoprotein A-I, Alzheimer amyloid precursor protein, prion protein, Prolactin, Atrial natriuretic protein, Procalcitonin, Insulin, Keratin…

The Past

1854 Virchow: Amyloid

1922 Bennhold: Congo red

1959 Cohen & CalkinsFibrillar structure

1968 Eanes & Glennercross- pleated struct.

X-ray diffraction pattern

The Beginning of AL Amyloidosis

1931 Magnus-Levy (Mount Sinai Hospital, New York)

Bence Jones protein is "Mother Substance”

1961 Kyle & Bayrd

Abnormal plasma cells in all

1964 Osserman

Bence Jones protein

1971 Glenner

Fibril & Bence Jones protein were the same

Merlini & Bellotti NEJM 2003

localized Amyloidosis

~30 proteins

systemic Amyloidosis

Amyloidosis: Protein Misfolding Diseases

Sipe et al, 2012

proteotoxicity

Misfolded FLC

structural damage

λ1*

1Merlini & Stone, Blood. 2006;

λ6**

*Perfetti et al, Blood. 2012; **Comenzo et al, Br J Haematol. 1999

Small dangerous clone1

(BMPC 7%)

53% LC only 75% l

Amyloid fibrils

Early detection of amyloid heart involvement is vital

Amyloidosis: Presentation

• Nephrotic syndrome

• Refractory CHF, Arrhythmia, Heart block

• Orthostatic hypotension, Peripheral neuropathy

• Bleeding diathesis (Raccoon eyes)

– Factor X deficiency, liver disease

• GI bleeding, Gastroparesis/Dysmotility, Malabsorption

• Macroglossia, Shoulder pad sign, Carpal tunnel syndrome, Organomegaly

• Skin thickening/waxy, easy bruising

Amyloidosis

Merlini et al, Blood 2013 121: 5124-5130

Diagnosis of Amyloidosis

Amyloidosis: Work-up

• Biopsy

– Involved organs or bone marrow

– Fat pad, salivary glands, rectal mucosa: 50-70% success for diagnosis

• Echocardiography suggestive

– Speckled myocardium

– Interventricular septal thickening

• Distinguish from hereditary forms (10%)

• Evaluate for myeloma (rare)

AL Amyloidosis: Course

• Rare progression to multiple myeloma (0.4%)

• Poor long-term prognosis

– Cardiac, renal, hepatic failure, and infection

– Prognostic factors: circulating plasma cells, high beta-2 microglobulin, marrow plasmacytosis >10%, dominant cardiac involvement

– High B2M, marrow plasmacytosis: median survival

• 0: 54 months

• 1: 19 months

• 2: 13.5 months

Dhodapkar, Blood 2004;104:3520.

Skinner, Annals 2004;140:85

AL Amyloidosis: Therapy

• Chemotherapy

– Dexamethasone with

Dex/IFN maintenance

• High-dose melphalan with

Auto transplantation

– Risky with cardiac, renal,

GI involvement

LDex12,13Dex5-71990 2000 2010MP1 ASCT2-4 MDex8,9 TDex10

%

B14 CyBorD15,16

1. Kyle, et al. NEJM 1997

2. Comenzo, et al. Blood 1996

3. Gertz, et al. Leuk Lymphoma 2010

4. Cibeira, et al. Blood 2011

5. Gertz, et al. Am J Hematol 1999

6. Merlini, et al. Br J Haematol 2001

7. Dhodapkar, et al. Blood 2004

8. Palladini, et al. Blood 2004

9. Jaccard, et al. NEJM 2007

10. Palladini, et al. Blood 2005

11. Wechalekar, et al. Blood 2007

12. Sanchorawala, et al. Blood 2007

13. Dispenzieri, et al. Blood 2007

14. Reece, et al. Blood 2011

15. Mikhael, et al. Blood 2012

16. Venner, et al. Blood 2012

Survival at 5 years

1131 AL patients

Pavia Center

CTD11

Therapy Development in AL Amyloidosis

aCR Negative s. & u.IFE, normal FLR

VGPR dFLC <40 mg/L

PR dFLC decrease 50%

NR other

New Criteria for Response to Treatment in Immunoglobulin Light Chain Amyloidosis

Based on Free Light Chain Measurement and Cardiac Biomarkers: Impact on Survival

Outcomes. Palladini et al, J Clin Oncol. 2012;30:4541-9

0 12 24 36 48

Time (months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

po

rtio

n s

urv

ivin

g

NT-proBNP progression (at least 300 ng/L and 30% increase), 169 patients

NT-proBNP stable, 108 patients

NT-proBNP response (at least 300 ng/L and 30% decrease), 100 patients

p<0.001

p<0.001

New cardiac response criteria

reduction of NT-proBNP >30% and

>300 ng/L

Renal response criteria under

validation19

NT-proBNP

0 12 24 36 48

Time (months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

po

rtio

n s

urv

ivin

g

CR (97 patients, 3.6 deaths/100 py)

VGPR (233 patients, 9.6 deaths/100 py)

PR (140 patients, 23.7 deaths/100 py)

NR (179 patients, 47.2 deaths/100 py)

p=0.01

p<0.001

p<0.001

FLC

Renal insufficiency and IMiDs may alter

NT-proBNP metabolism

o Treatment endpoint: at least VGPR

o Hematologic and cardiac response should be assessed

frequently, every 1-2 cycles (or three months after ASCT)

o Rapid switch if no response

o Therapy can be continued for 1-2 cycles beyond best

response for consolidation

Therapy is Highly Individualized and Must be Risk-adapted Based

on Cardiac Biomarkers and Response-tailored

<VGPR Bortez if unexposed and no severe neuropathy

Len, Pom1, Benda2 in resist. to alkyl/bortez/thal

Len requires monitoring renal function

New drugs, such as Ixazomib3

1Dispenzieri et al, Blood 2012;119 :5397-404 -2Merlini et al, Blood. 2012;120(21) Abstr 4057 - 3Merlini et al,

Blood 2012;120(21) Abstr 731

Treatment Selection is Based on Cardiac Biomarkers

Merlini et al, Blood 2013 121: 5124-5130

1

1Gertz et al, Bone Marrow Transplant. 2013;48:557-612Wechalekar et al, Blood 2013;121:3420-7

2

Summary

• Spectrum of mature B-cell neoplasms/plasma cell

dyscrasias

• Clinical manifestations:

– Tumor growth, marrow and tissue infiltration

– M-protein accumulation or infiltration

– Immune dysfunction

– Kidney and bone disease

• Therapy not curative, but increasingly effective