1. Multiple Myeloma
European Multiple Myeloma Initiative

2. MYELOMA
Definition: abnormal proliferation and accummulation of plasma cells producing one type of paraproteins . Clinical course has typical picture
myeloma activity laboratory, X-ray symptoms
anemia fatigue, weakness, etc.
Bone marrow infiltration neutropenia risk of infection
thrombocytopenia bleeding
X-ray: osteolysis pain + neurol. symptoms
osteolsis osteoporosis pathol. fractures
hypercalcemia nausea, thirst, coma
Paraprotein production paraproteinemia sy. of hyperviskosity
paraproteinuria „myeloma kidney“

3. Multiple myeloma incidence and mortality
Prevalence (1 year)
world: 32,947 (♂); 27,925 (♀)
Europe: 13,089 (♂); 12,512 (♀)
USA: 7,671 (♂); 5,868 (♀)
Incidence (age-standardized rates)
world: 1.7/100,000 (♂); 1.2/100,000 (♀)
Europe:
north, south, west: 3.5–4/100,000 (♂); 2.5–2.9/100,000 (♀)
central and east: 1.6/100,000 (♂); 1.3/100,000 (♀)
USA: 4.8/100,000 (♂); 2.9/100,000 (♀)
Mortality (age-standardized rates)
world: 1.2/100,000 (♂); 0.9/100,000 (♀)
Europe
north, south, west: 2.0–2.6/100,000 (♂); 1.6–1.9/100,000 (♀)
central and east: 1.0/100,000 (♂); 0.8/100,000 (♀)
USA: 2.9/100,000 (♂); 2.1/100,000 (♀)
Multiple myeloma incidence and mortality
MM incidence, mortality, and prevalence data from International Agency for Research on Cancer (IARC) GLOBOCAN 2002 data for the following regions:
World US
Central & Eastern Europe (Belarus, Bulgaria, Czech Republic, Hungary, Moldava, Poland, Romania, Russian Federation, Slovakia, Ukraine)
Northern Europe (Denmark, Estonia, Finland, Iceland, Ireland, Latvia, Lithuania, Norway, Sweden, United Kingdom)
Southern Europe (Albania, Bosnia Herzegovina, Croatia, Greece, Italy, Macedonia, Malta, Portugal, Serbia & Montenegro, Slovenia, Spain)
Western Europe (Austria, Belgium, France, Germany, Luxembourg, The Netherlands, Switzerland)
Breakdown of incidence by European region (age-standardized rates)
Central & Eastern: 1.6/100,000 (male); 1.3/100,000 (female)
Northern: 4/100,000 (male); 2.9/100,000 (female)
Southern: 3.5/100,000 (male); 2.5/100,000 (female)
Western: 4/100,000 (male); 2.7/100,000 (female)
Breakdown of incidence mortality by European region (age-standardized rates)
Central & Eastern: 1.0/100,000 (male); 0.8/100,000 (female)
Northern: 2.6/100,000 (male); 1.9/100,000 (female)
Southern: 2.0/100,000 (male); 1.6/100,000 (female)
Western: 2.5/100,000 (male); 1.9/100,000 (female)
Prevalence, incidence, and mortality slightly higher in women
Prevalence, incidence, and mortality higher in US and Northern, Southern, and Western Europe compared to the world as a whole
Reference
International Agency for Research on Cancer (IARC) GLOBOCAN 2002 data. Available at: www-dep.iarc.fr/.
International Agency for Research on Cancer (IARC) GLOBOCAN 2002 data.
Available at: www-dep.iarc.fr/

4. Multiple myeloma: epidemiology
Approximately 1% of all cancers
second most prevalent haematological cancer
Median age at diagnosis: 71 years
74 years (community population)
62 years (hospital population)
2% of cases < 45 years
Risk factors
age
male gender
African descent
occupational exposure to herbicides, insecticides, petroleum products, heavy metals, plastics, asbestos
exposure to radiation
Multiple myeloma: epidemiology
MM comprises 1% of all cancers but is the second most common blood cancer after lymphomas
Recent statistics indicate that MM is increasing in incidence and occurring more frequently in individuals aged <55 years
The median age of diagnosis is approximately 71 years (range 29-92). The median age of diagnosis is lower in patients in a hospital or clinic setting compared with patients in a community setting
Risk factors include age, male gender, African descent, and occupational or environmental exposure to toxins or radiation
References
Kyle RA, et al. J Clin Oncol. 1994;12:
Multiple Myeloma Research Foundation. Available at:
Kyle RA, et al. J Clin Oncol. 1994;12:

5. Pathogenesis

6. MM cells in bone marrow microenvironment
Diagrammatic depiction of MM cells in bone marrow microenvironment and key cytokines or growth factors regulating growth and survival of MM cells
Abbreviations
bFGF = basic fibroblast growth factor; ICAM = intercellular adhesion molecule; IFN = interferon; IL = interleukin; NK = natural killer; PBMC = peripheral blood mononuclear cells; TNF = tumour-necrosis factor; VEGF = vascular endothelial growth factor.
References
Hideshima T, et al. Blood. 2000;96:
Richardson PG, et al. Blood. 2002;100:

7. Signaling cascades mediate growth, anti-apoptosis, and migration in MM
Several signaling cascades are involved in the cellular decision pathways leading to an active MM cell. Each cascade, triggered by signals external to the cell, leads to the characteristic properties of a tumor cell: increased proliferation, anti-apoptotic or drug-resistant properties, increased cell cycling, and increased migration
Hideshima T, Anderson KC. Nat Rev Cancer. 2002;2:

8. MM plasma cells MM plasma cells
Bone marrow aspirate showing plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo)

9. Pathogenesis of MM
MM arises from a B cell of the normal germinal centre, either directly or via MGUS (≥ 30–50%). A period of smouldering myeloma is not always present
Initially, MM is confined to the bone marrow, but tumours can acquire the ability to grow outside the bone marrow
Abbreviations
IL = interleukin; MGUS = monoclonal gammopathy of undetermined significance.
Reference
Kuehl WM, Bergsagel PL. Nat Rev Cancer. 2002;2:

10. Development of plasma/MM cells
At a genetic level, multiple gene rearrangements occur during the transition from stem cell to myeloma cell. Ig gene rearrangement juxtaposes a strong genetic promoter or removes gene regulatory controlling elements in front of the Ig encoding gene. As cell differentiation progresses, cell surface markers also transition
Reference
Hideshima T, Anderson K. Nat Rev Cancer. 2002;2:

11. Bone marrow pathophysiology
Normal bone
Balanced osteoblast and osteoclast function
Osteoclasts express RANK
Osteoblasts or other cell types express and secrete RANKL
Bone marrow stromal cells secrete osteoprotegerin (OPG) as a decoy receptor MM
Increased osteoclast activity
MM cells interact with bone marrow stromal cells, immune cells
Upregulation of RANKL
Downregulation of OPG
Bone marrow pathophysiology
In normal bone, osteoblast and osteoclast function is balanced by the actions of RANKL and OPG
In MM, RANKL is increased, OPG is decreased, resulting in increased osteoclast activity
Reference
Barillé-Nion S, Bataille R. Leuk Lymphoma. 2003;44:1463.

12. Diagnosis

13. Monoclonal gammopathy of undetermined significance (MGUS)
Serum M protein < 30 g/l
Bone marrow plasma cells < 10% and low level of plasma cell infiltration in trephine biopsy (if done)
No evidence of other B-cell proliferative disorders
No ROTI
1% per year progress to MM
Monoclonal gammopathy of undetermined significance (MGUS)
The International Myeloma Working Group developed diagnostic criteria for monoclonal gammopathies, MM, and related disorders. Solitary plasmacytoma of bone, extramedullary plasmacytoma, and multiple solitary plasmacytomas (+/- recurrent) are also defined as distinct entities
In monoclonal gammopathy of undetermined significance (MGUS), the monoclonal protein is <30 g/l with <10% bone marrow clonal cells and no evidence of multiple myeloma, other B-cell proliferative disorders or amyloidosis
The incidence of progression of MGUS to MM or related disorders is about 1% per year
References
International Myeloma Working Group. Br J Haematol. 2003;121:
Kyle RA, et al. N Engl J Med. 2002;346:564-9.
ROTI = related organ or tissue impairment.
International Myeloma Working Group. Br J Haematol. 2003;121:

14. Related organ or tissue impairment (CRAB)
Calcium levels 
serum calcium > 0.25 mmol/l above upper limit of normal or > 2.75 mmol/l
Renal insufficiency
creatinine > 170 mmol/l
Anaemia
haemoglobin 2.0 g/dl below lower limit of normal or < 10 g/dl
Bone lesions
lytic lesions or osteoporosis with compression fractures (MRI or CT may clarify)
Other
symptomatic hyperviscosity, amyloidosis, recurrent infections (> 2 episodes in 12 months)
Related organ or tissue impairment (ROTI)
Symptomatic myeloma requires evidence of ROTI, which is typically manifested by increased calcium, renal insufficiency, anemia, or bone lesions (CRAB) attributed to the plasma cell proliferative process
Reference
International Myeloma Working Group. Br J Haematol. 2003;121:
CRAB (calcium, renal insufficiency, anaemia, or bone lesions)
International Myeloma Working Group. Br J Haematol. 2003;121:

15. Asymptomatic myeloma (smouldering myeloma)
Serum M protein ≥ 30 g/l
and/or
Bone marrow plasma cells ≥ 10%
No related organ or tissue impairment
Asymptomatic myeloma (smouldering myeloma)
The International Myeloma Working Group (IMWG) developed diagnostic criteria for monoclonal gammopathies, MM, and related disorders. Solitary plasmacytoma of bone, extramedullary plasmacytoma, and multiple solitary plasmacytomas (recurrent or non-recurrent) are also defined as distinct entities
In asymptomatic (smouldering) myeloma, M protein concentration is ≥ 30 g/l or bone marrow clonal cells ≥ 10% (or both), but there is no related organ or tissue impairment
Reference
International Myeloma Working Group. Br J Haematol. 2003;121:
International Myeloma Working Group. Br J Haematol. 2003;121:

16. Symptomatic MM M protein in serum and/or urine*
Bone marrow (clonal) plasma cells or plasmacytoma
ROTI (related Organ orTissue Involvement)
CRAB
Symptomatic MM
The International Myeloma Working Group developed diagnostic criteria for monoclonal gammopathies, MM, and related disorders. Solitary plasmacytoma of bone, extramedullary plasmacytoma, and multiple solitary plasmacytomas ( recurrent) are also defined as distinct entities
Symptomatic myeloma requires evidence of ROTI
Non-secretory myeloma is characterized by the absence of an M-protein in the serum and urine, bone marrow plasmacytosis, and ROTI
Reference
International Myeloma Working Group. Br J Haematol. 2003;121:
* No specific level required for diagnosis. Can have no detectable serum or urine M protein with ROTI.

17. Serum free-light-chain ratio as independent risk factor for progression in MGUS
All 3 factors abnormal (abnormal FLC ratio, non-IgG MGUS, and serum M protein ≥ 15 g/l)
Any 2 factors abnormal
Any 1 factor abnormal
Serum M-spike < 15 g/l, IgG subtype, and normal FLC ratio
Patients (%) 60 40 20 5 10 15 25 30
Serum free light chain ratio as independent risk factor for progression in MGUS
Baseline serum samples obtained within 30 days of diagnosis were available in 1148 of 1384 MGUS patients seen at the Mayo Clinic from 1960 to 1994
Malignant progression occurred in 87 (7.6%) patients at a median follow-up of 15 years
An abnormal free light chain (FLC) ratio (k/l ratio < 0.26 or > 1.65) was detected in 379 (33%) patients. The risk of progression in patients with an abnormal FLC ratio was significantly higher compared to patients with a normal ratio (P < 0.001) and was independent of the size and type of the serum monoclonal (M) protein
Patients with an abnormal serum FLC ratio, non-IgG MGUS, and a high serum M protein level (≥ 15 g/l) had a risk of progression at 20 years of 58% (high-risk MGUS) versus 37% with any 2 of these risk factors (high-intermediate risk), 21% with 1 risk factor (low-intermediate risk), and 5% when none of the risk factors were present (low risk)
Reference
Rajkumar SV, et al. Blood. 2005;106:812-7.
Time (years)
Reproduced with permission from Rajkumar SV, et al. Blood. 2005;106: ©Am Soc Hematol.

18. Presenting features of MM
S/U M protein
97%
Anaemia
73%
Lytic bone lesions
66%
Bone pain
58%
Renal insufficiency
19%
Hypercalcaemia
13%
Presenting features of MM
Kyle et al reviewed the records of 1027 patients in whom a diagnosis of MM was initially diagnosed at the Mayo Clinic in Rochester, Minnesota, USA, from January 1, 1985, to December 31, 1998, to determine the clinical and laboratory features of newly diagnosed patients with the disease
The initial findings were bone pain in 58% of patients, anemia in 73%, renal insufficiency (serum creatinine ≥ 176 mmol/l) in 19%, hypercalcemia in 13%, a palpable liver in 4%, and a palpable spleen in 1%. 97% of patients had serum or urine M-protein
Amyloidosis was found in 4% of the patients; an additional 2% developed the disorder  30 days after the diagnosis of MM was established
Reference
Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.
Minor or no abnormalities
11%
Hepatomegaly 4%
Amyloidosis 4%
Non-secretory (no S/U M protein) 3% 10 20 30 40 50 60 70 80 90
100
Patients (%)
Data from Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.

19. Types of serum monoclonal proteins in 1,027 patients with MM
This graph depicts the relative frequency of the Ig class of monoclonal proteins produced in MM, or the percent presence of either light or heavy chain of Ig in other diseases
Reference
Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.
IgG IgG IgA IgA IgM IgM IgD IgD Free  Free  Biclonal Negative only only
Type of monoclonal protein
Data from Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33.

20. Diagnosis and investigation
History and physical examination
Blood and urine
full blood count
serum or plasma electrolytes, urea, creatinine, calcium, albumin, uric acid
electrophoresis of serum and concentrated urine, immunofixation
quantification of non-isotypic serum immunoglobulins
quantification of serum paraprotein
quantification of urinary light chains
creatinine clearance, measured or calculated
2-microglobulin, C-related protein, LDH
plasma viscosity
(serum erythropoietin)
(vitamin B12/folate)
Skeletal survey
X-rays of spine, pelvis, skull, humeri, femora
MRI for investigation for suspected spinal cord compression
CT OR today: PET/CT for extramedullary disease
Bone marrow aspirate ± trephine biopsy
cytogenetics, FISH, immunophenotyping, (clonality studies)
Diagnosis and investigation
Patients typically present with bone pain, renal impairment, anemia, or a combination of these
Myeloma should also be considered in patients with unexplained backache, loss of height, or radiologic evidence of osteoporosis, recurrent bacterial infection
Asymptomatic patients may be diagnosed on routine testing
These guidelines for diagnosis and investigation are the recommendation of the British Committee for Standards in Haematology (BCSH). Tests in parentheses are useful in certain situations
References
Smith A, et al. Br J Haematol. 2005;132:
Full BCSH guidelines available at:

21. X-ray images of MM bone lesions
Plasmacytoma causing deformity of L4 vertebral body
Myeloma lesion in right femur

22. MRI of MM bone lesions
T1-weighted MRI reveals myelomatous involvement within the glenoid and coracoid process
In this T2-weighted, fat-suppressed image, the myeloma lesion is hyperintense
MRI of MM bone lesions

23. Staging

24. Durie-Salmon staging system for MM
Stage
Criteria
Myeloma cell mass ( 1012 cells/m2) I
All of the following: Haemoglobin > 10 g/dl Serum calcium < 2.6 mmol/l (normal) Normal bone or solitary plasmacytoma on X-ray Low M-component production rate: IgG < 50 g/l; IgA < 30 g/l Bence Jones protein < 4 g/24 hours
< 0.6 (low) II
Not fitting stage I or III
0.6–1.2 (intermediate)
III
One or more of the following: Haemoglobin < 8.5 g/dl Serum calcium > 3.0 mmol/l Advanced lytic bone lesions on X-ray High M-component production rate: IgG > 70 g/l; IgA > 50 g/l Bence Jones protein > 12 g/24 hours
> 1.2 (high)
Durie-Salmon staging system for MM
In the Durie-Salmon Staging System, the clinical stage of disease (Stage I, II, or III) is based on several measurements, including levels of M protein, the number of bone lesions, haemoglobin values, and serum calcium levels. Stages are divided further according to kidney function, which is determined by serum creatinine levels (classified as A or B)
Reference
Durie BG, Salmon SE. Cancer. 1975;36:
Subclassification Criteria
A Normal renal function (serum creatinine < 170 mmol/l)
B Abnormal renal function (serum creatinine  170 mmol/l)
Adapted from Durie BG, Salmon SE. Cancer. 1975;36:

25. International Staging System for MM
Stage
Criteria
Median survival,
months I
Serum 2-microglobulin < 3.5 mg/l
Serum albumin ≥ 35 g/l 62 II
Serum albumin < 35 g/l OR
Serum 2-microglobulin 3.5 to < 5.5 mg/l* 44
III
Serum 2-microglobulin ≥ 5.5 mg/l 29
International staging system for MM
The new International Staging System (ISS) for MM was published in 2005
Clinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate analysis. Three modeling approaches were then explored to develop a staging system including 2 non-tree and 1 tree survival assessment methodologies
A combination of serum b2-microglobulin and serum albumin provided a simple, powerful, and reproducible 3-stage classification
The ISS was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients either < 65 years of age or ≥ 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie-Salmon Staging System
Reference
Greipp PR, et al. J Clin Oncol. 2005;23:
* Irrespective of serum albumin level.
Reproduced with permission from Greipp PR, et al. J Clin Oncol. 2005;23: ©Am Soc Clin Oncol.

26. Patients surviving (%) Time after initial chemotherapy (months)
ISS: survival
Patients surviving (%)
Time after initial chemotherapy (months)
216
192
168
144
120 96 72 48 24 40 20 60 80
100
Median (range), months
Deaths/N
Stage I
606/1,111 62
(58–65)
Stage II
1,054/1,505 44
(42–45)
Stage III
968/1,305 29
(26–32)
ISS: survival
Survival durations were 62 months (Stage I), 44 months (Stage II), 29 months (Stage III)
Reference
Greipp PR, et al. J Clin Oncol. 2005;23:
Reproduced with permission from Greipp PR, et al. J Clin Oncol. 2005;23: ©Am Soc Clin Oncol.

27. ISS: cytogenetic data
n = 390
Cytogenetic data
Survival durations were 62 months (Stage I), 44 months (Stage II), 29 months (Stage III)
Reference
Greipp PR, et al. J Clin Oncol. 2005;23:
No strong correlation of cytogenetic data with ISS stage
t(4;14) occurred at lower incidence in stage I than in stage II or III patients (p = 0.035)
Data from Greipp PR, et al. J Clin Oncol. 2005;23:

28. Treatment schemes

29. Treatment initiation Immediate treatment for symptomatic MM
Patients without clinical symptoms, but with radiological evidence of bone disease should commence treatment immediately
Monitor patients with MGUS and asymptomatic myeloma until there are signs of progression
Treatment initiation
Monitoring of patients with MGUS and asymptomatic myeloma should be indefinite, with varying frequency according to the risk of progression (Grade B recommendation; level III evidence). Monitoring should include regular (every 3 months for asymptomatic and every 6 months to a year for MGUS) clinical assessment and measurement of both serum and urinary paraprotein. Repeat bone marrow examinations and skeletal X-rays required less often or when new symptoms or signs develop (Grade C recommendation; level IV evidence)
Patients and general practitioners should be provided with information on risk and clinical features of disease progression (Grade C recommendation; level IV evidence)
Treatment should be deferred until there is evidence of disease progression or ROTI (Grade A recommendation; level Ib evidence)
Patients without clinical symptoms but with radiologic evidence of bone disease should commence treatment immediately (Grade B recommendation; level IIb)
Reference
Smith A, et al. Br J Haematol. 2005;132:
Smith A, et al. Br J Haematol. 2005;132:

30. Treatment considerations
Attaining early CR important for stable disease control and for survival
Stem-cell-supported high-dose therapy
high CR rate
standard treatment for eligible patients
Classic chemotherapies
patients ineligible for high-dose therapy
Newer biological therapies
improving CR rate (especially with combinations)
newly diagnosed, relapsed/refractory, transplant induction
Treatment considerations
Smith A, et al. Br J Haematol. 2005;132:

31. Initial chemotherapy High-dose chemotherapy planned
High-dose chemotherapy not planned
Dexamethasone-based induction therapy
combinations with novel agents are superior to classic “VAD” regimens
Melphalan, prednisolone (MP)
Melphalan, prednisolone, thalidomide (MPT)
Melphalan, prednisolone, bortezomib (MPV)
Abbreviation
VAD = bortezomib, doxorubicin, dexamethasone.
Harousseau JL. Ann Oncol. 2009;20 Suppl 4:97-9.

32. Patient with perspective to undergo high dose therapy & ASCT (PBSCT)
ASCT = autologous (hematopoietic) stem cell transplantation
Standard consolidation treatment in MM after the induction therapy
Suitable patients: up to 65 years in general, biologically fit up to 70 years
Allogeneic transplantation: not satisfiable reesults

33. MM: induction treatment, 1. line in pts suitable for ASCT (PBSCT)
CTD: cyclophosphamide (C) + thalidomide + dexamehtasone OR
CVD: C + bortezomib (Velcade) + dexamethasone
Mobilization & harvest of auto PBSC (Peripheral Blood StemCcells)
High dose Melphalan (200mg/m2) i.v. + ASCT(APBSCT)
24–75% CR and a median survival of 4–5 years as first-line therapy

34. Principles of autologous hematopoietic stem cell transplantation
HSC harvest
Myeloablative therapy
HSC reinfusion - transplantation
Bone marrow PBSC (mobilization)
In vitro purging??
Thaw of the HSCT
freezing

35. OS according to presence or absence of VGPR at first ASCT
Very good partial response after first transplant
Absence of very good partial response after first transplant
100
100 75 75
Double-transplant group (n = 46)
Double-transplant group (n = 128)
Overall survival (%)
Overall survival (%) 50 50
p < 0.001 25
OS according to presence or absence of VGPR at first ASCT
Attal et al determined that the effect of a single or a double ASCT on OS differed according to the response achieved 3 months after the first ASCT
Only patients who did not have at least a VGPR after the first ASCT had a significant benefit from the second ASCT. The rates of survival at 7 years were 11% in the single-ASCT group vs 43% in the double-ASCT group (p < ). Patients who had ≥VGPR did not benefit significantly from the second ASCT (p = 0.70)
Reference
Attal M, et al. N Engl J Med. 2003;349: 25
Single-transplant group (n = 81)
Single-transplant group (n = 84) 22 44 66 88 22 44 66 88
Months after first transplant
Months after first transplant
Reproduced with permission from Attal M, et al. N Engl J Med. 2003;349: ©2003, MA Med Soc.

36. Supportive therapies Bone disease
analgesics for bone pain (avoid NSAIDs)
palliation of bone pain with radiation (8 Gy)
vertebroplasty or kyphoplasty for persistent pain
bisphosphonates
Anaemia: transfusions or RBC growth factors
consider trial of erythropoietin in patients with symptomatic anaemia
hold or reduce erythropoietin dose when Hb > 12.0 g/dl
Hypercalcaemia
rehydration, bisphosphonates
Renal dysfunction or hyperviscosity
rehydration, treatment of infection, plasmaphoresis
Infections: antibiotics, flu vaccination
Supportive therapies
Management of bone disease and maintenance of blood counts are central components of supportive therapies for MM
In newly diagnosed patients, EPO should usually not be considered before response to chemotherapy has been assessed (Grade C recommendation; level IV evidence). A therapeutic trial of EPO may be considered in patients with symptomatic anaemia receiving chemotherapy (Grade A recommendation; level Ib evidence). As part of the basis for this consideration, serum EPO concentration should be measured. A serum EPO > 200 iu/ml, a high transfusion requirement, and a low platelet count are negative prognostic factors for a response to EPO. The dose should be doubled if there is no sign of effect after 4–6 weeks (Grade B recommendation; level IIa evidence). The probability of effect is low if Hb has not risen by 1–2 g/dl after 6–8 weeks and EPO should then be stopped (Grade B recommendation; level IIb evidence). EPO should be stopped or the dose reduced when Hb rises above 12 g/dl (Grade C recommendation; level IV evidence). EPO may also be considered in patients not receiving chemotherapy who have symptomatic anaemia (Grade B recommendation; level IIa evidence). Iron status should be monitored during EPO treatment (Grade C recommendation; level IV evidence)
In mild hypercalcemia (corrected calcium 2.6–2.9 mmol/l), rehydrate with oral fluids. In moderate-severe hypercalcemia (corrected calcium ≥ 2.9 mmol/l) rehydrate with i.v. fluids and give furosemide if required. If not already on a bisphosphonate, start immediately. If already on a bisphosphonate, consider changing to a more potent bisphosphonate or increasing the dose. Additional therapy may be required in refractory patients
Initial management of renal failure should include vigorous rehydration and treatment of infection. Seek the advice of a nephrologist if renal failure does not improve within 48 hours. Consider plasma exchange, where possible, within the context of a clinical trial. Dialysis should be offered to patients where appropriate for the management of the renal failure
Reference
Smith A, et al. Br J Haematol. 2005;132:
Smith A, et al. Br J Haematol. 2005;132:

37. Bisphosphonates
Randomized placebo-controlled studies have shown a significant clinical benefit in MM
Recommended for all symptomatic MM patients requiring chemotherapy, whether or not bone lesions are evident
Oral clodronate (1600 mg/day), i.v. pamidronate (90 mg every 4 weeks) and i.v. zoledronate (4 mg every 4 weeks) are effective
Treatment continued ≥ 2 years
long-term therapy reduces skeletal events and improves quality of life
Monitor renal function
caution in patients with moderate to severe renal dysfunction
no zoledronate if creatinine > 265 mmol/l
Bisphosphonates
Bone pain, hypercalcemia, and pathological fractures are a major cause of morbidity and mortality in patients with MM
Randomized placebo-controlled studies have shown a significant clinical benefit in MM. Long-term use reduces skeletal events and improves quality of life
Bisphosphonate therapy is recommended for all patients with myeloma requiring chemotherapy, whether or not bone lesions are evident (Grade A recommendation; level Ib evidence)
Treatment should be continued for at least 2 years (Grade A recommendation; level Ib evidence); it is current practice to continue treatment indefinitely although there are few reported data on longer-term use
Oral clodronate (1600 mg daily or equivalent dosage according to formulation), i.v. pamidronate, and i.v. zoledronic acid (Grade A recommendation; level Ib evidence) may be used. Monthly i.v. pamidronate 90 mg and zoledronic acid 4 mg are equivalent in efficacy (Grade A recommendation; level Ib evidence)
Doses, infusion times, and frequencies should be as recommended by the manufacturer, and renal function should be monitored. Creatinine should be checked before each zoledronic acid infusion
Special caution is required with all bisphosphonates in patients with moderate to severe renal failure; zoledronic acid should not be used if creatinine is more than 265 mmol/l
There are insufficient data to make a recommendation for the use of bisphosphonates in patients with asymptomatic myeloma
Reference
Djulbegovic B, et al. Cochrane Database Syst Rev. 2002;3:CD
Smith A, et al. Br J Haematol. 2005;132:
Djulbegovic B, et al. Cochrane Database Syst Rev. 2002;3:CD
Smith A, et al. Br J Haematol. 2005;132:

38. Management of relapsed/refractory disease
Regimens similar to those used initially can induce a second remission
Regimens currently used:
lenalidomide combinations
thalidomide combinations
bortezomib combinations
Abbreviation
VAD = Bortezomib, adri
Harousseau JL. Ann Oncol. 2009;20 suppl 4:97-9.