Supportive Care and the Management of the
Newly Diagnosed and Initially Relapsing
Patient
Heinz Ludwig, MD
Patient 1 - Infections
· Laboratory work up
· Bacterial cultures from blood, urine, Port-A-Cath
· Chest X Ray pulmonary infiltrate
Start empiric antibiotic therapy immediately
Patient 1
· 69 year-old male, IgG, Stage III A
· Serum M 5,6 g/dl, lgA 120 mg/dL, IgM 50 mg/dL
· Multiple osteolytic lesions in spine, skull, pelvis
· Severe pain
· First line treatment: VAD through Port-A-Cath
· Day 10 after VAD:
weakness, fever, dyspnea during exercise
Factors Predisposing to Infections in Multiple Myeloma
Immunosuppression due to myeloma
Neutropenia - disease and / or treatment related
Steroid therapy
Damage to mucosal or skin barriers
Chemotherapy- or radiation-induced mucositis
Catheter-induced bacteremia
Frequently Identified Bacteria During Infections in Patients
with Myeloma, Lymphoma and Leukemia
Cagulase-negative staphylococci
17%
Escherichia coli(-)
16%
Alpha-haemolytic streptococci
12%
Staphylococcus aureus
9%
Klebsiella spp (-)
9%
Enterococcus spp
7%
Pseudomonas spp (-)
5%
*1402 episodes, ** 927 patients,
Cherif H., Hematol J. 2003.
Fungi and Viruses Frequently Involved in Myeloma-
Associated Infections
Class
Organism
Predominant
Source
Fungi
Candida spp.
Mucosal surfaces
Skin
Aspergillus spp.
Respiratory tract
Viruses
Adenovirus, RSV
Respiratory tract
Herpes simplex
Latent infections
Varicella zoster
Cytomegalovirus
Risk Factors for Infection During VAD
First 4 months of therapy (p<0.0001)
Renal function impairment (p<0.002)
Previously untreated disease (p<0.04)
Hypogammaglobulinemia (p=0.06)
Male sex (p=0.06)
Continuous infusion schedule (p=0.07)
Post-treatment neutropenia (p=0.08)
Cesana C. Haematologica. 2003.
Prophylaxis of Infections - When and How?
Anti-Bacterial: Co-Trimoxazole*
Chinolones
G-CSF (in case a previous febrile neutropenia)
*Reduction of the rate of bacterial infections
2.43 per patient-year for controls and 0.29 per patient-year
for the TMP-SMX group (P = 0.001).
Anti-Fungal:
Oral Amphotericin Suspension, Fluconazole
Important in Pts on high dose Dexamethasone, BMTX!
Anti-Viral:
Acyclovir, Famcilovir,Valacyclovir
Important in Pts on high dose Dexamethasone, BMTX!
*Oken et al. Am J Med. 1996.
Recommend Vaccination - But Be Aware of Incomplete
Protection
Antigen
% Myeloma Pts with Protective Antibody Titers
Before Vaccination
After Vaccination
Influenza*
0%
19%
Streptococcus
7%
61%
Pneumonia
Haemophilus
46%
75%
influenzae
*also to Health Care Personnel
and Close Family Members !!!
Robertson et al. Br J Cancer. 2000.
Consider iv Immunoglobulin Prophylaxis in Selected
Patients
Only patients in plateau
phase were enrolled
Time to first infection
Patients with poor antibody response to Pneumovax showed greatest benefit
Chapel HM et al. Lancet.1994.
Infections in Multiple Myeloma
Monitor patients carefully (clinically, CRP)
Consider anti-bacterial prophylaxis
- during first months of TX
- in patients with recurrent bacterial infections
Consider anti-viral and anti-fungal prophylaxis in patients
at high risk for these infections
Vaccination often results in incomplete protection
G-CSF and iv Immunoglobulins are additional treatment
options in selected cases
Start treatment immediately if infection is suspected
Patient 2 - Complications of Thalidomide and of
Bortezomib Therapy
68 year-old male in n-CR after VAD x 6, no maintenance
Relapse 6 months later with M 2.1 g/dL,
pain in lumbar spine
Thalidomide (200mg) ­ Dexamethasone Salvage
CR after 8 weeks
Toxicities: Constipation, occlusion of Port-A-Cath,
sensorimotor neuropathy, Feeling faint when standing up
from lying or sitting
Symptoms of Sensory Neuropathy
Numbness, "asleep feeling" or prickling sensation in
hands or arms and in feet or legs
Difficulty recognizing hot from cold water, feeling pain,
cuts or injuries
Burning, deep aching pain or tenderness in distal
extremities
Feeling unsteady walking on uneven ground
Symptoms of autonomic dysfunction
Feeling faint when standing up from lying or sitting
Risk Factors for Thalidomide Induced Sensory (motor)
Distal Axonal Neuropathy
Cumulative dose (<20 g: 10%)
Pre-treatment with neurotoxic drugs
Pre-existing neuropathy
Age
Deficiency of Vit B12 and Folate in
20% to 30% of patients with MM
Recommendations for Management of Thalidomide
Neuropathy
Severity of PN
Modification of dose and
regimen
Grade 1 with no pain
Monitor Patient carefully
Grade 1 with pain or Grade 2
Reduce dose of Thalidomide
by 50%
Withold Thalidomide,
Grade 2 with pain or Grade 3
Consider restart of
Thalidomide at lower dose
Grade 4
Discontinue
Supplement possible vitamin B12 and Folate deficiency
Value of Gabapentin (Neurontin®), Pregabalin (Lyrica®) and Alpha-
Lipoic Acid not established
Recommendations for Management of
Other Thalidomide Side Effects
Orthostatic/postural hypotension
Hydration and salt intake
Adjustment of treatment for hypertension
Consider Mineralcorticoid*
Recommend to rise slowly
Physical exercise
Sinusbradycardia
consider pacemaker
*Fludrocortisone
Thalidomide Associated Deep Vein Thrombosis
Usually venous (lower limbs), arterial thrombosis rare
Occurrence early after start of TX (time to DVT:
60 days; range 3-445 days)1
Risk increases with combination with
Dexamethasone
Chemotherapy (highest with Doxorubicine containing CTX)
Not related to response status
Mechanism unknown (Thalidomide
prothrombotic
factors2, activation of platelets and of vascular
endothelial cells3)
1Zangari et al. Blood. 2002. 2 Wang et al. Br.J.Haematol. 2001. 3 Kaushal et al. JCO. 2002.
Incidence, Prophylaxis and Treatment of Thalidomide
Associated DVT
Low molecular weight heparin or
therapeutic doses of coumarin
(INR: 2.5-3)
Low dose Coumarin not
effective!!
Controversial results with
Risk Factor
Odds Ratio
Aspirin
Doxorubicine containing CTX
4.3
Newly diagnosed disease
2.5
Thalidomide treatment may be
Chrom. 11 abnormality
1.8
reinstalled after DVT using LWMH
prophylaxis
Zangari et al. Br J Haematol.2004.
Recommendations for Management of
Other Thalidomide Side Effects
Sedation/Somnolence
Dose adjustment, Dexamethasone, Methylphenidate,
Methamphetamine, Modafenil
Constipation
High fiber diet, stool softeners, laxatives, hydration
Dermatologic: Rash, Pruritus
Steroids, dose reduction or cessation (temporary) of Thalidomide
Endocrine: Subclinical hypothyroidism
Thyroxine
Other: Depression, Nausea, Headache, Xerostomia
Bortezomib-Induced Neurotoxicity
Paresthesias, burning dysesthesias, numbness, tingling, difficulty
with fine motor skills, walking, feet < affected than hands
Incidence depends on baseline status (without baseline PN: 3%)
Incidence of Polyneuropathy in
(n=256)
SUMMIT & CREST phase II studies*
Overall (all grades)
35%
1.3 mg/m2 (n=228)
37%
1.0 mg/m2 (n=28)
23%
Grade 3**
13%
Grade 4**
<1%
Dose reduction/dose held
19%
Discontinuation
5%
with 80% showing some NP
**NCI toxicity criteria
at baseline
Richardson et al. ASH. 2003.
Onset of Polyneuropathy by Cumulative Dose
· Only 6 patients receiving bortezomib 1.0 mg/m2 developed any grade of PN
· At 30 mg/m2 (6 cycles), the probability of PN of any grade was 50%, and
the probability of grade 3 or 4 was 20%
Richardson et al. EHA. 2004.
Time to Response with Bortezomib Treatment
1.0
0.9
0.8
0.7
Patients 0.6
CR
of 0.5
0.4
PR
0.3
0.2
MR
Proportion
Range: 30­127 days
0.1
0
0
20
40
60
80 100 120 140 160 180 200
Days
Median time to response: 38 days
Summit Trial, Richardson et al. NEJM. 2003.
Recommendations for Bortezomib-
Induced Neuropathy
Severity of PN
Modification of dose and regimen
Grade 1 with no pain
No action
Grade 1 with pain or
Reduce dose to 1.0 mg/m2
Grade 2
Grade 2 with pain or
Withold Bortezomib
Grade 3
When toxicity resolves
Bortezomib 0.7 mg/m2 , once per
week
Grade 4
Discontinue Bortezomib
Outcome in 35 Patients With Significant
Polyneuropathy During Treatment
No change
14%
Resolution during treatment
n=5
Unknown
n=14
40%
14% n=5
PN resolved or improved in 25 of
35 patients (71%)
n=8
Median time to resolution of
n=3
improvement after end of therapy:
23%
9%
47 days (range, 1-529 days
Improved
Resolved
Early detection and appropriate
dose/schedule modification
Ongoing PN at last dose
important
(n=21)
Tolerability varies among patients
but seems to be higher when few
treatment options are available
Richardson et al. EHA. 2004
Lack of Cumulative Thrombocytopenia in Patients with
Adequate Marrow Function During Treatment
with Bortezomib or Dexamethasone
250
/L9
Dexamethasone
0
200
1
×
150
100
Count,
Bortezomib
50
Platelet
0
BL
3
6
9
1215
182124
Week
Mean
· Bortezomib arm: platelet counts measured on days 1, 4, 8, 11 of each 21-day cycle,
· Dexamethasone arm: platelet counts measured every 3 weeks
Thrombocytopenia develops almost exclusively
in patients with impaired bone marrow reserve
At onset of grade 4 Thrombocytopenia
withhold Bortezomib therapy
- Platelet transfusions at physician's discretion
- Once resolved, restart Bortezomib with 25% dose
reduction
Supportive Therapy and Management of
Toxicities of Treatment
May reduce mortality (infections)
Prevents or ameliorates disabling
toxicities of treatment (neuropathy,..)
Improves Quality of Life
Is an essential part of myeloma therapy

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