Evaluation of the Patient in Initial Relapse
and Selection of Second-Line Therapeutic
Options
James D. Cavenagh, MD
What is relapse?
· Consensus
EBMT/IBMTR/ABMTR criteria
Bladé et al. BRJ. 1998;102:1115-23.
Relapse from CR
1. Reappearance of original
serum/urinary paraprotein by
electrophoresis or immunofixation
2. >5% plasma cells in BM
3. New/enlarged lytic lesion or new soft
tissue plasmacytoma
4. Hypercalcemia
Progressive disease
1. >25% increase in serum/urinary
paraprotein/light chain which must be
>5 g/L or >200 mg/24 h respectively
2. >25% increase in BM PCs (>10%
absolute)
3. New/enlarged lytic lesion or new soft
tissue plasmacytoma
4. Hypercalcemia
Survival from relapse:
Non-intensive chemotherapy
1. PETHEMA: Overall survival 12.5 months
2. TTP
Median OS
<12 m
9 m
12-36 m
24 m
>36 m
30 m
Bladé. Hematol J. 2001, 2: 272-278.
Drayson. UK MRC data.
Survival from relapse
Relapse following HDT:
2-year OS
Low B2M, Response >12 m
79%
High B2M, Response <12 m
38%
Tricot et al. BMT. 1995;16:7-11.
Options for therapy
· Extremely divergent options
· HDT/Allogeneic transplant vs palliation
· Equally appropriate in different
situations
Paucity of data to guide evidence-based
care
Dexamethasone
· RR 25-35%
· Dex side effects
· Minimal BM
· Short-lived
suppression
responses
·Oral
· Rapid responses
Alexanian et al. Ann Intern Med.1986;105:8-11.
VAD
· RR 25% to 50%
· Infusional
· Minor BM
· Dex/Vinc side
suppression
effects
· Short-lived
responses
Alexanian et al. Eur J Haematol. 1989;51(suppl):140-144.
Thalidomide
· >MR 25% to 45%
· Sedation,
·Oral
constipation
· Neuropathy
· Dose uncertain
Singhal et al. NEJM. 1999;341:1565-1571.
Thalidomide + Dexamethasone
· >PR 55%
· Dex + Thal side
·Oral
effects
·DVT
Dimopoulos et al. Ann Oncol. 2001:991-995.
CTD: Cyclo/Thal/Dex
· RR 75%
· Dex + Thal side
·Oral
effects
·DVT +
· Myelosuppression
Garcia-Sanz et al. Hematol J. 2002;3:43-48.
Lenalidomide (REVLIMID)
· >MR 38%
· Thrombocytopenia
·Oral
· Neutropenia
· No sedation,
neuropathy, PN
Richardson et al. Blood. 2003;102:235a.
Bortezomib (VELCADE)
· CR/PR 27%
·IV
· CR/PR/MR 35%
· GI side effects
· Currently licensed
· Thrombocytopenia
for second relapse
· Peripheral
· APEX: superior to
neuropathy
Dex
· No infusion
Richardson et al. NEJM. 2003;348:2609-2617.
Time to Progression (Interim Analysis)
58% improvement in median TTP
P<0.0001
Bortezomib
(n = 327)
Patients
of
on
Dexamethason
Proporti
e (n = 330)
Months
Median TTP: Bortezomib 5.7 mo
Dexamethasone 3.6 mo
Richardson. ASCO. 2004.
Overall Survival
(Interim Analysis* Prior to Crossover)
Bortezomib (n = 327)
Dexamethasone (n = 330)
P =
Patients
0.038
of
on
Proporti
109 days median follow-up in survivors
- Bortezomib: 13 deaths (2 possibly drug related)
- Dexamethasone: 24 deaths (9 possibly/probably drug related)
Pts on dex arm censored at time to cross over to 040
Months
*October 10, 2003
Richardson. ASCO. 2004.
Arsenic trioxide
· MR 33%
· IV infusion
· QT prolongation
· Neutropenia
Hussein et al. BJH. 2004;125:470-476.
Oral alkylators:
Melphalan and cyclophosphamide
· Well tolerated
· Myelosuppressive
·Oral
(MEL>Cyclo)
· In subgroup with
durable first
response, approx
50% response rate
(RR)
Belch et al. BJC. 1988;57:94-99.
Evaluation of the Patient at Relapse
Evaluation of prior treatment / response
· Regimen used
· Duration of response
Evaluation of the Patient at Relapse
Evaluation of the patient:
·Age
· Co-morbidities
· Prior DVT, neuropathy
· BM reserve
· MM-related complications (eg SCC, renal
failure, pathological fractures)
· Patient's attitudes and wishes
UK Myeloma Forum Guidelines
The most appropriate management must
be determined on an individual basis
depending on:
1. Timing of relapse
2. Age
3. Prior therapy
4. Clinical state
UK Myeloma Forum Guidelines
· For patients who relapse after plateau
or remission following MP as first-line
therapy, MP is appropriate
· A thalidomide-based regimen should be
considered in other patients
· Where possible, patients should be
treated in the context of a clinical trial
UK Myeloma Forum Guidelines
Other approaches to be considered:
· Auto/Allo transplant
· Bortezomib
· Lenalidomide
· Steroids alone (eg, with pancytopenia)
BJH. 2001; 115: 522-540
Clinical Scenario 1
· 75-year-old female
· Treated 3 years ago with MP to plateau
· Progressive rise in M-band over
4 months
SUMMIT ­ Response to VELCADETM Alone:
Independent of Number and Types of Prior
Regimens
35%
CR+PR=27%
30%
25%
20%
Rate
15%
10%
Response
5%
0%
2-3
4-6
>7
Thal SCT
Prior Therapies
Richardson P et al. N Engl J Med. 2003;348:2609-2617.
Richardson P et al. Proc ASCO. 2003. Abstract 2338.
Clinical Scenario 2
· 70-year-old male
· Treated 6 months ago with MP
· Rapid onset of bone pain,
hypercalcemia, renal impairment, rapid
rise in M-band
Clinical Scenario 3
· 70-year-old male
· Treated 6 months ago with MP
· Sustained rise in M-band
Clinical Scenario 4
· 80-year-old male
· Initial presentation with cord
compression with paraparesis
· ECOG PS 4
· Rapidly evolving symptomatic relapse
3 months after MP
Clinical Trials (ASH 2004)
Thalidomide combinations:
· MPT, MDT, CTD, VAD-Thal
· DT + Bortezomib
· DT + Genasense
Clinical Trials (ASH 2004)
Lenalidomide combinations
·Dex
· Dex + Vinc + Doxil
· Rapamycin
Clinical Trials (ASH 2004)
Bortezomib combinations:
· Dex, Dex + Adria
·M, MP
· Thal, Thal + Doxil, Thal + Dex + Adria
Clinical Trials (ASH 2004)
ATO combinations:
· Vit C + MEL
· Vit C + Dex
Clinical Trials (ASH 2004)
Small-molecule inhibitors:
·IGF1-R
·FGF-R3
· VEGF-R
·HDAC
·Hsp 90

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