Haematologica 2003 - Supplements

9. Chemotherapy, maintenance treatment
and supportive care
P9.1
OPTIMAL CHEMOTHERAPY FOR INDUCTION AND
MAINTENANCE
Jan Westin, MD, PhD
Department of Hematology, University of Lund, Sweden and the
Nordic Myeloma Study Group
Before therapy of a myeloma patient is started two important
questions have to be answered. First, is the patient really in need
of chemotherapy? If the answer is no, i.e. the patient has
smoldering or stage I myeloma, he/she should be carefully
watched but no active therapy given. There are no established
means to delay the onset of symtomatic disease, but the results of
ongoing trials using thalidomide and other drugs are awaited.
Second, if the patient needs immediate therapy, next question to
be raised is if he/she is a candidate for intensive therapy (usually
high-dose melphalan with autologous stem cell support, given
once or twice; or in a small minority of patients allogeneic bone
marrow transplantation). This will today constitute the standard
therapy for patients below the age of 60 (at least), 65 (in most
places) or 70 years or more (at certain institutions).
If the patient will undergo high-dose therapy with stem cell
support up-front this decision influences the choice of initial
chemotherapy. Melphalan should be avoided, since it may
damage the hematopoietic stem cells and reduce the yield at the
stem cell harvest. The standard pretransplant induction therapy
has for many years been VAD (vincristine, adriamycin and
dexamethasone), usually given as a continous 4-day infusion.
This regimen is, however, both toxic and technically complex
(indwelling catheter, pump, frequent hospital visits).
Furthermore, neither vincristine nor adriamycin are potent antimyeloma
drugs, showing minimal activitity when given as single
drugs, and dexamethasone seems to be the most potent
component of the drug combination. This has led to several
ongoing trials, in which dexamethasone alone, dexamethasone
plus thalidomide (e.g. Mayo Clinic, ECOG) or dexamethasone
plus cyclophosphamide (NMSG) is compared to VAD as
induction therapy before stem cell harvest and high-dose
melphalan. A further advantage of a mainly dexamethasonebased
induction regimen might be a shortening of the time from
diagnosis/start of therapy to the high-dose melphalan (and
hopefully subsequent good response). Negative might be that
fewer patients would achieve a partial response on the induction
therapy, but this fact does not preclude a good response to highdose
melphalan.
For the patients not considered for intensive therapy (and with a
median age of 70 years in an unselected patient population this
will still be the majority of cases) intermittent melphalan and
prednisone (MP) has since more than 40 years been the therapy
of choice. Since the absorption of melphalan is variable the dose
should be stepwise escalated to achieve a moderate leuko- and
thrombocytopenia between the courses (nadir reached 14-
21days). In patients with renal failure the dose should be reduced.
High fluid intake is important. For patients with initial
cytopenias, especially thrombocytopenia cyclophosphamide may
be an alternative instead of melphalan. With MP a partial
response can be demonstrated in 50-60 % of patients (but CR in
less than 5 %), and the median duration of response is about two
years.
After a patient has entered a plateau phase continued MP therapy
is generally considered of no value.
Inspired by the dramatic effect multidrug cytostatic regimens was
shown to exert in other B-cell neoplasms a very large number of
clinical trials has been performed also in multiple myeloma, from
the early 60-ies onwards, evaluating combination chemotherapy
vs traditional MP therapy. A number of drug combinations have
been investigated, most of them comprising vincristine, an
anthracycline, one or two alkylating agents and corticosteroids.
This led to many years of discussion regarding the advantages of
different regimens, at least in certain situations, over MP.
However, in the overview, performed by the Myeloma Trialists'
Collaborative Group (1998), that included invididual data on
6623 patients from all known trials worldwide (n = 27), it was not
possible to demonstrate that combination chemotherapy has an
advantage in comparison to MP. It could neither be shown that
multiagent chemotherapy conferred a survival benefit to poor-risk
patients.
Interferon alone was in the early 80-ies shown to induce
responses in a certain fraction of newly diagnosed myeloma
patients, but the addition of this drug to MP or combination
chemotherapy did not convincingly increase the response rate and
not the overall survival.
Today several large clinical trials are ongoing, both in Europe
and in the US, exploring the value of adding thalidomide and/or
other drugs to the induction therapy, but no results are yet
available.
Patients responding to initial chemotherapy inevitably relapse
after a period of varying length, months to years. Great interest
has therefore been focused, and is focused today, on methods to
prevent or delay relapse. Alfa-interferon has since the early 80-
ties been used for this purpose in several trials, recently
summarized in an overview performed by the Myeloma Trialists'
Collaborative Group (2001), comprising 12 maintenance studies.
Even if a significant advantage was demonstrated for interferontreated
patients with regard to both time to progression and total
survival (c:a 6 months), this moderate gain is by most physicians
(and many patients) considered too small to upweigh the negative
side-effects and the cost of the therapy. Today much interest is
focused on a number of new drugs with activity in myeloma
(immunomodulators, proteasome-inhibitors, arsenic compounds),
and several of them are in different stages of clinical trial
evaluation. Almost every clinical trial group is in one or other
way including thalidomide maintenance in their running
protocols. Some results from these studies may be availabe at this
meeting. Other trials, in which prolonging the time in "remission"
for myeloma patients with the help of chemotherapy has been
explored, have not been successful. A number of options are still
not fully examined, e.g. repeated post-remission chemotherapy,
late intensification therapy, early treatment of "subclinical"
relapses with the help of minimal residual disease status.
However, it seems more realistic to believe that immunotherapy
(in some form) rather than chemotherapy will be a practicable
way to prolong remission or perhaps even cure myeloma patients
with a heavily reduced tumor burden or a stable plateau phase.
References
The Myeloma Trialists' Collaborative Group: Combination
chemotherapy versus melphalan plus prednisone as treatment for
multiple myeloma: An overview of 6.633 patients from 27
randomized trials. J Clin Oncol. 16: 3832-3842, 1998.
The Myeloma Trialists' Collaborative Group: Interferon as
therapy for multiple myeloma: an individual patient data
overview of 24 randomized trials and 4.012 patients. Brit J
Haematol. 113: 1020-1034, 2001.
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