Haematologica 2003 - Supplements

P9.2
CURRENT MANAGEMENT OF MYELOMA PATIENTS
WITH RENAL FAILURE
Jayesh Mehta MD
Professor of Medicine, Director, Hematopoietic Stem Cell
Transplant Program, Division of Hematology/Oncology, The
Feinberg School of Medicine, The Robert H. Lurie Comprehensive
Cancer Center, Northwestern University, Chicago, Illinois
Introduction: Renal failure is seen in up to 50% of patients with
myeloma at one time or another over the course of the disease,
and is secondary to cast nephropathy (myeloma kidney),
amyloidosis, light chain deposition disease, other metabolic
abnormalities and nephrotoxic therapy.
While the management is dependent upon the underlying cause,
the general principles of management are outlined below.
Supportive therapy: This is critical at all stages of therapy, and
includes the following:
Adequate hydration
Correction of hypercalcemia
Correction of other metabolic abnormalities
Plasmapheresis if hyperviscosity syndrome present
Consideration of limited plasmapheresis during induction
therapy in patients with acute renal failure even in the absence
of hyperviscosity syndrome
Avoidance of nephrotoxic drugs
Use of newer low-osmolar, non-ionic, monomeric contrast
agents such as iohexol if radiographic studies with contrast
adminisration are essential
Use of n-acetylcysteine with the use of unavoidable
nephrotoxic agents
Slow bisphosphonate administration (2-3 hours for
pamidronate and 30 minutes for zoledronate)
Induction therapy: Prompt initiation of therapy is important in
patients presenting with renal failure because, unless the renal
failure is purely of metabolic etiology, reduction of tumor burden
is essential for improvement of renal function. The reversibility
of renal failure decreases with passing time.
While standard induction chemotherapeutic regimens such as
VAD can be employed safely in patients with renal failure,
toxicity (particularly from vincristine) may be more significant.
High-dose dexamethasone is safe and effective, and is usually the
treatment of choice in patients with compromised renal function.
Thalidomide is another reasonable option; either by itself or in
combination with corticosteroids.
High-dose therapy and transplantation: High-dose therapy and
autotransplantation, which is effective in patients without renal
failure, is feasible in patients with renal failure too since melphalan
pharmacokinetics are not significantly affected by renal failure.
Adequate data exist to show that autografting is reasonably safe in
patients with renal failure. However, overall toxicity is higher than in
patients with normal renal function. High-dose therapy therefore
ought to be used judiciously in patients with renal failure; particularly
older individuals, those with concomitant medical problems, and
those who are already in complete remission. The place of tandem
transplantation, already debatable in myeloma, is questionable in
patients with renal failure.
Non-myeloablative allogeneic hematopoietic stem cell
transplantation is feasible in myeloma patients with renal failure.
However, in view of a 20% risk of treatment-related mortality, it
should only be undertaken in patients with high-risk disease.
Role of renal transplantation: Because myeloma is considered
incurable, myeloma patients can almost never qualify for a
cadaveric renal allograft. However, a renal allograft from a living
(usually related) donor is feasible. This should only be
undertaken only in patients who are in complete remission and
have disease that is expected to remain under control for a
reasonable period of time based upon its biological features. An
attractive possibility is a hematopoietic stem cell and a renal
allograft from the same donor (an HLA-identical sibling) which
could cure myeloma while inducing specific transplantation
tolerance.
P9.3
NEW ADVANCES IN THE USE OF BISPHOSPHONATES
IN MYELOMA.
James R. Berenson, MD
Director of the Myeloma and Bone Metastasis Programs at
Cedars-Sinai Medical Center
Recent large placebo-controlled clinical trials have shown the
efficacy of bisphosphonates in reducing skeletal complications in
myeloma patients, and suggested that these agents may also alter
the overall course of the disease. Large randomized trials of
long-term bisphosphonate use have now been published, and
involved evaluation of oral administration of daily etidronate,
clodronate, or pamidronate or intravenously administered
pamidronate, ibandronate or zoledronic acid.
In the Canadian study involving daily oral etidronate compared to
placebo for newly diagnosed myeloma patients who also received
oral melphalan and prednisone, there was no difference was
found between the two arms. Similarly, the other outcome
measures (new fractures, hypercalcemic episodes, and bone pain)
showed no differences between the two arms.
Two large randomized, double-blind trials have been published using
oral clodronate in myeloma patients. In the Finnish trial, 350
previously untreated patients were entered, and 336 randomized to
receive either clodronate (2.4 g) or placebo daily for 2 years.
Although the proportion of patients with progression of lytic lesions
was less in the clodronate treated group (12%) than in the placebo
group (24%), the progression of overall pathological fractures, as
well as both vertebral and non-vertebral fractures, was not different
between the arms. The Medical Research Council has published the
results of a large randomized trial involving 536 recently diagnosed
myeloma patients randomized to receive either oral clodronate 1.6 g
or placebo daily in addition to alkylator-based chemotherapy. After
combining the proportion of patients developing either non-vertebral
fractures or severe hypercalcemia including those leaving the trial
due to severe hypercalcemia, there were less clodronate-treated
patients experiencing these combined events than placebo patients.
However, the number of patients developing hypercalcemia was
similar between the two arms. The number of patients experiencing
non-vertebral and vertebral fractures was lower in the clodronate
group. The proportion of patients requiring radiotherapy was similar
between the two arms. There was no difference in time to first
skeletal event or overall survival.
In a double blind randomized trial, a Danish-Swedish cooperative
group evaluated daily oral pamidronate (300 mg/day) compared
to placebo in 300 newly diagnosed myeloma patients also
receiving intermittent melphalan and prednisone. After a median
duration of 18 months, there was no significant reduction in the
primary endpoint defined as skeletal-related morbidity (bone
fracture, surgery for impending fracture, vertebral collapse, or
increase in number and/or size of lytic lesions), hypercalcemic
episodes, or survival between the arms.
A large randomized, double-blind study was conducted to determine
whether monthly 90 mg infusions of pamidronate compared to
placebo for 21 months reduced skeletal events in patients with
multiple myeloma who were receiving chemotherapy. Patients were
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