May 18, 2010
Trio of drugs makes major mark against multiple myeloma
Trial results show that a new three-drug regimen reduces multiple myeloma by more than 90 percent in some patients. The treatment is based on research by a team in Paul Richardson's (center, seated) lab. Initial results of a novel three-drug combination therapy in
patients with multiple myeloma have been so encouraging that
researchers believe the treatment may delay the need for a stem
cell transplant in some cases, Dana-Farber investigators reported
in a recent paper.
When used together, the three agents – lenalidomide, bortezomib,
and dexamethasone – trigger protein circuits within myeloma cells
that cause the cells to die. The drugs boost one another's effect
against myeloma cells themselves and the surrounding tissue. In the study, posted online by the journal Blood, every patient
who received the combination had a significant reduction in the
extent of cancer in his or her body.
"The rate and quality of response to this combination is
unprecedented for newly diagnosed myeloma patients," says the
study's lead author, Paul Richardson, MD, of Medical Oncology.
"We're especially encouraged that it produced responses in patients
regardless of chromosomal differences in their myeloma cells, was
very active in both older and younger patients, and was generally
well tolerated."
The standard treatment for patients newly diagnosed with
multiple myeloma – a highly malignant and incurable blood cancer
which arises in the bone marrow – has been conventional
chemotherapy, either to control the disease or to prepare younger
patients for a stem cell transplant.
In recent years, the introduction of novel agents like
bortezomib, which shuts down a vital "garbage disposal" system in
cancer cells, as well as thalidomide and lenalidomide, which
influence the immune system's attack on disease and affect the
tumor and its surroundings, have dramatically increased survival
rates of myeloma patients.
The new study involved a phase I and II clinical trial to
determine the safety, proper dosage, and effectiveness of the
three-drug regimen in 68 newly diagnosed myeloma patients.
Participants received eight, three-week cycles of lenalidomide,
bortezomib, and dexamethasone on an outpatient basis, followed by
maintenance therapy, and were followed for at least the next two
years.
While all patients had at least a partial response to the
therapy, meaning a greater than 50 percent decrease in the extent
of their disease, a striking 74 percent of those who completed the
phase II portion of the trial had at least a "very good partial
response," meaning a greater than 90 percent reduction in disease.
Of these patients, 52 percent achieved a complete response. The
results were lasting as well; 18 months after completing the first
phase of the trial, 75 percent of the patients remained in
remission and 97 percent were alive.
Although most patients experienced side effects from the
treatment, these proved relatively mild and reversible. Eighty
percent of participants experienced neuropathy, including tingling
or numbness in their extremities; 64 percent felt fatigue; 14
percent had a reduction in the number of circulating lymph cells; 9
percent had a decline in the number of white blood cells called
neutrophils; and 6 percent had clots form in blood vessels. No
patients died as a result of the treatment.
"This combination enabled us to keep the option of stem cell
transplantation in reserve for a number of patients in the trial,"
Richardson states. "With early follow-up, we saw no difference in
progression-free survival [patients living with no worsening of
their disease] in those who went on to receive a stem cell
transplant versus in those who did not. In addition, while the
numbers are small, patients whose chromosome abnormalities usually
indicate a poorer response to treatment did as well as those
without them."
While the new study is cause for optimism, no definite
conclusions can be drawn until the three-drug regimen proves itself
in a phase III trial involving many hundreds of patients,
Richardson cautions. That trial opens this summer. When completed,
it will help researchers determine which patients benefit the most,
and the least, from the three-drug therapy, and which can therefore
defer the need for a stem cell transplant until later in their
course of treatment, or should have it performed early.
Other Dana-Farber authors of the study include senior author Ken Anderson, MD, and co-authors Edie Weller, PhD; Wanling Xie; Irene
Ghobrial, MD; Robert Schlossman, MD; Nikhil Munshi, MD; Deborah
Doss, RN, OCN; Diane Warren; Laura Lunde; Teru Hideshima, MD, PhD;
and Constantine Mitsiades, MD, PhD.
– Rob Levy
Robert_Levy@dfci.harvard.edu