Page 1585 - Hematology_ Basic Principles and Practice ( PDFDrive )

1412 Part VII Hematologic Malignancies

TABLE Randomized Studies Comparing Maintenance Therapy in Myeloma
86.22
Authors/Study Regimen PFS (Median Mo) OS (Median Mo)
Spencer et al Control vs. thalidomide/prednisone 23 vs. 42 (p < .001) 75 vs. 86 (p = .004)
Barlogie et al Control vs. thalidomide 44% vs. 57% (p = .01) Not reached
a
Attal et al Control vs. thalidomide + pamidronate 36 vs. 52 77 vs. 87
(p = .009) (p = .04)
Attal et al Control vs. lenalidomide 24 vs. NA (p < .0001) 80% vs. 88%
b
Palumbo et al MPRR vs. MPR Not reached vs. 13.2 (p = .002) Not reached
c
McCarthy et al Control vs. lenalidomide Not reached vs. 25.5 (p < .001) Not reached
Mateos et al VP vs. VT 32 vs. 24 (p = .01) Not reached
a 5-year PFS rate.
b Survival after 3 years.
c Time to progression.
MPR, Melphalan-prednisone-lenalidomide; MPRR, melphalan-prednisone-lenalidomide followed by lenalidomide maintenance; NA, not available; OS, overall survival;
PFS, progression-free survival; VP, bortezomib-prednisone; VT, bortezomib-thalidomide.

had an intensive therapy arm (stem cell transplant) and a nonintensive proteasome inhibitors, and glucocorticoids) and progressing during
arm (no stem cell transplant); once the patients had completed the the last line of therapy. These patients have a life expectancy less than
intensive or nonintensive treatment arm, they were randomized to 1 year.
receive thalidomide maintenance or no maintenance. There was There are several considerations in choosing the treatment for
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improvement in PFS but no improvement in OS when the two patients with relapsed myeloma. These include disease-related
groups were compared. Results of major randomized studies evaluat- factors such as slow, indolent, or single site of relapse or rapid and
ing maintenance therapy are summarized in Table 86.22. multiple sites of relapse. Patients with a single site of relapse may
There have been three large randomized trials exploring the role benefit from radiation treatment. Special considerations need to be
of lenalidomide as maintenance therapy. Two of these studies were given to patients presenting with extramedullary soft tissue plasma-
maintenance therapy after autologous stem cell transplant (CALGB cytomas, CNS relapses, or plasma cell leukemia. Patients presenting
and IFM), and the third study was in elderly patients receiving MP. with an elevated LDH, high β 2 -microglobulin, del(17p), and multiple
All three studies showed improvement in PFS by 18 months; only copies of 1q generally have a poor prognosis. Patients presenting with
the CALGB study showed improvement in OS. There appears to be advanced age, poor performance status, renal impairment, and poor
a slightly increased risk of occurrence of a second malignancy when hematologic reserve or concurrent myelodysplastic syndrome from
lenalidomide is administered along with melphalan immediately after prior therapy present a great challenge. The choice of treatment is
HDT with melphalan. Lenalidomide therapy is also unable to alter also predicated on prior drug exposure, whether the relapse is on or
the poor prognosis attributed to adverse cytogenetics or FISH results. off therapy, and ongoing toxicity from prior therapy. For more
Bortezomib has also been used in the maintenance setting. Gener- information, see box on Treatment of Relapsed Multiple Myeloma.
ally, bortezomib maintenance has been restricted to clinical trials in
which bortezomib was also used during the induction phase of the
treatment. Bortezomib maintenance seemingly improved the outcome Thalidomide
in patients with high-risk cytogenetics or FISH results. Bortezomib
is given less frequently in the maintenance setting; different studies Thalidomide monotherapy was originally introduced for the treat-
have used different schedules of administration. ment of advanced and refractory myeloma. In the initial phase II trial,
thalidomide was administered at 200 mg daily with increments every
2 weeks up to 800 mg for 169 patients. A partial response or better
RELAPSED DISEASE was noted in 30% of patients with a 2-year EFS of 20% and OS of
48%. A phase III trial (OPTIMUM) compared dexamethasone with
Relapse is defined as reappearance of signs and symptoms of the thalidomide monotherapy at 100 mg, 200 mg, and 400 mg daily
disease or signs of increasing disease and/or end-organ dysfunction doses. The median times to progression were 6, 7, 8, and 9.1 months,
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that are related to the underlying myeloma. Patients presenting with respectively. The response rates and the median survival were similar
a symptomatic relapse require treatment intervention. Patients with in all treatment groups. In a systematic review published by Glasm-
rapidly rising paraprotein, doubling of the paraprotein within a short acher, partial responses or better in 30% of relapsed patients with
interval, also require treatment. Patients with asymptomatic bio- 1-year survival of 60% were reported. Thalidomide has been com-
chemical relapse do not require treatment. Generally, serum M spike bined successfully with other conventional chemotherapy agents as
greater than 1 g/dL, Bence Jones proteinuria greater than 500 mg per well as proteasome inhibitors for improved response rates and better
day, or serum free light chain level greater than 200 mg/L would be disease control. Thalidomide is especially useful when a patient pre-
a minimum requirement to consider intervention with systemic sents with renal impairment and cytopenias. It is also useful for
therapy. Occasionally, myeloma cells may become dedifferentiated or palliation when combined with oral cyclophosphamide and predni-
anaplastic and may produce only light chain components (Bence sone in patients with a poor performance status.
Jones escape phenomenon) or no paraprotein at all. These patients
generally tend to have a more aggressive clinical course. The develop-
ment of compression fractures and fractures at a site of previous lytic Lenalidomide
lesion per se does not constitute progression of myeloma. Develop-
ment of hypercalcemia, progressive anemia, and new or worsening In two large phase III randomized trials (MM 009, MM 010),
kidney function would merit prompt treatment intervention. lenalidomide and dexamethasone was found to be superior to dexa-
Currently, relapsed and refractory disease is defined as having methasone in patients with relapsed myeloma after one to three lines
failed three or more lines of prior therapy with previous exposure to of prior therapy. Updated results with a median follow-up of 48
all four classes of drugs (cytotoxic agents, immunomodulatory agents, months showed an ORR of 61%, median time to progression of 13.4