Page 1575 - Hematology_ Basic Principles and Practice ( PDFDrive )

1402 Part VII Hematologic Malignancies

years for solitary bone plasmacytoma as compared with median age paved the way for this improved outcome. This includes (1) tradi-
of onset at 71 years for MM in the National Cancer Institute Surveil- tional chemotherapy agents targeting the DNA, including melphalan,
lance, Epidemiology, and End Results program (SEER) data. The cyclophosphamide, doxorubicin, bendamustine, etoposide, and cis-
incidence of solitary plasmacytoma increased by 10% in 1999–2004 platin; (2) immunomodulatory drugs thalidomide, lenalidomide, and
relative to 1992–2008, whereas the incidence of MM declined by 3% pomalidomide; (3) proteasome inhibitors bortezomib, ixazomib, and
during the same period. carfilzomib; (4) the HDAC inhibitor panobinostat; and (5) mono-
Patients presenting with solitary plasmacytomas require a com- clonal antibodies elotuzumab and daratumumab. There has been
plete workup to confirm the diagnosis. They should undergo serum progress in understanding the biology of the disease. In every patient,
protein electrophoresis, serum immunofixation, serum free light there are multiple clones (three to five) at the time of diagnosis, as
chain assay, urine protein electrophoresis, urine immunofixation, a well as ongoing mutations during the course of the illness, and
diagnostic bone marrow aspiration and biopsy with flow cytometry recurrences are caused by expansion of different clones (clonal tides)
to detect clonal plasma cells, and detailed skeletal imaging that should over time. Therefore combination therapy that includes drugs from
include either PET-CT or a skeletal survey and MRI of the spine and different classes is likely to be more successful in eradicating the
pelvis. One-third of the patients may present with a detectable tumor. Achieving deep remission (CRs) predicts a better PFS. In
monoclonal paraprotein in the serum or urine or both. Persistence of addition, treatment should be tailored to tumor genetics, the age and
the monoclonal paraprotein after local treatment is predictive of a frailty of the patient, comorbidities, and renal impairment.
recurrence of MM. Patients with less than 10% plasma cells in the
bone marrow biopsy may be managed with therapies directed against
the solitary lesion initially. However, these patients will also progress TREATMENT OF NEWLY DIAGNOSED MYELOMA
to MM over the subsequent years of follow-up.
Solitary plasmacytomas are generally treated with local radiation Chemotherapy With Stem Cell–Sparing Agents
therapy at a dose of 40–50 Gy. Depending upon the location, small
extramedullary soft tissue plasmacytomas may be treated with excision Patients considered for stem cell harvest are generally treated with
biopsy alone. Solitary plasmacytomas of the bone may require surgical combinations that are stem cell sparing. Before immunomodulatory
intervention for stabilization followed by local radiation therapy. agents and proteasome inhibitors became widely available, patients
The disease-free survival at 10 years is 63% for patients with soli- were treated with pulse dexamethasone alone or in combination with
tary plasmacytomas. The disease-specific survival seems to plateau at vincristine and adriamycin (VAD) and cyclophosphamide (CVAD or
about 80% for extramedullary plasmacytomas, compared with 50% CVAMP; methylprednisolone substituted for dexamethasone). For
for solitary bone plasmacytomas. Less than one-third of solitary more information, see box on Treatment of Newly Diagnosed Mul-
extramedullary plasmacytoma patients died as a result of myeloma, tiple Myeloma.
as compared with 58% of the patients with solitary bone plasmacy-
tomas. Progression to myeloma generally occurs within 5 years from
initial diagnosis. Patients presenting with medullary plasmacytomas, Dexamethasone
patients with persistence of a monoclonal paraprotein after treatment
for the solitary plasmacytoma, patients with detectable low levels of Glucocorticoids induce apoptosis in myeloma cells. Glucocorticoids
clonal plasma cells in the bone marrow, patients between 40 and 60 induce IκB production, which then sequesters NFκB, resulting in
years of age, and patients of African American descent are at higher downregulation of IL-6 and other inflammatory cytokines. Dexa-
risk for progression to MM. These patients should be followed closely methasone 40 mg is administered in a pulsed fashion for 4 days,
for the next 5 years. starting on days 1, 9, and 17 for the first cycle. Some researchers have
used this dose and schedule every 35 days, whereas others have given
dexamethasone on days 1–4, every other cycle, on a 28-day schedule.
Symptomatic Myeloma Results achieved with pulsed dexamethasone alone compare well with
those of VAD chemotherapy, and MP, with equivalent response rates
Patients presenting with symptoms caused by the myeloma tumor and OS. Single-agent dexamethasone is no longer advocated as a
mass, such as anemia, lytic bone disease, hypercalcemia, or renal treatment for newly diagnosed MM. However, under selected clinical
impairment (CRAB), require systemic therapy. Myeloma-defining situations, the use of pulsed dexamethasone is helpful in specific situ-
events that warrant systemic therapy include a clonal bone marrow ations, including severe spinal cord compromise, hypercalcemia, and
plasma cell percentage (aspirate or biopsy, whichever is higher) 60% acute renal failure caused by light chain nephropathy. While patients
or above, elevated serum free light chain 100 mg/L or greater associ- are on intensive dexamethasone, close monitoring for hyperglycemia
ated with involved/uninvolved free light chain ratio ≤100, and/or and antibiotic and prophylaxis against bacterial, Pneumocystis carinii
more than one focal lesions on MRI studies. In addition, patients pneumonia, and fungal infections are recommended. Weight gain,
with a low tumor mass but with organ dysfunction caused by a mood swings, insomnia, fluid retention, proximal myopathy, and
paraprotein or immunodeficiency such as monoclonal immunoglobu- steroid-induced psychosis are known side effects. Cataracts, osteopo-
lin deposition disease or amyloidosis of an organ, progressive periph- rosis, and avascular necrosis of the hips are some of the long-term
eral neuropathy, two are more serious infections (pneumonia, consequences of steroid exposure.
bacteremia) that require treatment. Related organ or tissue impair-
ment also warrants initiation of systemic therapy. 20
Front-line therapy for MM is often predicated on whether the Vincristine, Adriamycin, and Dexamethasone
patient is eligible, willing, and able to proceed with HDT and stem
cell transplant. The treatment given before stem cell harvest and Infusional therapy with vincristine and doxorubicin (Adriamycin)
transplant is called induction therapy followed by consolidation with with pulsed dexamethasone is an effective stem cell–sparing induc-
HDT and stem cell rescue. Patients not embarking on HDT are tion regimen. Vincristine and doxorubicin are administered by con-
2
started on initial therapy for 9–18 months. Both groups of patients tinuous infusion at doses of 0.4 mg/day and 9 mg/m /day along with
may subsequently receive maintenance therapy. oral dexamethasone 40 mg/day for 4 days. Following six to nine
cycles of VAD chemotherapy, the overall response rate (ORR) is 45%
to 55%, and the CR rate is less than 5%. There are no differences in
Induction Regimen/Initial Treatment the median PFS (18 months) or OS (3 years) from those achieved
with standard alkylating agent treatments (MP, VMCP/VBAP,
Tremendous progress has been made in the treatment of MM, with VBMCP). However, if the induction therapy is followed by consoli-
improvement in life expectancy. The availability of new drugs has dation with high-dose melphalan and autologous stem cell transplant,