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1756 Part XI: Malignant Lymphoid Diseases Chapter 107: Myeloma 1757

Reduced-intensity conditioning regimens were introduced to pamidronate and zoledronic acid, inhibit osteoclast activity and can
reduce transplantation-related mortality and extend the age limit for palliate pain and prevent bone-related complications. 219,526,527 Hyper-
allografting. 504–509 Autografting has been performed prior to nonmye- calcemia is associated with increased bone resorption in myeloma, and
loablative transplantation by several investigators, demonstrating the bisphosphonates also play a key role in the treatment of hypercalcemia.
feasibility of this approach to cytoreduce tumor and then enhance Zoledronic acid, which is more potent than pamidronate, is superior to
antimyeloma immunity. 510,511 Bruno and colleagues published a pro- pamidronate for the treatment of hypercalcemia. 528
spective trial of initial autologous SCT followed by mini-allogeneic The International Myeloma Working Group (IMWG) and the
transplantation versus double autologous transplantation. 512,513 The National Comprehensive Cancer Network (NCCN) panels advocate the
median OS was 80 months for allografting versus 54 months for dou- use of either pamidronate or zoledronic acid monthly for patients with
ble autografting. The CR rate after allografting was 55 percent versus myeloma and lytic bone disease. Both pamidronate and zoledronic acid
26 percent after double autograft. In contrast, a randomized trial in are considered equally effective in reducing skeletal complications. 529,530
high-risk myeloma showed that the combination of autologous SCT These guidelines recommend the use of pamidronate at 90 mg delivered
followed by dose-reduced allogeneic transplantation (IFM 99–03) was intravenously for at least 4 hours or zoledronic acid at 4 mg intrave-
514
not superior to tandem autotransplant (IFM 99–04). BMT CTN nously for 15 minutes every 3 to 4 weeks for patients with myeloma and
0102, also evaluated autologous SCT followed by second autologous lytic bone disease.
versus nonmyeloablative allogeneic SCT. In both standard- and high- In addition to playing an important supportive role, bisphos-
risk patients, nonmyeloablative allogeneic HSCT after auto-HSCT was phonates may have a direct antitumor effect. The MRC Myeloma IX
not more effective than tandem auto-HSCT. 515,516 Bjorkstand and col- trial compared zoledronic acid to oral clodronic acid and found that
leagues conducted a prospective study of single or tandem autologous zoledronic acid reduced mortality by 16 percent and increased median
531
SCT versus reduced-intensity allogeneic SCT based on availability of an OS from 44.5 months to 50 months. The benefit of zoledronic acid
human leukocyte antigen (HLA)-identical sibling. Long-term followup on skeletal morbidity was also seen in patients without bone lesions at
of 357 patients who received either autologous SCT (single or double) baseline. 532
or autologous–allogeneic with HLA-identical sibling matched donor A key concern with bisphosphonates, especially zoledronic acid, is
533
demonstrated that PFS was superior (35 percent versus 18 percent; the risk of osteonecrosis of the jaw (ONJ). In the MRC Myeloma IX
p = 0.001) at 60 months for those receiving an autologous–allogeneic trial, the rate of ONJ was 4 percent. Attention to dental hygiene and
531
tandem transplantation. Nonrelapse mortality was 12 percent after minimizing invasive procedures may reduce the risk of ONJ. 534
autologous–allogeneic versus 3 percent in the autologous group Denosumab is a monoclonal antibody to RANK ligand that also
(p <0.001) and the incidence of limited to extensive graft-versus-host inhibits osteoclasts; it showed promising activity in myeloma in a
disease (GVHD) was 31 percent and 23 percent. 517 phase II trial. Although denosumab was superior to zoledronic acid
188
The use of allogeneic transplantation as salvage therapy, while in patients with solid tumors and bone metastases, denosumab was
feasible, is unlikely to be of significant benefit in a heavily pretreated inferior in a subset analysis of myeloma patients in a phase III trial.
187
population. The EBMT reported on the outcomes of 229 patients who However, interpretation is limited based on the small numbers in the
received reduced-intensity conditioning allogeneic SCT. Transplant-re- trial. A larger phase III study (NCT01345019) focusing on patients with
lated mortality at 1 year was 22 percent and 3-year OS and PFS were myeloma is ongoing.
41 percent and 21 percent, respectively, with 25 percent of patients Vertebroplasty (injection of methyl methacrylate or bone cement)
developing extensive chronic GVHD. The best outcomes were seen in and kyphoplasty (use of an inflatable balloon followed by instillation
518
patients who received a transplant in remission and early in the course of bone cement) are percutaneous procedures for treating compression
of the disease. Adverse OS was associated with chemoresistant disease, fractures, and have also been used in the setting of myeloma. 535,536
transplantation more than 1 year after diagnosis, and in male patients
transplanted with female donors. Palliative Radiation Therapy
In patients whose disease does not respond to or relapses after Radiation also plays a key role for palliation of painful bony lesions in
allogeneic SCT, donor lymphocyte infusion (DLI) can be considered. myeloma. An estimated 38 percent of patients are expected to receive
Molecular remissions are more common after allografting than after radiation over the course of their illness. The primary indication for
537
autografting, 492,519–521 and DLI can treat relapsed myeloma post allograft- the use of radiation therapy is palliation of bone pain. Other indications
ing, 490,522,523 indicating a clinically significant GVM effect. In an effort include impending fracture, cord compression, or relief of symptoms
to reduce toxicity and exploit GVM, CD4+ DLI have been used at 6 associated with a mass (i.e., cranial nerve palsies, cosmesis or organ or
months post–CD6-depleted marrow allografting so as to enhance GVM joint dysfunction). Doses of 20 to 35 Gy can be used, but it is essential to
524
and thereby improve outcome. Although prophylactic DLI induces consider ability to retreat when designing treatment fields, particularly
significant GVM responses after allogeneic marrow transplantation, of the spine. Doses of 20 Gy, delivered in either 5 or 10 fractions, typi-
only 58 percent of patients were able to receive DLI despite T-cell– cally provide adequate symptom relief.
depleted marrow transplantation.
Allografting should only be undertaken in the context of clin- EMERGENT COMPLICATIONS OF NEW
ical trials, which aim to reduce chronic GVHD, separate GVM from
GVHD, and amplify the GVM effect to improve outcome by amelio- MYELOMA THERAPY
rating toxicity and maximizing the antimyeloma effect of immunologic Venous Thromboembolism
effector cells. 525 Patients with myeloma are at an increased risk for deep vein thrombo-
sis and pulmonary embolism, particularly when known risk factors are
432
ADJUNCTIVE THERAPIES present (history of VTE, immobilization, dehydration, other factors).
Genetic predispositions include high levels of homocysteine and defi-
Bone Disease ciencies of antithrombin, protein C, and protein S, as well as muta-
Bone involvement is one of the defining characteristics of myeloma, tions that predispose to thrombosis, such as the factor V Leiden allele
either as lytic lesions or diffuse osteopenia. Bisphosphonates, such as and/or the prothrombin gene G20210A allele. Genetic abnormalities

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