National Comprehensive Cancer Network

Clinical Recommendations

JNCCN – The Journal of the National Comprehensive Cancer Network

Table of Contents - Volume 7, Number 9 October 2009

• NCCN Clinical Practice Guidelines in Oncology™
• Multiple Myeloma
• Chronic Myelogenous Leukemia
• Featured Articles
• Novel Therapies in the Treatment of Multiple Myeloma
• Hematopoietic Stem Cell Transplantation in Multiple Myeloma
• Supportive Therapies in Multiple Myeloma
• New Agents in the Treatment of CML

NCCN Clinical Practice Guidelines in Oncology™

Multiple Myeloma

Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. The American Cancer Society estimates that 20,580 new cancer cases of MM will occur in the United States in 2009, including 11,680 cases in men and 8900 cases in women, with an estimated 10,580 deaths. The mean age of affected individuals is 62 years for men (75% > 70 years) and 61 years for women (79% > 70 years). The treatment for MM has dramatically improved over the past decade. MM is typically sensitive to various cytotoxic drugs, both as initial treatment or as treatment of relapsed disease. Unfortunately responses are transient, and MM is not considered curable with current approaches. These guidelines address diagnosis, treatment, and follow up for MM, systemic light chain amyloidosis, and the related Waldenström’s macroglobulinemia.

Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) accounts for 15% of adult leukemias. The median age of disease onset is 67 years; however, CML occurs in all age groups. In 2009, an estimated 5050 cases will be diagnosed and 470 patients will die of the disease in the United States. CML occurs in 3 difference phases (chronic, accelerated, and blast phase), but is usually diagnosed in the chronic phase. Untreated chronic-phase CML will eventually progress to advanced-phase disease in 3 to 5 years. The development of imatinib mesylate, a potent and specific inhibitor of the bcr abl tyrosine kinase, has revolutionized the treatment of CML. Allogeneic hematopoietic stem cell transplant (HSCT) is indicated only for patients with inadequate or no responses to imatinib therapy and those whose disease progresses on imatinib. For most patients, a trial of dasatinib or nilotinib is reasonable before proceeding to allogeneic HSCT. Tyrosine kinase inhibitor (TKI) treatment options for CML depend on the stage of the disease, and the agent’s side effect profile and its relative effectiveness against BCR ABL mutations. Availability of more potent TKIs has widened the treatment options for CML and the outlook for patients with CML continues to look promising. These guidelines discuss the clinical management of chronic and advanced phases of CML and monitoring response to treatment.

Featured Articles

Novel Therapies in the Treatment of Multiple Myeloma
Jacob P. Laubach, MD, MPP; Constantine S. Mitsiades, MD, PhD; Anuj Mahindra, MD; Robert L. Schlossman, MD; Teru Hideshima, MD, PhD; Dharminder Chauhan, PhD; Nicole A. Carreau; Irene M. Ghobrial, MD; Noopur Raje, MD; Nikhil C. Munshi, MD; Kenneth C. Anderson, MD; and Paul G. Richardson, MD

Multiple myeloma (MM) used is a clonal B-cell malignancy characterized by aberrant expansion of plasma cells within the bone marrow, and extramedullary sites. In 2008, 19,920 new cases of MM and 10,690 deaths from the disease occurred in the United States. Treatment traditionally consists of systemic chemotherapy, with adjunctive use of radiation or surgery in selected cases associated with extramedullary disease. The therapeutic landscape in MM has changed markedly in the past decade with the introduction of the novel immunomodulatory agents (IMiDs) thalidomide and lenalidomide, and the first-in-class proteasome inhibitor bortezomib. Although MM remains an incurable malignancy, new approaches to therapy incorporating these agents have produced significantly higher response rates and improved intervals of both progression-free and overall survival in the context of randomized, controlled trials. In aggregate, the use of novel therapies in MM has been associated with substantial improvements in patient outcome. The 2009 NCCN Clinical Practice Guidelines for the treatment of MM reflect the promising results associated with therapies incorporating thalidomide, lenalidomide, and bortezomib. These guidelines include various regimens incorporating novel agents in combination with dexamethasone, conventional chemotherapeutic agents, and other novel agents.

Hematopoietic Stem Cell Transplantation in Multiple Myeloma
Jean-Luc Harousseau, MD

The introduction of novel agents (thalidomide, bortezomib, lenalidomide) is changing the management of patients with multiple myeloma who are candidates for stem cell transplantation. Bortezomib-dexamethasone given as induction treatment before autologous stem cell transplantation is significantly superior to the classical vincristine-doxorubicin-dexamethasone regimen in terms of complete response and very good partial response, both before and after transplantation. Triple combinations with thalidomide and bortezomib plus either cyclophosphamide or doxorubicin also yield excellent response rates, with the combination of bortezomib with thalidomide and dexamethasone seeming to be the most promising. The addition of novel agents before and after autotransplant yields a very high complete response rate and prolonged progression-free and overall survival. However, outstanding results have also been achieved with novel agents without transplantation. Therefore, randomized trials comparing novel agents with and without early transplantation are awaited.

Supportive Therapies in Multiple Myeloma
Charise Gleason, NP; Ajay Nooka, MD, MPH; and Sagar Lonial, MD

The outlook for patients with myeloma has improved dramatically over the past few years, largely because of improvements in supportive care, the use of high-dose therapy, and the introduction of the novel agents thalidomide, bortezomib, and lenalidomide. These new treatment options have changed the natural history for patients with myeloma, but clinicians must consider treatment-related toxicities. Some of the most common short- and long-term toxicities include the development of peripheral neuropathy, hematologic complications, thrombosis, and bone-related complications, such as fracture and osteonecrosis of the jaw. Careful consideration of patient-reported symptoms and appropriate dose modification or prophylaxis to prevent the development of toxicity are critical, and will result in improved quality of life and better tolerance of delivered therapy.

New Agents in the Treatment of CML
Javier Pinilla-Ibarz MD, PhD, and Alfonso Quintás-Cardama, MD

The discovery of molecularly targeted agents that selectively inhibit bcr-abl tyrosine kinase activity, such as imatinib, has revolutionized the treatment and natural history of chronic myelogenous leukemia (CML). Patients with CML can now expect excellent long-term survival, often without major side effects. In most patients, however, residual leukemic burden remains detectable. In addition, many patients undergoing imatinib therapy either will not respond or will lose their response over time because of resistance or intolerance. The introduction of second-generation TKIs reestablishes response in approximately half of these patients. Several agents are being developed for treating patients who experience suboptimal response to second-generation TKIs and for those who develop resistance caused by the emergence of highly resistant BCR-ABL1 mutations. This article provides an overview of novel targeted agents available for CML.