Multiple Myeloma

World-renowned thought leaders discussed important clinical advances and new guidelines in the diagnosis and treatment of hematologic malignancies, at the first annual National Comprehensive Cancer Network (NCCN) Hematologic Malignancies Congress.

Multiple myeloma is now the most common indication for autologous stem cell transplantation (ASCT) in North America, with over 5,000 transplants performed yearly (Center for International Blood and Marrow Transplant Research [CIBMTR] data). While the role of ASCT as initial therapy in multiple myeloma has been established by randomized studies, newer therapies are challenging the traditional paradigm. The availability of novel induction agents and newer risk stratification tools, and the increasing recognition of durability of remissions are changing the treatment paradigm. However, even with arduous therapy designed to produce more complete remissions—for example, tandem autologous transplants—we have seen no plateau in survival curves. A tandem autologous procedure followed by maintenance therapy may be performed in an attempt to sustain remission. Sequential autologous transplants followed by nonmyeloablative allotransplants are pursued with the hope of "curing" multiple myeloma. We examine how the key challenges of increasing the response rates and maintaining responses are being addressed using more effective induction and/or consolidation treatments and the need for maintenance therapies after ASCT. We argue that given the biologic heterogeneity of multiple myeloma, risk-adapted transplant approaches are warranted. While the role of curative-intent, dose-intense toxic therapy is still controversial, conventional myeloablative allogeneic transplants need to be reexamined as an option in high-risk aggressive myeloma, given improvements in supportive care and transplant-related mortality.

The combination of lenalidomide (Revlimid) with melphalan and prednisone (R-MP) is highly active and well tolerated in older adults with newly diagnosed multiple myeloma.

The addition of bortezomib (Velcade) to tandem transplantation as upfront therapy for multiple myeloma is safe and associated with high rates of complete and near complete response

Patients with newly diagnosed multiple myeloma have better progression-free survival with the combination of thalidomide (Thalomid) and dexamethasone (Thal/Dex) than Dex alone

Patients with relapsed or refractory multiple myeloma have a higher response rate and longer time to progression when lenalidomide (Revlimid) is added to dexamethasone (Len/Dex), regardless of prior thalidomide (Thalomid).

Elderly patients with newly diagnosed multiple myeloma are likely to survive nearly 2 years longer if thalidomide (Thalomid) is added to the standard melphalan/prednisone (MP) regimen, and they may gain about 10 months longer progression-free survival (PFS),

The FDA has approved Celgene's Supplemental New Drug Application for Revlimid (lenalidomide) in combination with dexamethasone (Rev/Dex) for the treatment of multiple myeloma patients who have received at least one prior therapy.

Thalidomide (Thalomid) has "changed the paradigm" for treating multiple myeloma, and advances in understanding the relationship between myeloma cells and the bone marrow microenvironment promise to change it even more, Kenneth C. Anderson, MD, of the Dana-Farber Cancer Institute, said at the National Comprehensive Cancer Network (NCCN) 11th Annual Conference.

During the past 18 months, researchers have developed substantial evidence supporting the notion that stem cells play a critical role in the development of at least some cancers, their progression, and the prognosis of patients, including breast, brain, lung, and prostate cancer, multiple myeloma, and melanoma.

For patients with refractory or relapsed multiple myeloma, a lower dose of thalidomide (100 mg/d) offers similar efficacy to the higher dose (400 mg/d), but with fewer side effects. Ibrahim Yakoub-Agha, MD, of CHRU Lille, France, reported the results of IFM-01-02 at the 47th Annual Meeting of the American Society of Hematology (abstract 364), for the Intergroupe Francophone du Myelome.

The FDA has given priority review status to Celgene Corporation's supplemental new drug application for lenalidomide (Revlimid) in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma.

Keryx Biopharmaceuticals, Inc. has initiated a clinical program to evaluate KRX-0401 (perifosine) for the treatment of multiple myeloma.

A trial of melphalan (Alkeran)/prednisone plus thalidomide in newly diagnosed elderly patients with multiple myeloma suggests that the oral regimen should be the reference treatment for patients in this population who are ineligible for high-dose therapy, according to Thierry Facon, MD, Inter-Groupe Francophone du Myelome (IFM), Lille, France.

Combination therapy with lenalidomide (Revlimid) plus dexamethasone (Len/Dex) appears to provide a survival advantage over dexamethasone alone in patients with relapsed or refractory multiple myeloma, according to a study presented at the 2005 annual meeting of the American Society of Hematology (abstract 6).

In 2004, multiple myeloma was diagnosed in more than 15,000 peoplein the United States and will account for approximately 20% of deathsdue to hematologic malignancies. Although traditional therapies suchas melphalan (Alkeran)/prednisone, combination chemotherapy withVAD (vincristine, doxorubicin [Adriamycin], and dexamethasone), andhigh-dose chemotherapy with stem cell transplantation have shownsome success, median survival remains between 3 to 5 years. Treatmentoptions for patients with multiple myeloma have increased in recentyears, with the promise of improvement in survival. New agents, suchas the proteasome inhibitor bortezomib (Velcade), the antiangiogenicand immunomodulator thalidomide (Thalomid) and its analogs, suchas lenalidomide (Revlimid), together with other small molecules, includingarsenic trioxide (Trisenox), and other targeted therapies, havebeen studied alone and in combination with other antineoplastic therapies,either as induction therapy prior to stem cell transplantation or inpatients with relapsed disease. Bortezomib recently was approved inthe United States for the treatment of multiple myeloma in patientswho have received at least one prior therapy. The use of bortezomibbasedregimens as front-line therapy as well as the use of other agentsin multiple myeloma remain under investigation, and approvals forboth thalidomide and lenalidomide are hoped for soon, with the overallprospect of patient outcome continuing to be increasingly positive.

ORLANDO - Thalidomide (Thalomid) added to intensive front-line therapy for multiple myeloma proved superior to intensive therapy alone in a randomized trial led by Bart Barlogie, MD, PhD, director, University of Arkansas Myeloma Institute for Research & Therapy, Little Rock, and lead investigator of the trial. He reported the findings at the American Society of Clinical Oncology 41st Annual Meeting (abstract 6502). The researchers also found that cytogenetic abnormalities were strongly associated with response and survival. Thalidomide benefited only patients without the abnormalities. The phase III trial randomized 668 newly diagnosed patients to receive Total Therapy 2, which involves several rounds of stem cell transplants and chemotherapy, with or without thalidomide, given from the beginning of treatment and continued until recurrence.

Standard therapy for multiple myeloma, which accounts for 10% ofall hematologic malignancies, has been autologous stem cell transplantation(ASCT), alkylator-based chemotherapy, and corticosteroids. Severaladvances have been made in the treatment of multiple myelomaover the past decade, especially the arrival of new, active agents suchas thalidomide (Thalomid), bortezomib (Velcade), and lenalidomide(Revlimid). These have shown significant clinical activity as singleagents. Trials are ongoing to incorporate these new agents into thevarious stages of treatment and to combine them with other effectivetreatment modalities, including ASCT.

NEW ORLEANS-A combination of oral thalidomide (Thalomid) and dexamethasone is sufficiently active in newly diagnosed multiple myeloma that current intravenous regimens are no longer required for most patients, S. Vincent Rajkumar, MD, associate professor of medicine, Mayo Clinic, Rochester, Minnesota, said at the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 6508).

NEW ORLEANS-Bortezomib (Velcade), a first-in-class proteasome inhibitor, provides significant benefit when used as a single agent in the treatment of relapsed or refractory multiple myeloma. This was the principal finding of an interim analysis of

WASHINGTON-The FDA has approved Millennium Pharmaceuticals’ Velcade (bortezomib) injection for patients with multiple myeloma that has relapsed after two prior treatments and has shown resistance to the last treatment. Velcade was granted priority review by the FDA on March 10, 2003, and was approved approximately 2 months later. It has been just 4½ years from the first human dose to FDA approval.

PHILADELPHIA-Final data from a French prospective randomized trial show that high-dose therapy and double autologous transplantation improves survival of younger patients with multiple myeloma.

In the early 1980s, McElwain andcolleagues demonstrated thathigh-dose melphalan (Alkeran,100–400 mg/m2) was very effectivein patients with aggressive (plasmacell leukemia) or refractory myeloma.[1] Other researchers subsequentlyconfirmed these results.[2-4]Unfortunately, the duration of cytopeniaassociated with such treatmentwas excessive (3 to 4 weeks), leadingto a treatment-related mortalityrate of 10% to 20%.

Bolaños-Meade et al provide aconcise review of tandemtransplantation for patientswith multiple myeloma. High-dosechemotherapy with autologous stemcell support has been shown to improveresponse rates, event-free survival,and overall survival overconventional chemotherapy in a majorrandomized clinical trial-the IntergroupeFrançais du Myélome(IFM)-90 trial.[1] This procedure isnow accepted as the standard of carefor newly diagnosed myeloma patientsyounger than age 70 years. However,the same study demonstrated the needto improve upon single autografts, asthe overall survival rate at 7 years inthe transplant group was only 43%.Conceptual Basis ofTandem AutograftsUsing tandem transplants, investigatorshave aimed to improve outcomesby incrementally achievinghigher complete response rates withrepeated cycles of high-dose therapyrequiring stem cell support. With theirTotal Therapy protocol-a series ofnon–cross-resistant chemotherapyregimens culminating in tandemtransplantation-researchers from theArkansas Cancer Research Centershowed that the complete responserate increased from 26% to 41%following the first and second transplant,respectively.[2] On multivariateanalysis, complete response wasa significant prognostic factor forimproved outcome.

The use of high-dose chemotherapy and autologous stem cellsupport in the past decade has changed the outlook for patients withmultiple myeloma. In newly diagnosed patients, complete remissionrates of 25% to 50% can be achieved, with median disease-free andoverall survivals exceeding 3 and 5 years, respectively. Despite theseresults, autologous transplantation has not changed the ultimatelyfatal outcome of the disease, as there is no substantial evidence of“cure” in most published studies. An additional high-dose chemotherapycourse (with tandem transplants) appears to improve progressionfreesurvival, although the effect is not discernible until 3 to 5 yearsposttransplant. The recent reports of tandem autologous transplant formaximum cytoreduction followed by nonmyeloablative allogeneictransplant for eradication of minimal residual disease appears promisingand deserve further investigation. A central issue of tandemtransplants, whether they involve autologous or allogeneic transplants,revolves around defining the subsets of patients who will benefitfrom the procedure. Good-risk patients (defined by normal cytogeneticsand low beta-2–microglobulin levels), especially those who achievea complete or near-complete response after the first transplant, appearto benefit the most from a second cycle. High-risk patients (defined bychromosomal abnormalities usually involving chromosomes 11 and 13and high beta-2–microglobulin levels) whose median survival aftertandem transplant is less than 2 years should be offered novel therapeuticinterventions such as tandem “auto/allo” transplants. Until theefficacy and safety of this procedure is fully established, it should belimited to high-risk patients.

PHILADELPHIA-Two phase II clinical trials presented at the 44th Annual Meeting of the American Society of Hematology (ASH) have established the activity of the investigational proteasome inhibitor bortezomib (Velcade, also known as PS-341, Millennium Pharmaceuticals) in relapsed or refractory multiple myeloma.

PHILADELPHIA-Several novel biological agents active against multiple myeloma have recently moved from the laboratory to clinical trials. These agents work by targeting the interaction of the tumor cell and its bone marrow microenvironment, offering the potential for more specific, less toxic treatment, compared with conventional chemotherapy.

SEATTLE-A two-stage procedurethat combines high-dose chemotherapywith autologous stemcell transplantation (SCT) with animmunosuppressive (but notmyeloablative) allogeneic SCT inmultiple myeloma improves completeresponse rate and decreasestreatment-related mortality.

ROCKVILLE, Maryland-En-treMed, Inc. has begun a phase I study of its thalidomide derivative ENMD 0995 at the Mayo Clinic, Rochester, Minnesota, in patients with multiple myeloma. ENMD 0995 recently received orphan drug designation from the FDA for the disease.

ROCHESTER, Minnesota-Previous studies have shown the benefits of thalidomide (Thalomid) in patients with relapsed multiple myeloma. Now, researchers from the Mayo Clinic report that the oral combination of thalidomide and dexamethasone is feasible and active as initial therapy of the disease.