UP-FRONT/INDUCTION THERAPY
Dimopoulos MA et al. VMP (bortezomib, melphalan, and prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, and results in reversal of renal impairment: Cohort analysis of the phase III VISTA study. J Clin Oncol 2009;27(36):6086-93. Abstract
Among patients with myeloma and moderate renal impairment, addition of bortezomib to MP as initial therapy is a safe and effective approach that reverses renal insufficiency in a substantial proportion (44 percent) of patients.
Hulin C et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 2009;27(22):3664-70. Abstract
The MPT regimen demonstrates acceptable toxicity and superior overall survival (44 months) when compared to MP (29 months) in elderly (>75 years) patients with multiple myeloma.
Ludwig H et al. Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood 2009;113(15):3435-42. Abstract
High-dose dexamethasone in combination with thalidomide is associated with significant toxicities and poorer survival for patients who are elderly or with poor performance status and thus a less aggressive approach is more appropriate.
Harousseau J-L et al. Bortezomib plus dexamethasone (VD) versus reduced-dose bortezomib plus thalidomide plus dexamethasone (vTD) as induction treatment prior to autologous stem-cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM). Proc ASH 2009;Abstract 354.
The combination of reduced-dose bortezomib and thalidomide with dexamethasone results in minimal peripheral neuropathy (Grade ≥III = 2 percent) and induces significantly more responses (50 percent ≥VGPR) than VD (30 percent ≥VGPR).
Jakubowiak AJ et al. Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol 2009;27(30):5015-22. Abstract
Acceptable safety and promising efficacy (57.5 percent ≥VGPR) are seen in newly diagnosed myeloma with bortezomib, pegylated liposomal doxorubicin and dexamethasone combination therapy.
Hussein MA et al. Phase II study of thalidomide plus dexamethasone induction followed by tandem melphalan-based autotransplantation and thalidomide-plus-prednisone maintenance for untreated multiple myeloma: A Southwest Oncology Group trial (S0204). J Clin Oncol 2009;27(21):3510-7. Abstract
Tandem transplantation is feasible and shows improved VGPR rates and survival outcomes when compared to a matched cohort receiving single transplants or chemotherapy without transplantation.
Kapoor P et al. Melphalan and prednisone (MP) versus melphalan, prednisone and thalidomide (MPT) as initial therapy for previously untreated elderly and/or transplant ineligible patients with multiple myeloma: A meta-analysis of randomized controlled trials. Proc ASH 2009;Abstract 615.
A meta-analysis of four randomized controlled trials for elderly and/or transplant-ineligible patients with myeloma confirms that MPT is significantly superior to MP as initial therapy with respect to response rates and overall survival.
Palumbo AP et al. A phase III study of VMPT versus VMP in newly diagnosed elderly myeloma patients. Proc ASCO 2009;Abstract 8515.
Among elderly patients with newly diagnosed myeloma, the combination of thalidomide with VMP, using weekly bortezomib dosing, improves response rates (≥VGPR 55 percent versus 45 percent) without an increase in peripheral neuropathy.
Attal M et al. Lenalidomide after autologous transplantation for myeloma: First analysis of a prospective, randomized study of the Intergroupe Francophone Du Myelome (IFM 2005 02). Proc ASH 2009;Abstract 529.
An interim analysis including only the lenalidomide-consolidation data after transplant showed that response was upgraded with consolidation in 15 percent of patients. Results from the lenalidomide-maintenance phase are not yet available.
Spencer A et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol 2009;27(11):1788-93. Abstract
Among patients receiving transplants, thalidomide/prednisolone consolidation for 12 months improves three-year survival (86 percent versus 75 percent) with an increased incidence of peripheral neuropathy (0 percent to 10 percent ≥Grade III).
Mellqvist U-H et al. Improved response rate with bortezomib consolidation after high dose melphalan: First results of a Nordic Myeloma Study Group randomized Phase III trial. Proc ASH 2009;Abstract 530.
Bortezomib consolidation for 21 weeks after transplant shows improvement in responses (CR/nCR 54 percent versus 35 percent) and in six-month relapse rate (one percent versus six percent) in this placebo-controlled study.
Loiseau HA et al. Induction with Velcade®/dexamethasone partially overcomes the poor prognosis of t(4;14), but not that of Del(17p), in young patients with multiple myeloma. Proc ASH 2009;Abstract 957.
A retrospective analysis shows that the outcome (PFS and OS) for patients with t(4;14) is partially improved with bortezomib/dexamethasone induction therapy, although this combination does not improve the outcome for patients with del(17p).
Dawson MA et al. Clinical and immunohistochemical features associated with a response to bortezomib in patients with multiple myeloma. Clin Cancer Res 2009;15(2):714-22. Abstract
A prior complete response with an alternative drug and cyclin D1 expression are associated with an improved response to bortezomib, while expression of p16, cytoplasmic p53 and high Bcl-2 staining is associated with a poor response.
STEM CELL HARVESTING/AUTO, ALLO AND MINI-ALLO TRANSPLANTS
DiPersio JF et al, on behalf of the 3102 Investigators. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood 2009;113(23):5720-6. Abstract
For patients with myeloma, a mobilization regimen of plerixafor and G-CSF results in a significantly improved ability to achieve optimal CD34+ cell targeting for tandem transplantation in fewer apheresis procedures compared to G-CSF alone.
Stiff P et al. Treatment with plerixafor in non-Hodgkin’s lymphoma and multiple myeloma patients to increase the number of peripheral blood stem cells when given a mobilizing regimen of G-CSF: Implications for the heavily pretreated patient. Biol Blood Marrow Transplant 2009;15(2):249-56. Abstract
A combination of plerixafor and G-CSF is safe and effective in mobilizing stem cells in patients with heavily pretreated non-Hodgkin lymphoma or multiple myeloma.
Giralt S et al, on behalf of the IMWG. International Myeloma Working Group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100). Leukemia 2009;23(10):1904-12. Abstract
G-CSF alone is reasonable for stem cell collection in myeloma. Plerixafor should be considered as part of the mobilization regimen for patients who have risk factors such as age >60, extensive prior therapy or prolonged disease duration.
RELAPSED/REFRACTORY DISEASE
Richardson PG et al. Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol 2009;27(34):5713-9. Abstract
For patients with relapsed/refractory myeloma, the combination of lenalidomide and bortezomib is safe and is associated with promising activity evident in a median survival of 37 months and a minimal or better response rate of 61 percent.
Stadtmauer EA et al. Lenalidomide in combination with dexamethasone at first relapse in comparison with its use as later salvage therapy in relapsed or refractory multiple myeloma. Eur J Haematol 2009;82(6):426-32. Abstract
A greater benefit in response rates and survival (42.0 months versus 35.8 months, p = 0.041) occurs when lenalidomide/dexamethasone therapy is administered at first relapse rather than later as salvage therapy for patients with relapsed or refractory myeloma.
Knop S et al. Lenalidomide, Adriamycin, and dexamethasone (RAD) in patients with relapsed and refractory multiple myeloma: A report from the German Myeloma Study Group DSMM (Deutsche Studiengruppe Multiples Myelom). Blood 2009;113(18):4137-43. Abstract
Addition of doxorubicin to the RD regimen induces substantial remission (73 percent OR and 61 percent ≥VGPR) in heavily pretreated myeloma. Side effects are manageable and are mainly hematologic.
Petrucci MT. Efficacy and safety of retreatment with bortezomib in patients with multiple myeloma: Interim results from RETRIEVE, a prospective international Phase 2 study. Proc ASH 2009;Abstract 3866.
Among patients with relapsed myeloma who had responded previously to bortezomib, re-treatment was safe and active with an overall response rate of 40 percent.
Dimopoulos MA et al. Treatment of patients with relapsed/refractory multiple myeloma (MM) with lenalidomide and dexamethasone with or without bortezomib: Prospective evaluation of the impact of cytogenetic abnormalities. Proc ASH 2009;Abstract 958.
The addition of bortezomib to lenalidomide/dexamethasone may overcome to a certain extent the adverse prognosis of the cytogenetic abnormalities t(4;14), del(13q) and add1q21 but not that of del(17p).
TREATMENT-RELATED SIDE EFFECTS/SUPPORTIVE CARE
Zangari M et al. Survival effect of venous thromboembolism in patients with multiple myeloma treated with lenalidomide and high-dose dexamethasone. J Clin Oncol 2010;28(1):132-5. Abstract
Lenalidomide/high-dose dexamethasone is associated with an increased incidence of venous thromboembolism (17 percent) in relapsed or refractory myeloma, but no effect on survival or time to disease progression was associated with this adverse event.
Vij R et al. An open-label, phase 2 trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma. Am J Hematol 2009;84(10):650-6. Abstract
Denosumab appears safe and active, with 21 percent of patients whose multiple myeloma relapsed less than three months before study entry maintaining stable disease up to 16.5 months and 46 percent of patients with plateau-phase myeloma maintaining stable disease up to 18.3 months.
Katz J et al. Bisphosphonate-induced osteonecrosis of the jaw: Long-term outcomes. J Support Oncol 2009;7(1):9-10. Abstract
This retrospective analysis suggests that bisphosphonate-induced osteonecrosis of the jaw is reversible in most cases after discontinuation of the bisphosphonate and becomes asymptomatic with minimal dental intervention.
INVESTIGATIONAL AGENTS
Richardson P et al. A Phase 1/2 multi-center, randomized, open label dose escalation study to determine the maximum tolerated dose, safety, and efficacy of pomalidomide alone or in combination with low-dose dexamethasone in patients with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide and bortezomib. Proc ASH 2009;Abstract 301.
Pomalidomide is an active agent in heavily pretreated myeloma and shows a low incidence of neuropathy, thromboembolism, somnolence or constipation, with myelosuppression being the most common adverse event.
Niesvizky R et al. Phase Ib multicenter dose escalation study of carfilzomib plus lenalidomide and low dose dexamethasone (CRd) in relapsed and refractory multiple myeloma (MM). Proc ASH 2009;Abstract 304.
Among patients with relapsed or refractory myeloma, a carfilzomib/lenalidomide/low-dose dexamethasone combination has shown promising activity without dose-limiting toxicities. A Phase III trial is now planned to compare CRd to Rd.
Wang L et al. Updated results of bortezomib-naïve patients in PX-171-004, an ongoing open-label, Phase II study of single-agent carfilzomib (CFZ) in patients with relapsed or refractory myeloma (MM). Proc ASH 2009;Abstract 302.
Single-agent carfilzomib is active (OR = 45 percent) in relapsed or refractory myeloma, with infrequent peripheral neuropathy (Grade III = two percent) and relatively uncommon myelosuppression.
MGUS/SMOLDERING MYELOMA
Mateos M-V et al. Multicenter, randomized, open-label, Phase III trial of lenalidomide-dexamethasone (len-dex) vs therapeutic abstention in smoldering multiple myeloma at high risk of progression to symptomatic MM: Results of the first interim analysis. Proc ASH 2009;Abstract 614.
High-risk smoldering myeloma is associated with a substantial risk of early progression to symptomatic myeloma. Lenalidomide/dexamethasone can result in high response rates and a significant delay in disease progression.
Rossi F et al. Proposal and validation of prognostic scoring systems for IgG and IgA monoclonal gammopathies of undetermined significance. Clin Cancer Res 2009;15(13):4439-45. Abstract
Clinicohematologic features of 1,283 patients with MGUS were correlated with evolution into myeloma. IgA class, serum M protein levels and light-chain proteinuria are the most important variables correlated with disease progression.
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Attal M et al. Lenalidomide after autologous transplantation for myeloma: First analysis of a prospective, randomized study of the Intergroupe Francophone Du Myelome (IFM 2005 02). Proc ASH 2009;Abstract 529.
Attal M et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 2006;108(10):3289-94. Abstract
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Harousseau JL et al. Bortezomib/dexamethasone versus VAD as induction prior to autologous stem cell transplantation (ASCT) in previously untreated multiple myeloma (MM): Updated data from IFM 2005/01 trial. Proc ASCO 2008;Abstract 8505.
Hulin C et al. Melphalan-prednisone-thalidomide (MP-T) demonstrates a significant survival advantage in elderly patients 75 years with multiple myeloma compared with melphalan-prednisone (MP) in a randomized, double-blind, placebo-controlled trial, IFM 01/01. Blood 2007;110;Abstract 75.
Katzmann JA et al. Elimination of the need for urine studies in the screening algorithm for monoclonal gammopathies by using serum immunofixation and free light chain assays. Mayo Clin Proc 2006(12);81:1575-8. Abstract
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Lentzsch S et al. Immunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and angiogenesis in vivo. Leukemia 2003;17(1):41-4. Abstract
Mateos MV et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: Updated time-to-events results and prognostic factors for time to progression. Haematologica 2008;93(4):560-5. Abstract
Mateos MV et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: Results of a multicenter phase 1/2 study. Blood 2006;108(7):2165-72. Abstract
McCarthy PL et al. Phase III Intergroup study of lenalidomide (CC-5013) versus placebo maintenance therapy following single autologous stem cell transplant for multiple myeloma (CALGB 100104): Initial report of patient accrual and adverse events. Proc ASH 2009;Abstract 3416.
Palumbo A et al. A Phase III study to determine the efficacy and safety of lenalidomide in combination with melphalan and prednisone (MPR) in elderly patients with newly diagnosed multiple myeloma. Proc ASH 2009;Abstract 613.
Palumbo A et al. Melphalan, prednisone, and lenalidomide for newly diagnosed myeloma: Kinetics of neutropenia and thrombocytopenia and time-to-event results. Clin Lymphoma Myeloma 2009;9(2):145-50. Abstract
Palumbo A et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: Updated results of a randomized controlled trial. Blood 2008;112(8):3107-14. Abstract
Rajkumar SV et al, for the Eastern Cooperative Oncology Group. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: An open-label randomized controlled trial. Lancet Oncol 2010;11(1):29-37. Abstract
Rajkumar SV et al. Randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed myeloma (E4A03), a trial coordinated by the Eastern Cooperative Oncology Group: Analysis of response, survival, and outcome with primary therapy and with stem cell transplantation. Proc ASCO 2008;Abstract 8504.
Rajkumar SV et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: A clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2006;24(3):431-6. Abstract
Rajkumar SV et al. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood 2005;106(13):4050-3. Abstract
Richardson P et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006;108(10):3458-64. Abstract
Richardson PG et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 2002;100(9):3063-7. Abstract
Rifkin RM et al. Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: A Phase III multicenter randomized trial. Cancer 2006;106(4):848-58. Abstract
Ripamonti CI et al. Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol 2009;20(1):137-45. Abstract
San Miguel JF et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359(9):906-17. Abstract
San Miguel JF et al. Longer duration of treatment and maintenance of best response with lenalidomide and dexamethasone prolongs overall survival in patients with relapsed or refractory multiple myeloma. Proc ASH 2008;Abstract 3702.
Snozek CL et al. Prognostic value of the serum-free light chain ratio in patients with newly diagnosed myeloma and proposed incorporation into the International Staging System. Leukemia 2008;22(10):1933-7. Abstract
Sonneveld P et al. First analysis of HOVON-65/GMMG-HD4 randomized Phase III trial comparing bortezomib, Adriamycin, dexamethasone (PAD) vs VAD as induction treatment prior to high dose melphalan (HDM) in patients with newly diagnosed multiple myeloma (MM). Blood 2008;112;Abstract 653.
Streetly MJ et al. Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation. Br J Haematol 2008;141(1):41-51. Abstract
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