A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma

TY - JOUR

T1 - A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma

AU - Larocca, A.

AU - Bringhen, S.

AU - Petrucci, Maria T.

AU - Oliva, S.

AU - Falcone, A.P.

AU - Caravita, T.

AU - Villani, O.

AU - Benevolo, Giulia

AU - Liberati, A. M.

AU - Morabito, F.

AU - Montefusco, V.

AU - Passera, R.

AU - Rosa, L.

AU - Omedé, P.

AU - Vincelli, I.D.

AU - Spada, S.

AU - Carella, A.M.

AU - Ponticelli, E.

AU - Derudas, Daniele

AU - Genuardi, M.

AU - Guglielmelli, Tommasina

AU - Nozzoli, C.

AU - Aghemo, E.

AU - Paoli, Lorenzo

AU - Conticello, C.

AU - Musolino, Caterina

AU - Offidani, M.

AU - Boccadoro, M.

AU - Sonneveld, P.

AU - Palumbo, A. A.

N1 - Cited By :2 Export Date: 16 March 2017 CODEN: LEUKE Correspondence Address: Palumbo, A.; Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria (AOU), Via Genova, 3, Italy; email: appalumbo@yahoo.com References: Kumar, S.K., Rajkumar, S.V., Dispenzieri, A., Lacy, M.Q., Hayman, S.R., Buadi, F.K., Improved survival in multiple myeloma and the impact of novel therapies (2008) Blood, 111, pp. 2516-2520; Brenner, H., Gondos, A., Pulte, D., Expected long-term survival of patients diagnosed with multiple myeloma in 2006-2010 (2009) Haematologica, 94, pp. 270-275; Altekruse, S.F., Kosary, C.L., Krapcho, M., Neyman, N., Aminou, R., Waldron, W., SEER Cancer Statistics Review, 1975-2007, , http://seer.cancer.gov/csr/19752007/S, Available at (last accessed 10 July 2015; Palumbo, A., Bringhen, S., Mateos, M.V., Larocca, A., Facon, T., Kumar, S.K., Geriatric assessment predicts survival and toxicities in elderly myeloma patients: An International Myeloma Working Group report (2015) Blood, 125, pp. 2068-2074; Bringhen, S., Mateos, M.V., Zweegman, S., Larocca, A., Falcone, A.P., Oriol, A., Age and organ damage correlate with poor survival in myeloma patients: Meta-analysis of 1435 individual patient data from 4 randomized trials (2013) Haematologica, 98, pp. 980-987; San Miguel, J.F., Schlag, R., Khuageva, N.K., Dimopoulos, M.A., Shpilberg, O., Kropff, M., Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma (2008) N Engl J Med, 359, pp. 906-917; Fayers, P.M., Palumbo, A., Hulin, C., Waage, A., Wijermans, P., Beksaç, M., Thalidomide for previously untreated elderly patients with multiple myeloma: Meta-analysis of 1685 individual patient data from 6 randomized clinical trials (2011) Blood, 118, pp. 1239-1247; San Miguel, J.F., Schlag, R., Khuageva, N.K., Dimopoulos, M.A., Shpilberg, O., Kropff, M., Continued overall survival benefit after 5 years' follow-up with bortezomibmelphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with previously untreated multiple myeloma, and no increased risk of second primary malignancies: Final results of the Phase 3 VISTA Trial [abstract] (2011) Blood, 118; Mateos, M.V., Richardson, P.G., Schlag, R., Khuageva, N.K., Dimopoulos, M.A., Shpilberg, O., Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: Updated follow-up and impact of subsequent therapy in the phase III VISTA trial (2010) J Clin Oncol, 28, pp. 2259-2266; Wijermans, P., Schaafsma, M., Termorshuizen, F., Ammerlaan, R., Wittebol, S., Sinnige, H., Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: The HOVON 49 Study (2010) J Clin Oncol, 28, pp. 3160-3166; Hulin, C., Facon, T., Rodon, P., Pegourie, B., Benboubker, L., Doyen, C., Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial (2009) J Clin Oncol, 27, pp. 3664-3670; Niesvizky, R., Flinn, I.W., Rifkin, R., Gabrail, N., Charu, V., Clowney, B., Communitybased phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens (2015) J Clin Oncol, 33, pp. 3921-3929; Kumar, S., Flinn, I., Richardson, P.G., Hari, P., Callander, N., Noga, S.J., Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma (2012) Blood, 119, pp. 4375-4382; Facon, T., Mary, J.Y., Pégourie, B., Attal, M., Renaud, M., Sadoun, A., Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high dose therapy (2006) Blood, 107, pp. 1292-1298; Durie, B.G., Kyle, R.A., Belch, A., Bensinger, W., Blade, J., Boccadoro, M., Myeloma management guidelines: A consensus report from the Scientific Advisors of the International Myeloma Foundation (2003) Hematol J, 4, pp. 379-398; Kyle, R.A., Rajkumar, S.V., Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma (2009) Leukemia, 23, pp. 3-9; Lawton, M.P., Scales to measure competence in everyday activities (1988) Psychopharmacol Bull, 24, pp. 609-614; Charlson, M.E., Pompei, P., Ales, K.L., MacKenzie, C.R., A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation (1987) J Chronic Dis, 40, pp. 373-383; Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0, , http://ctep.cancer.gov/protocolDevelopment/electronicapplications/docs/ctcaev3.pdf, National Cancer Institute Available at (accessed 3 January 2015); Simon, R., Optimal two-stage designs for phase II clinical trials (1989) Control Clin Trials, 10, pp. 1-10; Kaplan, E.L., Meier, P., Nonparametric estimation from incomplete observations (1958) J Am Stat Assoc, 53, pp. 457-481; Mateos, M.V., Oriol, A., Martínez-López, J., Gutiérrez, N., Teruel, A.I., De Paz, R., Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: A randomised trial (2010) Lancet Oncol, 11, pp. 934-941; Palumbo, A., Bringhen, S., Rossi, D., Cavalli, M., Larocca, A., Ria, R., Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: A randomized controlled trial (2010) J Clin Oncol, 28, pp. 5101-5109; Mateos, M.V., Oriol, A., Martínez-López, J., Gutiérrez, N., Teruel, A.I., López De La Guiá, A., Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial (2012) Blood, 120, pp. 2581-2588; Palumbo, A., Hajek, R., Delforge, M., Kropff, M., Petrucci, M.T., Catalano, J., Continuous lenalidomide treatment for newly diagnosed multiple myeloma (2012) N Engl J Med, 366, pp. 1759-1769

PY - 2016

Y1 - 2016

N2 - This phase 2 trial evaluated three low-dose intensity subcutaneous bortezomib-based treatments in patients ≥75 years with newly diagnosed multiple myeloma (MM). Patients received subcutaneous bortezomib plus oral prednisone (VP, N=51) or VP plus cyclophosphamide (VCP, N=51) or VP plus melphalan (VMP, N=50), followed by bortezomib maintenance, and half of the patients were frail. Response rate was 64% with VP, 67% with VCP and 86% with VMP, and very good partial response rate or better was 26%, 28.5% and 49%, respectively. Median progression-free survival was 14.0, 15.2 and 17.1 months, and 2-year OS was 60%, 70% and 76% in VP, VCP, VMP, respectively. At least one drug-related grade ≥3 non-hematologic adverse event (AE) occurred in 22% of VP, 37% of VCP and 33% of VMP patients; the discontinuation rate for AEs was 12%, 14% and 20%, and the 6-month rate of toxicity-related deaths was 4%, 4% and 8%, respectively. The most common grade ≥3 AEs included infections (8-20%), and constitutional (10-14%) and cardiovascular events (4-12%); peripheral neuropathy was limited (4-6%). Bortezomib maintenance was effective and feasible. VP, VCP and VMP regimens demonstrated no substantial difference. Yet, toxicity was higher with VMP, suggesting that a two-drug combination followed by maintenance should be preferred in frail patients . © 2016 Macmillan Publishers Limited.

AB - This phase 2 trial evaluated three low-dose intensity subcutaneous bortezomib-based treatments in patients ≥75 years with newly diagnosed multiple myeloma (MM). Patients received subcutaneous bortezomib plus oral prednisone (VP, N=51) or VP plus cyclophosphamide (VCP, N=51) or VP plus melphalan (VMP, N=50), followed by bortezomib maintenance, and half of the patients were frail. Response rate was 64% with VP, 67% with VCP and 86% with VMP, and very good partial response rate or better was 26%, 28.5% and 49%, respectively. Median progression-free survival was 14.0, 15.2 and 17.1 months, and 2-year OS was 60%, 70% and 76% in VP, VCP, VMP, respectively. At least one drug-related grade ≥3 non-hematologic adverse event (AE) occurred in 22% of VP, 37% of VCP and 33% of VMP patients; the discontinuation rate for AEs was 12%, 14% and 20%, and the 6-month rate of toxicity-related deaths was 4%, 4% and 8%, respectively. The most common grade ≥3 AEs included infections (8-20%), and constitutional (10-14%) and cardiovascular events (4-12%); peripheral neuropathy was limited (4-6%). Bortezomib maintenance was effective and feasible. VP, VCP and VMP regimens demonstrated no substantial difference. Yet, toxicity was higher with VMP, suggesting that a two-drug combination followed by maintenance should be preferred in frail patients . © 2016 Macmillan Publishers Limited.

U2 - 10.1038/leu.2016.36

DO - 10.1038/leu.2016.36

M3 - Article

VL - 30

SP - 1320

EP - 1326

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 6

ER -