JULY 2014

High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial.
Lancet Oncol. 2014 Jul;15(8):874-85.
Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA, Ashcroft AJ, Fletcher M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Chalmers A, O'Connor S, Drayson MT, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group.
This study, done in 51 institutions in the UK, randomized 174 patients with multiple myeloma who relapsed after the first transplant: one group (89 patients) was treated with conventional chemotherapy (cyclophosphamide 400 mg/m2 PO once a week for 12 weeks), and the other group (85 patients) with a "salvage" autologous stem cell transplantation (using melphalan 200 mg/m2 IV, and no maintenance), i.e., as a second transplant done late in the course of the disease. Median follow-up was 31 months. Results were better in the transplant group: median time to progression was 19 months in the transplant group, and 11 months in the non-transplant group. Median overall survival was similar in the two groups, but median follow-up was relatively short to formally assess impact of therapy on overall survival. Moreover, 20% of patients in the cyclophosphamide group eventually received a salvage autologous transplant.

Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study.
Blood. 2014 Jul 3;124(1):63-9.
Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, Musto P, Boccadifuoco L, Offidani M, Omedé P Gentilini F, Ciccone G, Benevolo G, Genuardi M, Montefusco V, Oliva S, Caravita T, Tacchetti P, Boccadoro M, Sonneveld P, Palumbo A.
At present time, carfilzomib is approved only for relapsing/refractory multiple myeloma. The authors of this study enrolled 58 patients with newly diagnosed myeloma, transplant-ineligible, with carfilzomib, cyclophophamide, and dexamethasone (CCyD) for 9 cycles, followed by maintenance therapy with carfilzomib. Median follow-up was 18 months. Results:
  - Response rate: 95% (75% at least VGPR, 49% at least near-CR, and 20% stringent CR)
  - Progression-free survival at 2 years: 76%
  - Overall survival at 2 years: 87%
  - Most important adverse reactions: cytopenias, peripheral neuropathy (9%), cardiopulmonary (7%)

The association of diabetes and anti-diabetic medications with clinical outcomes in multiple myeloma.
Br J Cancer. 2014 Jul 29;111(3):628-36.
Wu W, Merriman K, Nabaah A, Seval N, Seval D, Lin H, Wang M, Qazilbash MH, Baladandayuthapani V, Berry D, Orlowski RZ, Lee MH, Yeung SC.
In this retrospective study of 1240 myeloma patients, diabetes -especially steroid-induced diabetes- was associated with inferior survival. Median OS was 65 months in diabetic patients, and 98 months in non-diabetic patients.



Activity of 129 Single-Agent Drugs in 228 Phase I and II Clinical Trials in Multiple Myeloma.
Clin Lymphoma Myeloma Leuk. 2014 Aug;14(4):284-290.
Kortuem KM, Zidich K, Schuster SR, Khan ML, Jimenez-Zepeda VH, Mikhael JR, Fonseca R, Stewart AK.
This study analyzed the efficacy of 129 drugs administered as single agents in 228 clinical trials involving 7421 myeloma patients. The 10 best drugs according to the average response reported in the clinical trials were the following (in order of decreasing efficacy): melphalan, bortezomib, fotamustine, dexamethasone, thalidomide, carfilzomib, pomalidomide, prednisone, bendamustine, teniposide.

A phase 2 single-center study of carfilzomib 56 mg/m2 with or without low-dose dexamethasone in relapsed multiple myeloma.
Blood. 2014 Aug 7;124(6):899-906.
Lendvai N, Hilden P, Devlin S, Landau H, Hassoun H, Lesokhin AM, Tsakos I, Redling K, Koehne G, Chung DJ, Schaffer WL, Giralt SA.
The standard dose of carfilzomib is 20-27 mg/m2 IV over 2-10 minutes. These authors administered carfilzomib at 56 mg/m2 over 30 min (after the first cycle with 20 mg/m2) in 44 patients with myeloma, relapsed after other chemotherapy agents including bortezomib. In case of progression, dexamethasone 20 mg prior to each dose was added. Response rate was 55%, and 86% of patients achieved at least stable disease. Median progression-free survival was 4 months (median duration of response was approximately 12 months), and median overall survival was 20 months (reflecting the effectiveness of other salvage regimens). Discontinuation of treatment due to toxicity was required in 16% of patients. 

Plasma cell myeloma with unusual morphology - a series of 6 cases.
Eur J Haematol. 2014 Aug;93(2):165-70.
Gupta R, Hussain N, Rahman K, Nityanand S.
The authors describe 6 cases of myeloma with atypical morphology of the malignant plasma cells, which could be challenging for a pathologist:
  - Plasma cells with deep nuclear convolution
  - Plasma cells with irregular and deeply indented nuclear contour
  - Plasma cells with vacuolated cytoplasm and Burkitt-like morphology
  - Crystal-storing histiocytes

Clarithromycin overcomes resistance to lenalidomide and dexamethasone in multiple myeloma.
Am J Hematol. 2014 Aug;89(8):E116-20.
Ghosh N, Tucker N, Zahurak M, Wozney J, Borrello I, Huff CA.
This is a retrospective study of 24 patients with multiple myeloma who progressed while on lenalidomide and dexamethasone. The addition of clarithromycin induced disease remission (at least PR) in 10 patients (42%). The median duration of response was approximately 7 months, and the median PFS was 4 months. The mechanism of action of clarithromycin upon the malignant plasma cells is unclear. One possible explanation is that this antibiotic enhances the therapeutic effect of dexamethasone, by inhibiting CYP3A and increasing the area under the curve of dexamethasone.

Chromosome 8q24.1/c-MYC abnormality: a marker for high-risk myeloma.
Leuk Lymphoma. 2014 Aug 18:1-6.
Glitza IC1, Lu G, Shah R, Bashir Q, Shah N, Champlin RE, Shah J, Orlowski RZ, Qazilbash MH.
This study of 23 patients with myeloma and c-MYC rearrangement showed aggressive clinical features of this subset of myeloma: 12 patients had plasma cell leukemia (primary or secondary) or extrameduallary disease, and the median overall survival of the entire group was only 20 months.

Multiparameter flow cytometry for staging of solitary bone plasmacytoma: new criteria for risk of progression to myeloma.
Blood. 2014 Aug 21;124(8):1300-3.
Paiva B, Chandia M, Vidriales MB, Colado E, Caballero-Velázquez T, Escalante F, Garcia de Coca A, Montes MC, Garcia-Sanz R, Ocio EM, Mateos MV, San Miguel JF.
Flow cytometry for detecting plasma cells was obtained in the marrow aspirates of 35 patients with solitary plasmacytoma of the bone, and 29 patients with extramedullary plasmacytoma. Among patients with solitary plasmacytoma of the bone, 17 (49%) were positive, and 71% of them  progressed to multiple myeloma (vs 8% of flow-negative patients).

Mortality study of civilian employees exposed to contaminated drinking water at USMC Base Camp Lejeune: a retrospective cohort study.
Environ Health. 2014 Aug 13;13:68.
Bove FJ, Ruckart PZ, Maslia M, Larson TC.
Two drinking water systems at U.S. Marine Corps Base Camp Lejeunem (North Carolina) were contaminated with solvents during the years 1950s-1985. Among 4,647 civilian, full-time workers exposed to drinking contaminated waters in 1973-1985, the mortality hazard ratio for multiple myeloma was elevated (1.84, 95% CI: 0.45-7.58).



Autologous transplantation and maintenance therapy in multiple myeloma.
N Engl J Med. 2014 Sep 4;371(10):895-905.
Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M.
This is a study done in 62 centers in Italy and Israel. It compared 4 tandem autologous transplants (141 patients) and MPR chemotherapy (132 patients), with a second randomization of maintenance with lenalidomide (10 mg) until disease progression vs no maintenance.
MPR was given orally every 28 days, as follows:
  - Melphalan 0.18 mg/Kg on days 1-4
  - Lenalidomide 10 mg on days 1-21
  - Prednisone 2 mg/Kg on days 1-4
Median follow-up was 51 months. The results were better with transplant and with maintenance.
273 patients were treated with induction therapy with lenalidomide and dexamethasone.
  - Median progression-free survival:
    43 months in the transplant group vs 22 months in the MPR group
    42 months in the maintenance group vs 22 months without maintenance
  - Overall survival:
    at 4 years: 82% in the transplant group vs 65% in the MPR group
    at 3 years: 88% in the maintenance group vs 79% without maintenance (statistically not significant)
Of note, the advantage of stem cell transplant was maintained despite the fact that 63% of patients assigned to the MPR group received the transplant at progression. Transplant was not always feasible at the time of relapse, sometimes because of worsening of patients' medical conditions. This study is limited by the fact that it did not include proteasome inhibitors in the induction and maintenance phases.

Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma.
N Engl J Med. 2014 Sep 4;371(10):906-17.
Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T; FIRST Trial Team.
This study was conducted in 246 centers of 18 countries, and it randomized 1623 myeloma patients ineligible for transplant in 3 groups:
  - Lenalidomide (25 mg) + dexamethasone (40 mg once a week) indefinitely, until tumor progression.
  - Lenalidomide-dexamethasone for 18 cycles (72 weeks)
  - MPT (melphalan-prednisone-thalidomide) for 12 cycles of 42 days (72 weeks)
The best outcome was in the group treated with Len-Dex indefinitely. The improvement was statistically significant, but overall modest.
  - Median progression-free survival: 25.5 months with Len-Dex indefinitely, 21 months with Len-Dex x18, 21 months with MPT
  - Overall survival at 4 years: 59% with Len-Dex indefinitely, 56% with Len-Dex x18, 51% with MPT

Chalazia associated with bortezomib therapy for multiple myeloma.
Ophthalmology. 2014 Sep;121(9):1845-1847.e3.
Grob SR, Jakobiec FA, Rashid A, Yoon MK.

A multicenter phase II study of single-agent enzastaurin in previously treated multiple myeloma.
Leuk Lymphoma. 2014 Sep;55(9):2013-7.
Jourdan E, Leblond V, Maisonneuve H, Benhadji KA, Hossain AM, Nguyen TS, Wooldridge JE, Moreau P.
Enzastaurin is an oral serine/threonine kinase inhibitor. It was ineffective in this clinical trial, as it produced only 1 minimal response among 14 patients with relapsed/refractory myeloma.

Inter-laboratory discordance of beta-2 microglobulin results: impact on the validity of the international staging system for multiple myeloma.
Br J Haematol. 2014 Sep;166(6):951-3.
Fedele PL, Choy KW, Doery JC, Grigoriadis G, Shortt J, Lu ZX.
In this study, 21 patient serum samples were sent to 4 different laboratories for determining the beta-2 microglobulin levels. Two laboratories used a turbidimetric method, one nephelometry, and one chemiluminescence. Interestingly, the results among the laboratories were discordant, and it resulted in a different risk stratification by the ISS staging system. The concordance of the ISS stage among the 4 laboratories was only 57%.



Giampaolo Talamo, MD