A randomized study of melphalan 200 mg/m(2) vs 280 mg/m(2) as a preparative regimen for patients with multiple myeloma undergoing auto-SCT.
Bone Marrow Transplant. 2016 Jan;51(1):67-71.
Bensinger WI, Becker PS, Gooley TA, Chauncey TR, Maloney DG, Gopal AK, Green DJ, Press OW, Lill M, Ifthikharuddin JJ, Vescio R, Holmberg LA, Phillips GL.
In this study, 131 patients with multiple myeloma underwent an autologous stem cell transplant using high-dose melphalan. They were randomized to receive either the standard dose 200 mg/m2 (Mel200), or a higher dose 280 mg/m2 (Mel280). Melphalan was given IV over 30 minutes on day -2. All patients received cryotherapy and amifostine. Results:
  - nCR + CR: 22% with Mel200 and 39% with Mel280 (p=0.03)
  - Progression-free survival at 1 year: 83% with Mel200 and 78%
  - Progression-free survival at 3 years: 46% with Mel200 and 54% with Mel280
  - Grade 3 mucositis: 0 with Mel200 and 1 with Mel280
  - No patient died in the entire study group
In conclusion, Mel280 was safe and induced a higher rate of deep responses. The size of the trial was judged to be too small to demonstrate a survival advantage for Mel280.

Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM.
Blood. 2016 Jan 28;127(4):420-5.
Mateos MV, Martínez-López J, Hernández MT, Ocio EM, Rosińol L, Martínez R, Teruel AI, Gutiérrez NC, Martín Ramos ML, Oriol A, Bargay J, Bengoechea E, González Y, Pérez de Oteyza J, Gironella M, Encinas C, Martín J, Cabrera C, Paiva B, Cedena MT, Puig N, Bladé J, Lahuerta JJ, San-Miguel J.
In this study, 233 patients with newly diagnosed myeloma were randomized into two groups: the first received "sequential" chemotherapy, with VMP (bortezomib, melphalan, prednisone) x 9 cycles, followed by RD (lenalidomide and dexamethasone) x 9 cycles (118 patients). The second group received "alternating" chemotherapy, with VMP x 1 cycle followed by RD x 1 cycke, and so on, up to 18 cycles (115 patients). There were no differences of clinical outcomes between the "sequential" and "alternating" chemotherapy regimens:
  - With the "sequential" regimen:  RR 42%, median PFS 32 months, 3-year OS 72%
   - With the "alternating" regimen: RR 40%, median PFS 34 months, 3-year OS 74%

Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study.
Lancet Oncol. 2016 Jan;17(1):27-38.
Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosińol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR Investigators.
This is a randomized phase III study of 929 patients with relapsed/refractory multiple myeloma. These were randomly assigned to receive either bortezomib + dexamethasone (VD, 465 patients) or carfilzomib + dexamethasone (KD, 464 patients). After a median follow-up of 11-12 months, median progression-free survival was 9.4 months with VD and 18.7 months with KD (p <0.0001).



Clonal Immunoglobulin against Lysolipids in the Origin of Myeloma.
N Engl J Med. 2016 Feb 11;374(6):555-61.
Nair S, Branagan AR, Liu J, Boddupalli CS, Mistry PK, Dhodapkar MV.
Gaucher's disease is a genetic disease characterized by the accumulation of glucocerebroside, a sphyngolipid. These patients have an increased risk of monoclonal gammopathies. In this study, the authors showed that the clonal immunoglobulin present in patients with Gaucher's disease are directed against lyso-glucosylceramide (LGL1). The same reactivity was found in about one third of patients with sporadic monoclonal gammopathies.

Minimal residual disease following autologous stem cell transplant in myeloma: impact on outcome is independent of induction regimen.
Haematologica. 2016 Feb;101(2):e69-71.
de Tute RM, Rawstron AC, Gregory WM, Child JA, Davies FE, Bell SE, Cook G, Szubert AJ, Drayson MT, Jackson GH, Morgan GJ, Owen RG.
The MRC Myeloma IX trial randomized 397 patients with newly diagnosed myeloma in one group receiving CTD (cyclophosphamide, thalidomide, and dexamethasone), and another group receiving CVAD (another regimen, currently of historical interest, which consisted of cyclophosphamide, vincristine, doxorubicin, dexamethasone). The induction chemotherapy was given for 4-6 cycles, and it was followed by an autologous stem cell transplant. At the traditional 100-day evaluation post-transplant, the CTD regimen was found to induce a higher response rate (82% vs 71%). However, this difference disappeared when the outcome was assessed according to the minimal residual disease (MRD) status, done by flow cytometry:
  - In patients who were MRD positive, median PFS was 16 months, and OS 59 months
  - In patients who were MRD negative, median PFS was 29 months, and OS 81 months
For MRD-negative patients, median PFS was 29 months with either CTD or CVAD.
The conclusion of the study was that the clinical outcome of myeloma patients is independent of the induction chemotherapy regimen, if a status of MRD is achieved after the autologous transplant. It seems that the level of disease is more important that the type of chemotherapy in determining the prognosis of these patients.

First-in-Human Experience of CXCR4-Directed Endoradiotherapy with 177Lu- and 90Y-Labeled Pentixather in Advanced-Stage Multiple Myeloma with Extensive Intra- and Extramedullary Disease.
J Nucl Med. 2016 Feb;57(2):248-51.
Herrmann K, Schottelius M, Lapa C, Osl T, Poschenrieder A, Hänscheid H, Lückerath K, Schreder M, Bluemel C, Knott M, Keller U, Schirbel A, Samnick S, Lassmann M, Kropf S, Buck AK, Einsele H, Wester HJ, Knop S.
Pentixather is a chemokine receptor 4 (CXCR4) inhibitor. The authors studied the effect of 177Lu- and 90Y-labeled pentixather in three patients with aggressive and heavily pretreated multiple myeloma. They used a radiolabeled CXCR4 ligand (pentixafor) for diagnostic receptor targeting. Patients received additional chemotherapy and autologous transplant. A significant therapeutic response was observed in 2 patients.

Higher Stem Cell Dose Infusion after Intensive Chemotherapy Does Not Improve Symptom Burden in Older Patients with Multiple Myeloma and Amyloidosis.
Biol Blood Marrow Transplant. 2016 Feb;22(2):226-31.
Shah N, Shi Q, Williams LA, Mendoza TR, Wang XS, Reuben JM, Dougherty PM, Bashir Q, Qazilbash MH, Champlin RE, Cleeland CS, Giralt SA.
In this study, 80 patients 60 year-old and older with either myeloma or amyloidosis were treated with an autologous transplant using melphalan 200 mg/m2. They were randomized to receive either a standard dose of stem cells (median, 5.1 million CD34+ cells/Kg) or a higher dose (median, 10.5 million CD34+ cells/Kg). The results were negative: patients receiving the high dose of stem cell did not experience a more rapid engraftment of neutrophils and platelets, and they did not experience an improvement of their transplant-related symptoms. 


MARCH 2016

A randomized phase II study of stem cell mobilization with cyclophosphamide+G-CSF or G-CSF alone after lenalidomide-based induction in multiple myeloma.
Bone Marrow Transplant. 2016 Mar;51(3):372-6. doi: 10.1038/bmt.2015.236. Epub 2015 Oct 5.
Silvennoinen R, Anttila P, Säily M, Lundan T, Heiskanen J, Siitonen TM, Kakko S, Putkonen M, Ollikainen H, Terävä V, Kutila A, Launonen K, Räsänen A, Sikiö A, Suominen M, Bazia P, Kananen K, Selander T, Kuittinen T, Remes K, Jantunen E.
In this randomized study of stem cell collection after induction therapy with lenalidomide, 35 patients received G-CSF10 mcg/Kg, and 34 patients cyclophosphamide 2 g/m2 IV followed by G-CSF 5 mcg/Kg. The target stem cell yield was 3 million CD34+ cells/Kg. The apheresis was started when the circulating CD34+ cells were >10 x10(6) on day +5 with G-CSF or day +10 with cyclophosphamide + G-CSF. The collection with cyclophosphamide was more effective, because the target was achieved in 94% vs 77% of patients.

Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma.
Blood. 2016 Mar 3;127(9):1109-16.
Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukĺs E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A.
These authors randomized 668 patients with newly diagnosed myeloma in two groups, one receiving MPT (318 pts), and the other receiving MPR (319 pts).
MPT was given as follows:
  - Melphalan 0.18 mg/Kg on days 1-4
  - Prednisone 2 mg/Kg on days 1-4
  - Thalidomide 200 mg/day
Cycles were repeated every 4 weeks x9, followed by maintenance with thalidomide 100 mg/day, until progression.
MPR was given as follows:
  - Melphalan 0.18 mg/Kg on days 1-4
  - Prednisone 2 mg/Kg on days 1-4
  - Lenalidomide 10 mg on days 1-21
Cycles were repeated every 4 weeks x9, followed by maintenance with lenalidomide 10 mg on days 1-21 every 28 days, until progression.
Thrombosis prophylaxis was given during induction, with either aspirin 75 mg daily, or carbasalasate calcium 100 mg daily.
The results of MPT and MPR were equivalent:
  - Response rate, defined as at least a VGPR, was 47% with MPT and 45% with MPR.
  - Progression-free survival was 20 months with MPT, and 23 months with MPR (p=0.12).
As expected, the toxicity profile was different, because of more neuropathy with MPT, and more myelosuppression with MPR.

Flow cytometry characterization in central nervous system and pleural effusion multiple myeloma infiltration: an Italian national cancer institute experience.
Br J Haematol. 2016 Mar;172(6):980-2.
Marchesi F, Masi S, Summa V, Gumenyuk S, Merola R, Orlandi G, Cigliana G, Palombi F, Pisani F, Romano A, Spadea A, Papa E, Canfora M, De Bellis F, Conti L, Mengarelli A, Cordone I.

Comparison of serum free light chain and urine electrophoresis for the detection of the light chain component of monoclonal immunoglobulins in light chain and intact immunoglobulin multiple myeloma.
Haematologica. 2016 Mar;101(3):356-62.
Dejoie T, Attal M, Moreau P, Harousseau JL, Avet-Loiseau H.
This study compared results of FLC and UPEP in 182 myeloma patients. As expected, there was an agreement between results of FLC and UPEP, but the FLC assay was more sensitive than the UPEP for monitoring response to therapy.

A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple Myeloma.
Clin Cancer Res. 2016 Mar 1;22(5):1067-75.
Holkova B, Zingone A, Kmieciak M, Bose P, Badros AZ, Voorhees PM, Baz R, Korde N, Lin HY, Chen JQ, Herrmann M, Xi L, Raffeld M, Zhao X, Wan W, Tombes MB, Shrader E, Weir-Wiggins C, Sankala H, Hogan KT, Doyle A, Annunziata CM, Wellons M, Roberts JD, Sullivan D, Landgren O, Grant S.
In this study, 36 patients with relapsed/refractory myeloma received treatment with selumetinib 75 mg twice a day. unfortunately, the activity in this heavily pretreated patient population was minimal (response rate was only 6%, and the median progression-free survival was 3.5 months).

Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma.
Blood. 2016 Mar 3;127(9):1102-8.
Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A.
This is a phase 3 clinical trial that involved 58 oncology centers in Italy and 9 in the Czech Republic. It included 662 patients with newly diagnosed myeloma, with a median age of 74 years (range, 63-91). There were 3 groups, MPR (melphalan, prednisone, and lenalidomide - 218 patients), CPR (cyclophosphamide, prednisone, and lenalidomide - 222 patients), and RD (lenalidomide and dexamethasone - 222 patients).
  - Melphalan 0.18 mg/Kg on days 1-4 (0.3 mg/Kg if age >75)
  - Prednisone 1.5 mg/Kg on days 1-4
  - Lenalidomide 10 mg on days 1-21
  - Cyclophosphamide 50 mg every day or every other day (x 21 days only if age >75)
  - Prednisone 25 mg every other day
  - Lenalidomide 10-25 mg on days 1-21
  - Lenalidomide 25 mg on days 1-21
  - Dexamethasone 40 mg once a week (20 mg if age >75)
Cycles were repeated every 4 weeks x9, followed by maintenance with either lenalidomide alone 10 mg on days 1-21 every 28 days, or lenalidomide + prednisone 25 mg every other day, continued until progression.
After a median follow-up of 39 months, median survival was not reached, and median progression-free survival was equivalent in the three groups: 22 months with MPR and CPR, and 21 months with RD (p=0.28). Therefore, the authors concluded that triplet (lenalidomide and alkylator-containing) regimens were not superior to doublet (lenalidomide-containing) regimens in newly diagnosed multiple myeloma. Of note, the doublet regimen contained a higher dose of lenalidomide, and dexamethasone instead of prednisone (the latter is a less potent corticosteroid).

Bone Marker-Directed Dosing of Zoledronic Acid for the Prevention of Skeletal Complications in Patients with Multiple Myeloma: Results of the Z-MARK Study.
Clin Cancer Res. 2016 Mar 15;22(6):1378-84.
Raje N, Vescio R, Montgomery CW, Badros A, Munshi N, Orlowski R, Hadala JT, Warsi G, Argonza-Aviles E, Ericson SG, Anderson KC.
This is a prospective study conducted in 67 centers in the U.S. Patients received zoledronic acid either monthly or every 3 months, based on the urine levels of the N-telopeptide of type 1 collagen (uNTX), a bone turnover marker. If levels were high (>50 mmol/mmol creatinine), consistent with increased bone resorption, zoledronic acid was given every 4 weeks, if levels were low (<50) every 12 weeks. Only 6% of patients developed a skeletal-related event, despite the fact that the vast majority of patients received zoledronic acid every 12 weeks. No major toxicities were observed. ONJ incidence was 3.3% beyond 3 years.

The ubiquitin ligase HERC4 mediates c-Maf ubiquitination and delays the growth of multiple myeloma xenografts in nude mice.
Blood. 2016 Mar 31;127(13):1676-86.
Zhang Z, Tong J, Tang X, Juan J, Cao B, Hurren R, Chen G, Taylor P, Xu X, Shi CX, Du J, Hou J, Wang G, Wu D, Stewart AK, Schimmer AD, Moran MF, Mao X.



Giampaolo Talamo, MD