JULY 2017

A Multicenter, Open-Label, Phase 1b Study of Carfilzomib, Cyclophosphamide, and Dexamethasone in Newly Diagnosed Multiple Myeloma Patients (CHAMPION-2).
Clin Lymphoma Myeloma Leuk. 2017 Jul;17(7):433-437.
Boccia RV, Bessudo A, Agajanian R, Conkling P, Harb W, Yang H, Pinchasik D, Kimball AS, Berenson JR.
In this trial, 16 patients with newly diagnosed myeloma were treated with the "KCyD" regimen, which consisted of:
  - Carfilzomib 56 mg/m2 IV on days 1,2, 8,9, 15,16
  - Cyclophosphamide 300 mg/m2 PO on days 1, 8, 15
  - Dexamethasone 40 mg PO/IV on days 1, 8, 15, 22
Cycles were repeated every 28 days. Response rate was 88%, and median time to response was 1 month.

Variability of high-dose melphalan exposure on oral mucositis in patients undergoing prophylactic low-level laser therapy.
Lasers Med Sci. 2017 Jul;32(5):1089-1095.
Rodrigues GH, Jaguar GC, Alves FA, Guollo A, Camandoni VO, Damascena AS, Lima VCC.

Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma.
Blood. 2017 Jul 6;130(1):30-34.
Rasche L, Angtuaco E, McDonald JE, Buros A, Stein C, Pawlyn C, Thanendrarajan S, Schinke C, Samant R, Yaccoby S, Walker BA, Epstein J, Zangari M, van Rhee F, Meissner T, Goldschmidt H, Hemminki K, Houlston R, Barlogie B, Davies FE, Morgan GJ, Weinhold N.
Among 227 patients with newly diagnosed multiple myeloma, the rate of false-negative FDG-PET was 11%. Interestingly, the false-negativity was not correlated to the tumor load (as represented by percentage of plasma cells infiltrating the bone marrow, or the plasma cell proliferation rate), but it was found to be associated with low expression of hexokinase-2, an enzyme involved in the glycolysis. This would explain the low uptake of fluorodeoxyglucose by the malignant cells.

Effects of single-agent bortezomib as post-transplant consolidation therapy on multiple myeloma-related bone disease: a randomized phase II study.
Br J Haematol. 2017 Jul;178(1):61-71.
Sezer O, Beksac M, Hajek R, Sucak G, Cagirgan S, Linkesch W, Meltem Akay O, Gülbas Z, Nahi H, Plesner T, Snowden JA, Timurağaoğlu A, Dechow T, Lang A, Tuğlular T, Drach J, Armbrecht G, Potamianou A, Couturier C, Olie RA, Feys C, Allietta N, Terpos E.
This is a phase II study which included 104 patients with multiple myeloma treated with an autologous stem cell transplant. Patients were randomized in two groups, one treated with bortezomib as consolidation therapy (51 patients), and another left with observation only (53 patients). Bortezomib was given at 1.6 mg/m2 IV on days 1, 8, 15, 22, every 35 days for 4 cycles. Patients receiving the consolifdation with bortezomib had better outcomes:
  - Rate of CR/sCR: 11% with observation, and 22% with bortezomib (p=0.19)
  - Median progression-free survival: 22 months with observation, and 45 months with bortezomib (p=0.22)

CD117 (KIT) is a useful marker in the diagnosis of plasmablastic plasma cell myeloma.
Histopathology. 2017 Jul;71(1):81-88.
Marks E, Shi Y, Wang Y.

Ricolinostat, the First Selective Histone Deacetylase 6 Inhibitor, in Combination with Bortezomib and Dexamethasone for Relapsed or Refractory Multiple Myeloma.
Clin Cancer Res. 2017 Jul 1;23(13):3307-3315.
Vogl DT, Raje N, Jagannath S, Richardson P, Hari P, Orlowski R, Supko JG, Tamang D, Yang M, Jones SS, Wheeler C, Markelewicz RJ, Lonial S.
Ricolinostat is a selective HDAC inhibitor. In this trial, single -agent ricolinostat did not induce responses in patients with relapsed/refractory myeloma. In combination with bortezomib and dexamethasone, the response rate was 37% (14% in patients previously refractory to bortezomib).



Involved/uninvolved heavy/light chain index can predict progression in transplanted multiple myeloma patients.
Bone Marrow Transplant. 2017 Aug;52(8):1206-1207.
Espiño M, Arteche-López A, Medina S, Muñoz-Calleja C, Blanchard MJ, Alegre A, López-Jiménez FJ, Villar LM.

Longitudinal fluorescence in situ hybridization reveals cytogenetic evolution in myeloma relapsing after autologous transplantation.
Haematologica. 2017 Aug;102(8):1432-1438.
Merz M, Jauch A, Hielscher T, Mai EK, Seckinger A, Hose D, Bertsch U, Neben K, Raab MS, Salwender H, Blau IW, Lindemann HW, Schmidt-Wolf I, Scheid C, Haenel M, Weisel K, Goldschmidt H, Hillengass J.
This is a retrospective study which compared FISH results in the bone marrow of 128 patients with multiple myeloma at baseline and at relapse, after an upfront autologous stem cell transplant. The results confirmed the presence of clonal evolution of myeloma over time: high-risk cytogenetic features, such as 17p- and 1q21+, were present more often at the time of relapse, and they were associated with a very poor outcome.

CD38-negative relapse in multiple myeloma after daratumumab-based chemotherapy.
Eur J Haematol. 2017 Aug;99(2):186-189.
Minarik J, Novak M, Flodr P, Balcarkova J, Mlynarcikova M, Krhovska P, Pika T, Pikalova Z, Bacovsky J, Scudla V.
This is a case report. Based on their immune phenotype analysis, the authors believe that the resistance to daratumumab was not associated to the development and expansion of a CD38-negative clone within the malignant plasma cell population, but it involved just the loss of the CD38 surface molecules in the same cells.

A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma.
Br J Haematol. 2017 Aug;178(4):547-560.
Laubach JP, Moslehi JJ, Francis SA, San Miguel JF, Sonneveld P, Orlowski RZ, Moreau P, Rosiñol L, Faber EA Jr, Voorhees P, Mateos MV, Marquez L, Feng H, Desai A, van de Velde H, Elliott J, Shi H, Dow E, Jobanputra N, Esseltine DL, Niculescu L, Anderson KC, Lonial S, Richardson PG.
After analyzing data from  2509 myeloma patients treated with bortezomib-containing regimens, and 1445 control patients, the incidence of cardiac events was low: arrhythmias 1-6%, ischemic heart disease 1-3%, CHF (grade 3 or 4) 1-5%, and cardiac death about 1%. More importantly, there were no significant differences between the bortezomib-treated patients and the controls.

IgM myeloma: A multicenter retrospective study of 134 patients.
Am J Hematol. 2017 Aug;92(8):746-751.
Castillo JJ, Jurczyszyn A, Brozova L, Crusoe E, Czepiel J, Davila J, Dispenzieri A, Eveillard M, Fiala MA, Ghobrial IM, Gozzetti A, Gustine JN, Hajek R, Hungria V, Jarkovsky J, Jayabalan D, Laubach JP, Lewicka B, Maisnar V, Manasanch EE, Moreau P, Morgan EA, Nahi H, Niesvizky R, Paba-Prada C, Pika T, Pour L, Reagan JL, Richardson PG, Shah J, Spicka I, Vij R, Waszczuk-Gajda A, Gertz MA.

Clinical characteristics and prognostic factors in multiple myeloma patients with light chain deposition disease.
Am J Hematol. 2017 Aug;92(8):739-745
Mohan M, Buros A, Mathur P, Gokden N, Singh M, Susanibar S, Jo Kamimoto J, Hoque S, Radhakrishnan M, Matin A, Davis C, Grazziutti M, Thanendrarajan S, van Rhee F, Zangari M, Davies F, Morgan G, Epstein J, Barlogie B, Schinke C.
This is a retrospective study of 69 patients with multiple myeloma and concomitant light chain deposition disease (LCDD). One-third of these patients had cardiac involvement and, as expected, had a worse survival.

Phase I/II study of the novel proteasome inhibitor delanzomib (CEP-18770) for relapsed and refractory multiple myeloma.
Leuk Lymphoma. 2017 Aug;58(8):1872-1879.
Vogl DT, Martin TG, Vij R, Hari P, Mikhael JR, Siegel D, Wu KL, Delforge M, Gasparetto C.

Among 61 patients enrolled in this clinical trial, the median time to progression was only 2.5 months. The development of delanzomib was discontinued.

Gain of chromosome 1q portends worse prognosis in multiple myeloma despite novel agent-based induction regimens and autologous transplantation.
Leuk Lymphoma. 2017 Aug;58(8):1823-1831.
Shah GL, Landau H, Londono D, Devlin SM, Kosuri S, Lesokhin AM, Lendvai N, Hassoun H, Chung DJ, Koehne G, Jhanwar SC, Landgren O, Levine R, Giralt SA.
In this retrospective study of 95 patients with multiple myeloma treated with an autologous stem cell transplant, 21% of them had gains of chromosome 1 (+1q). These patients had a worse median progression-free survival (2.1 vs 4.3 years), even with the transplant, confirming the high-risk nature of this chromosomal abnormality.

Circulating tumour DNA analysis demonstrates spatial mutational heterogeneity that coincides with disease relapse in myeloma.
Leukemia. 2017 Aug;31(8):1695-1705.
Mithraprabhu S, Khong T, Ramachandran M, Chow A, Klarica D, Mai L, Walsh S, Broemeling D, Marziali A, Wiggin M, Hocking J, Kalff A, Durie B, Spencer A.
This is an interesting study, which compares mutational status of malignant plasma cells in the bone marrow aspirate (the traditional analysis) with the one in the circulating free tumor DNA. Paired bone marrow and peripheral blood were analyzed in 48 patients. The results favor the peripheral blood analysis, not only because it was a noninvasive test, but also because it revealed a higher frequency of mutations. Evidently, myeloma consists of a heterogeneous population of malignant cells which may have different clonal evolution both in time and space, even due to the heterogeneous and multifocal involvement of the bone marrow. A bone marrow aspirate from a single focus may fail to reveal the genomic complexity of the whole neoplasm.

Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing.
Nat Commun. 2017 Aug 16;8(1):268.
Rasche L, Chavan SS, Stephens OW, Patel PH, Tytarenko R, Ashby C, Bauer M, Stein C, Deshpande S, Wardell C, Buzder T, Molnar G, Zangari M, van Rhee F, Thanendrarajan S, Schinke C, Epstein J, Davies FE, Walker BA, Meissner T, Barlogie B, Morgan GJ, Weinhold N.
This study shows results of sequencing in both bone marrow and distant focal lesions of 51 patients with multiple myeloma. They demonstrated that there is a high degree of genomic heterogeneity between myeloma clones, as "spatial" differences were found in more than 75% of patients. The results supported the notion that patients with advanced disease have a more significant genomic heterogeneity between different anatomical sites.

Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma.
Blood. 2017 Aug 24;130(8):974-981.
Chari A, Suvannasankha A, Fay JW, Arnulf B, Kaufman JL, Ifthikharuddin JJ, Weiss BM, Krishnan A, Lentzsch S, Comenzo R, Wang J, Nottage K, Chiu C, Khokhar NZ, Ahmadi T, Lonial S.
In this phase II trial, 103 patients with relapsed/refractory myeloma were treated with Dara-Pom-Dex:
  - Daratumumab 16 mg/Kg in standard schedule
  - Pomalidomide 4 mg on days 1-21 every 28 days
  - Dexamethasone 40 mg once a week (20 mg if age >75)
Patient needed to be in relapse after at least 2 prior lines of therapy in order to participate to the trial. The median number of prior therapies was 4 (range, 1-13), and the majority of them (76%) had at least 3 lines of therapy. Results, after a median follow-up of 13 months:
  - Response rate: 60%. VGPR or better: 42%. CR or better: 17%
  - Median progression-free survival: 8.8 months
  - Median overall survival: 17.5 months
  - 1-year overall survival: 66%
  - Toxicity was similar to that observed with Pom-Dex, with the exception of infusion-related reactions to daratumumab (50%), and neutropenia (but without increase in the rate of infections) 

Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: a study of the International Myeloma Working Group.
Blood Cancer J. 2017 Aug 25;7(8):e599.
Hillengass J, Moulopoulos LA, Delorme S, Koutoulidis V, Mosebach J, Hielscher T, Drake M, Rajkumar SV, Oestergaard B, Abildgaard N, Hinge M, Plesner T, Suehara Y, Matsue K, Withofs N, Caers J, Waage A, Goldschmidt H, Dimopoulos MA, Lentzsch S, Durie B, Terpos E.

Based on this study and other studies, the International Myeloma Working Group recommended that either CT or PET-CT should be the standard of care for the detection of osteolytic lesions in patients with multiple myeloma. The CT is more sensitive than the conventional skeletal survey (i.e., plain x-rays): CT identified lytic lesions in in 54 of 212 (25%) patients with negative skeletal survey, and in 12 of 66 (22%) patients with presumed smoldering myeloma.



Prospective Evaluation of Magnetic Resonance Imaging and 18-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography at Diagnosis and Before Maintenance Therapy in Symptomatic Patients With Multiple Myeloma Included in the IFM/DFCI 2009 Trial: Results of the IMAJEM Study.
J Clin Oncol. 2017 Sep 1;35(25):2911-2918.
Moreau P, Attal M, Caillot D, Macro M, Karlin L, Garderet L, Facon T, Benboubker L, Escoffre-Barbe M, Stoppa AM, Laribi K, Hulin C, Perrot A, Marit G, Eveillard JR, Caillon F, Bodet-Milin C, Pegourie B, Dorvaux V, Chaleteix C, Anderson K, Richardson P, Munshi NC, Avet-Loiseau H, Gaultier A, Nguyen JM, Dupas B, Frampas E, Kraeber-Bodere F.
In this prospective study comparing skeletal MRI and PET/CT in 134 patients with myeloma, no difference was found in the detection of bone lesions at diagnosis between the 2 techniques.

Plasmablastic lymphoma versus plasmablastic myeloma: an ongoing diagnostic dilemma.
J Clin Pathol. 2017 Sep;70(9):775-780.
Ahn JS, Okal R, Vos JA, Smolkin M, Kanate AS, Rosado FG.

A novel dual inhibitor of microtubule and Bruton's tyrosine kinase inhibits survival of multiple myeloma and osteoclastogenesis.
Exp Hematol. 2017 Sep;53:31-42.
Pandey MK, Gowda K, Sung SS, Abraham T, Budak-Alpdogan T, Talamo G, Dovat S, Amin S.

Haploidentical Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma Using Post-Transplantation Cyclophosphamide Graft-versus-Host Disease Prophylaxis.
Biol Blood Marrow Transplant. 2017 Sep;23(9):1549-1554.
Castagna L, Mussetti A, Devillier R, Dominietto A, Marcatti M, Milone G, Maura F, de Philippis C, Bruno B, Furst S, Blaise D, Corradini P, Montefusco V.
In this study, 30 patients with heavily pretreated myeloma underwent haploidentical SCT. Results, after a median follow-up of 25 months:
  - Grade II-IV aGVHD at day +100: 39%
  - cGVHD at 18 months: 7%
  - Non-relapse mortality at 18 months: 10% (95% CI, 2-24%)
  - Progression-free survival at 18 months: 33% (95% CI, 17-50%)
  - Overall survival at 18 months: 63% (95% CI, 44-78%)

Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials.
J Clin Oncol. 2017 Sep 1;35(25):2900-2910.
Lahuerta JJ, Paiva B, Vidriales MB, Cordón L, Cedena MT, Puig N, Martinez-Lopez J, Rosiñol L, Gutierrez NC, Martín-Ramos ML, Oriol A, Teruel AI, Echeveste MA, de Paz R, de Arriba F, Hernandez MT, Palomera L, Martinez R, Martin A, Alegre A, De la Rubia J, Orfao A, Mateos MV, Blade J, San-Miguel JF; GEM (Grupo Español de Mieloma)/PETHEMA (Programa para el Estudio de la Terapéutica en Hemopatías Malignas) Cooperative Study Group.
These authors analyzed data of flow cytometry to assess minimal residual disease (MRD) in 609 patients enrolled in previous clinical trials. They found that the achievement of a stringent complete remission by flow cytometry was associated with a superior long-term survival. The achievement of MRD-negative status had a better prognostic value than the achievement of CR (complete remission, traditionally defined as a negative immunofixation and <5% plasma cells in the bone marrow). The authors conclude that MRD negativity should one of the most important end point for the treatment of multiple myeloma in eligible patients (i.e., those who can undergo a stem cell transplant or those without major comorbidities that prevent the administration of adequate chemotherapy regimens).

Pembrolizumab, pomalidomide, and low-dose dexamethasone for relapsed/refractory multiple myeloma.
Blood. 2017 Sep 7;130(10):1189-1197.
Badros A, Hyjek E, Ma N, Lesokhin A, Dogan A, Rapoport AP, Kocoglu M, Lederer E, Philip S, Milliron T, Dell C, Goloubeva O, Singh Z.
Pembrolizumab is a monoclonal antibody directed against the PD-1 (programmed death 1) receptor. This is a membrane protein that inhibits the immune response by T lymphocytes. In this phase II study, 48 patients with relapsed/refractory myeloma were treated with pembrolizumab and 200 mg IV every 2 weeks, pomalidomide 4 mg daily for 21 days, and dexamethasone 40 mg once a week. with cycles repeated every 28 days. Patients were heavily pretreated: 73% of them were refractory to both an IMiD and a proteasome inhibitor, and 70% had an autologous transplant. 62% of them had high-risk cytogenetics. Nonetheless, 48 patients (60%) had an objective response (CR/sCR 8%). After a median follow-up of about 16 months, progression-free survival was 17.4 months, and overall survival was not reached. Autoimmune events, known side effects of pembrolizumab, included pneumonitis (13%) and hypothyroidism (10%).

Olanzapine Reduces Chemotherapy-induced Nausea and Vomiting Compared With Aprepitant in Myeloma Patients Receiving High-dose Melphalan Before Stem Cell Transplantation: A Retrospective Study.
Clin Lymphoma Myeloma Leuk. 2017 Sep;17(9):584-589.
Trifilio S, Welles C, Seeger K, Mehta S, Fishman M, McGowan K, Strejcek K, Eiten E, Pirotte C, Lucier E, DeFrates S, Mehta J.

Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma.
Blood. 2017 Sep 7;130(10):1198-1204.
Paludo J, Mikhael JR, LaPlant BR, Halvorson AE, Kumar S, Gertz MA, Hayman SR, Buadi FK, Dispenzieri A, Lust JA, Kapoor P, Leung N, Russell SJ, Dingli D, Go RS, Lin Y, Gonsalves WI, Fonseca R, Bergsagel PL, Roy V, Sher T, Chanan-Khan AA, Ailawadhi S, Stewart AK, Reeder CB, Richardson PG, Rajkumar SV, Lacy MQ.
In this phase I/II trial, 50 patients with relapsed myeloma, refractory to lenalidomide, received combination chemotherapy with VPD:
  - Bortezomib 1.0-1.3 mg/m2 SC/IV once a week
  - Pomalidomide 4 mg PO on days 1-21
  - Dexamethasone 40 mg PO once a week
Cycles were repeated every 28 days. Median follow-up was 42 months. Results:
  - Response rate: 86%. PR 36%, VGPR 28%, CR 10%, sCR 12%
  - Median progression-free survival: about 14 months
  - OS at 42 months: 66%
  - Most common toxicities: mild cytopenias. No significant peripheral neuropathy was observed.

Outcome of autologous hematopoietic stem cell transplantation in refractory multiple myeloma.
Cancer. 2017 Sep 15;123(18):3568-3575.
Veltri LW, Milton DR, Delgado R, Shah N, Patel K, Nieto Y, Kebriaei P, Popat UR, Parmar S, Oran B, Ciurea S, Hosing C, Lee HC, Manasanch E, Orlowski RZ, Shpall EJ, Champlin RE, Qazilbash MH, Bashir Q.

Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial.
Leukemia. 2017 Sep;31(9):1922-1927.
Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J.
In this phase III trial (GEM05MENOS65), 390 patients with newly diagnosed myeloma (MM), treated with various induction chemotherapy and an autologous stem cell transplantation, were randomized in 3 groups: one treated with thalidomide (T, 88 patients), one with bortezomib and thalidomide (VT, 91 patients), and another one with alfa-2b interferon (IFN, 92 patients). The maintenance therapy was continue for up to 3 years. After a median follow-up of 58.6 months, PFS was significantly longer with TV compared with T and IFN (about 51 vs 40 vs 32 months, p=0.03), but overall survival was not significantly different among the three arms. Of note, at the time of the publication, the type and schedule of induction therapy and maintenance were considered obsolete.

Single vs. multiple fraction regimens for palliative radiotherapy treatment of multiple myeloma : A prospective randomised study.
Strahlenther Onkol. 2017 Sep;193(9):742-749.
Rudzianskiene M, Inciura A, Gerbutavicius R, Rudzianskas V, Macas A, Simoliuniene R, Dambrauskiene R, Kiavialaitis GE, Juozaityte E.
In this randomized study, 101 patients with myeloma were randomized to receive palliative radiation therapy in either a single fraction (8 Gy x 1, 58 patients), or multiple fractions (3 Gy x 10 - control arm, 58 patients). Pain relief occurred in 81 of 101 patients (80%), and it was partial (31%) or complete (69%). Although the analgesic effect was similar in the two groups, the quality of life was reported to be better in the control group (with multiple fractions).



Giampaolo Talamo, MD