Multiple myeloma with extramedullary disease: impact of autologous stem cell transplantation on outcome.
Bone Marrow Transplant. 2017 Oct;52(10):1473-1475.
Kumar L, Gogi R, Patel AK, Mookerjee A, Sahoo RK, Malik PS, Sharma A, Thulkar S, Kumar R, Biswas A, Sharma OD, Gupta R.
This is a retrospective study of 44 myeloma patients with extramedullary disease who underwent an autologous stem cell transplant. After a median follow-up of 7.5 years, 13 patients (30%) were alive, and 9 of them were in CR. As expected, patients with extramedullary disease had lower PFS and OS compared with the rest of myeloma patients. The study did not provide cytogenetic data. The most important predictor for PFS and OS was the achievement of CR after the stem cell transplant. 

Effectiveness of IHD with Adsorptive PMMA Membrane in Myeloma Cast Nephropathy: A Cohort Study.
Am J Nephrol. 2017 Oct 10;46(5):355-363.
Sens F, Chaintreuil D, Jolivot A, Guebre-Egziabher F, Robinson P, Karlin L, Bridoux F, Juillard L.

Monoclonal IgG in MGUS and multiple myeloma targets infectious pathogens.
JCI Insight. 2017 Oct 5;2(19).
Bosseboeuf A, Feron D, Tallet A, Rossi C, Charlier C, Garderet L, Caillot D, Moreau P, Cardó-Vila M, Pasqualini R, Arap W, Nelson AD, Wilson BS, Perreault H, Piver E, Weigel P, Girodon F, Harb J, Bigot-Corbel E, Hermouet S.
Contrary to traditional thought, these authors showed that the monoclonal antibodies secreted by MGUS and myeloma cells can target infectious pathogens: the antigen specificity of purified monoclonal paraprotein of 244 patients was found to be directed against one known pathogen in 23% of cases: EBV (16%), HSV-1 (3%), VZV (2%), CMV (1%), and HCV (1%). The authors believe that MGUS and myeloma could be the result of a dysregulated immune response to an infection.

Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial.
Lancet Oncol. 2017 Oct;18(10):1327-1337.
Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, Orlowski RZ, Ludwig H, Facon T, Hajek R, Weisel K, Hungria V, Minuk L, Feng S, Zahlten-Kumeli A, Kimball AS, Moreau P.

The ENDEAVOR trial is a phase III study comparing bortezomib and carfilzomib in patients with relapsed/refractory multiple myeloma. Patients received 1-3 previous lines of chemotherapy. Bortezomib was given at 1.3 mg/m2 SC/IV on days 1, 4, 8, 11 every 21 days, and carfilzomib at 56 mg/m2 IV on days 1 on days 1,2, 8,9, 15,16 every 28 days (20 mg/m2 on the first two doses). Both groups received dexamethasone. 929 patients were randomized, 465 to the bortezomib group and 464 to the carfilzomib group. Median overall survival: 40 months with bortezomib vs 47.6 months with carfilzomib. The authors note that, at the time of publication, carfilzomib was the only agent in multiple myeloma that demonstrated an improved overall survival in the relapsed setting.



Benefit of continuous treatment for responders with newly diagnosed multiple myeloma in the randomized FIRST trial.
Leukemia. 2017 Nov;31(11):2435-2442.
Bahlis NJ, Corso A, Mugge LO, Shen ZX, Desjardins P, Stoppa AM, Decaux O, de Revel T, Granell M, Marit G, Nahi H, Demuynck H, Huang SY, Basu S, Guthrie TH, Ervin-Haynes A, Marek J, Chen G, Facon T.
This is a subanalysis of the FIRST trial, which randomized patients with newly diagnosed multiple myeloma to receive lenalidomide + dexamethasone indefinitely, until disease progression ("Rd continuous"), vs MPT (melphalan , thalidomide, and prednisone) x 12 cycles, or lenalidomide + dexamethasone x 18 cycles (Rd x18). Patients were ineligible for an autologous stem cell transplant. Rd continuous was the winner, as it improved efficacy outcomes compared with fixed duration therapies. The 4-year overall survival for those patients who achieved a partial response or better was 64.6% with Rd continuous, 62.5% with Rd x18, and 57.2% with MPT.

Bortezomib and low-dose dexamethasone with or without continuous low-dose oral cyclophosphamide for primary refractory or relapsed multiple myeloma: a randomized phase III study.
Ann Hematol. 2017 Nov;96(11):1857-1866.
Kropff M, Vogel M, Bisping G, Schlag R, Weide R, Knauf W, Fiechtner H, Kojouharoff G, Kremers S, Berdel WE.
In this randomized phase III study, 96 patients with relapsed/refractory myeloma received either VD (bortezomib and dexamethasone) every 21 days x 8 cycles (48 patients), or VCD: VD + cyclophosphamide 50 mg orally once a day, continuously (48 patients). Although the study was terminated prematurely, due to insufficient sample size, the results with VCD did not seem to be better than with VD. Response rate was 74% with VD, and 70% with VCD. Time to progression, which was the primary endpoint of the trial, was 12.6 months with VD, and 9.9 months with VCD.

Peripheral blood stem cell mobilization with a single dose of PEG-filgrastim in patients with multiple myeloma previously treated with radiotherapy.
Leuk Lymphoma. 2017 Nov;58(11):2724-2727.
Anguita-Compagnon AT, Dibarrart MT, Paredes L, Araos D, Vargas M, Majlis A.
In this small study, 22 patients with myeloma underwent collection of stem cells with PEG-filgrastim 18 mg SC x1 (day 0). Of note, 11 of them previously received radiation therapy to the spine, which could have compromised the yield of the stem cell collection. CD34+ cells were counted since day +3 or +4, and collection started when their number was >7/mL. The collection was successful, with a median number of CD34+ cells/Kg collected of 5.48 x106, and the range was 2.86 - 13.84 x106.

Correlation of multiparameter flow cytometry and bone marrow trephine immunohistochemistry in the identification and characterization of neoplastic plasma cells.
Br J Haematol. 2017 Nov;179(3):499-501.
Menter T, Abdulsalam AH, Nadal-Melsio E, Yebra-Fernandez E, Flora RS, Ahmad R, Rahemtulla A, Naresh KN.
In this study, the authors compared two techniques to quantify the clonal plasma cells in the bone marrow of 89 patients with multiple myeloma, the flow cytometry (FC) and the immunohistochemistry (IHC). The percentage of plasma cells in the bone marrow was significantly higher with IHC than with FC (median 50% vs 6%, p< 0.001). As expected, the FC usually underestimated the % of plasma cells, due to the dilutional effect in the aspirates. There was a positive correlation between the percentage of plasma cells enumerate  by FC and IHC (Spearman correlation coefficient R = 0.44). Of note, the presence of light chain restriction was documented in 90% of cases by FC, and in 98% of cases by IHC, but the combination of the two techniques was able to document the light chain restriction in all cases. The authors conclude that the two techniques are complimentary. The best method to estimate the number of plasma cells in the bone marrow was the CD138 immunostain of the biopsy.

Efficacy of daratumumab-based therapies in patients with relapsed, refractory multiple myeloma treated outside of clinical trials.
Am J Hematol. 2017 Nov;92(11):1146-1155.
Lakshman A, Abeykoon JP, Kumar SK, Rajkumar SV, Dingli D, Buadi FK, Gonsalves WI, Leung N, Dispenzieri A, Kourelis TV, Go RS, Lacy MQ, Hobbs MA, Lin Y, Warsame R, Lust J, Fonder AL, Hwa YL, Hayman SR, Russell SJ, Kyle RA, Gertz MA, Kapoor P.
The authors studied the outcomes of combination therapies containing daratumumab in 126 patients with relapsed/refractory multiple myeloma in the "real world", i.e., outside of the context of clinical trial. The other drugs given with daratumumab were bortezomib, lenalidomide, pomalidomide, and others. The patients in the study were heavily pretreated. Median number of previous lines of therapy was 4 (range, 1-14), and 33% of patients had high-risk cytogenetics. The median time between the diagnosis of myeloma and the therapy with daratumumab was 4.3 years (range, 0.4 - 13 years). The response rate was 47%, and the median progression-free survival was only 5.5 months, lower than that reported in clinical trials with daratumumab. This is expected, because clinical trials usually select patients with better performance status and better clinical features and parameters.

Natural history of relapsed myeloma, refractory to immunomodulatory drugs and proteasome inhibitors: a multicenter IMWG study.
Leukemia. 2017 Nov;31(11):2443-2448.
Kumar SK, Dimopoulos MA, Kastritis E, Terpos E, Nahi H, Goldschmidt H, Hillengass J, Leleu X, Beksac M, Alsina M, Oriol A, Cavo M, Ocio EM, Mateos MV, O'Donnell EK, Vij R, Lokhorst HM, van de Donk NWCJ, Min C, Mark T, Turesson I, Hansson M, Ludwig H, Jagannath S, Delforge M, Kyriakou C, Hari P, Mellqvist U, Usmani SZ, Dytfeld D, Badros AZ, Moreau P, Kim K, Otero PR, Lee JH, Shustik C, Waller D, Chng WJ, Ozaki S, Lee JJ, de la Rubia J, Eom HS, Rosinol L, Lahuerta JJ, Sureda A, Kim JS, Durie BGM.
The authors of this study reviewed the clinical outcomes of 543 patients with multiple myeloma, when the disease became refractory to both an IMiD (lenalidomide or pomalidomide) and a proteasome inhibitor (bortezomib or carfilzomib). The median duration between the diagnosis of myeloma and the dual refractoriness was 3.1 years, and the median number of lines of therapy was 4 (range, 3-13). The median overall survival from the time of dual refractoriness was 13 months.

Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma.
Blood. 2017 Nov 30;130(22):2401-2409.
Kumar S, Kaufman JL, Gasparetto C, Mikhael J, Vij R, Pegourie B, Benboubker L, Facon T, Amiot M, Moreau P, Punnoose EA, Alzate S, Dunbar M, Xu T, Agarwal SK, Enschede SH, Leverson JD, Ross JA, Maciag PC, Verdugo M, Touzeau C.
This is a phase I study of 66 patients with relapsed/refractory myeloma treated with single-agent venetoclax. Patients were heavily pretreated, because the median number of prior lines of therapy was 5, and 61% of patients were refractory to both bortezomib and lenalidomide. The overall response rate was 21%, with 15% VGPR or better. In the group with t(11;14), which constituted 46% of cases, the response rate was 40%, with 27% VGPR or better. 86% of responses were seen in patients with the t(11;14) translocation. The safety profile was very good, and the main toxicities were gastrointestinal and hematological.

Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM.
Blood. 2017 Nov 30;130(22):2392-2400.
Moreau P, Chanan-Khan A, Roberts AW, Agarwal AB, Facon T, Kumar S, Touzeau C, Punnoose EA, Cordero J, Munasinghe W, Jia J, Salem AH, Freise KJ, Leverson JD, Enschede SH, Ross JA, Maciag PC, Verdugo M, Harrison SJ.
This is a phase I study of 66 patients with relapsed/refractory myeloma treated with venetoclax, in combination with bortezomib and dexamethasone. The median number of prior lines of therapy was 3. The overall response rate was 67%, with 42% VGPR or better. Median progression-free survival was 9.5 months.



Effect of High-Cutoff Hemodialysis vs Conventional Hemodialysis on Hemodialysis Independence Among Patients With Myeloma Cast Nephropathy: A Randomized Clinical Trial.
JAMA. 2017 Dec 5;318(21):2099-2110.
Bridoux F, Carron PL, Pegourie B, Alamartine E, Augeul-Meunier K, Karras A, Joly B, Peraldi MN, Arnulf B, Vigneau C, Lamy T, Wynckel A, Kolb B, Royer B, Rabot N, Benboubker L, Combe C, Jaccard A, Moulin B, Knebelmann B, Chevret S, Fermand JP; MYRE Study Group.
This is a prospective randomized study that evaluated the use of high-cutoff hemodialysis in patients with multiple myeloma and renal failure due to cast nephropathy. High-cutoff hemodialysis involves the use of larger membrane pores, which are highly permeable to the serum light chains (which are nephrotoxic). 98 patients from 48 centers in France were randomized to either intensive hemodialysis (8 sessions of 5 hours over 10 days) with a standard filter (48 pts), or the same using a high-cutoff dyalizer (46 pts). All patients received bortezomib-based chemotherapy regimens. The primary end point of the study was hemodialysis independence at 3 months. Unfortunately, this study did not clarify in a definitive way whether high-cutoff hemodialysis is beneficial. The primary endpoint was not met, because it did not reach statistical significance: dialysis independence was achieved in 33% of patients with standard membranes, and 41% with high-cutoff hemodialysis (p=0.42). However, at 12 months, the difference was statistically significant: 37% vs 61% (p=0.02). The authors noted that the study was underpowered to identify an early difference in the outcomes.

Inpatient vs outpatient autologous hematopoietic stem cell transplantation for multiple myeloma.
Eur J Haematol. 2017 Dec;99(6):532-535.
Shah N, Cornelison AM, Saliba R, Ahmed S, Nieto YL, Bashir Q, Parmar S, Hosing C, Popat U, Shpall EJ, Champlin RE, Qazilbash M.
This single-center retrospective study describes feasibility and outcomes of an autologous stem cell transplant in 1046 patients with myeloma, treated between 2008 and 2012. There were 669 patients who were transplanted as inpatients, and 377 as outpatients. 55% of the outpatients required admission to the hospital, mainly because of neutropenic fever (46%). Of note, neutropenic fever occurred more frequently in the inpatient group: 381/669 (57%) vs 154/377 (41%, p<0.001). The median number of days from day 0 (day of transplant) to hospital admission was 8, and the median number of hospital days was 6.

A Phase 1 and 2 study of Filanesib alone and in combination with low-dose dexamethasone in relapsed/refractory multiple myeloma.
Cancer. 2017 Dec 1;123(23):4617-4630.
Shah JJ, Kaufman JL, Zonder JA, Cohen AD, Bensinger WI, Hilder BW, Rush SA, Walker DH, Tunquist BJ, Litwiler KS, Ptaszynski M, Orlowski RZ, Lonial S.

In this study, 63 patients with relapsed/refractory myeloma received filanesib (ARRY-520), a selective inhibitor of kinesin spindle protein, either as single agent or in combination with dexamethasone. Patients were heavily pretreated. In the phase I of the study, the most common dose-limiting toxicities were neutropenic fever and mucositis. Among 32 evaluable patients treated in the phase 2 of the study, response rates were 16% as single agent and 15% in combination with dexamethasone.

Infectious complications in multiple myeloma receiving autologous stem cell transplantation in the past 10 years.
Int J Hematol. 2017 Dec;106(6):801-810.
Park H, Youk J, Kim HR, Koh Y, Kwon JH, Yoon SS, Park S, Choe PG, Kim NJ, Oh MD, Park WB, Kim I.
This is a retrospective analysis of 324 autologous stem cell transplants in 285 myeloma patients treated between 2006 and 2015. The authors observed 68 episodes of infections (21%). The most common type of infection was bacteremia (24 cases), followed by other bacterial infections (7), CMV (17), HSV (12), VZV (3), Aspergillus (3) and Pneumocystis jiroveci (2). Mortality was 1.2%, and all deaths were infection-related.

Systolic dysfunction associated with carfilzomib use in patients with multiple myeloma.
Blood Cancer J. 2017 Dec 13;7(12):642.
Jain T, Narayanasamy H, Mikhael J, Reeder CB, Bergsagel PL, Mayo A, Stewart AK, Mookadam F, Fonseca R.
This is a retrospective review of 136 myeloma patients at Mayo Clinic in Arizona who received carfilzomib between 2012 and 2016. Cardiac dysfunction was defined as a decrease of the LVEF by 5% (with LVEF <55%) with symptoms of CHF, or a decrease of the LVEF by 10% (with LVEF <55%) regardless of symptoms. This was observed in 12 patients (9%). Of note, no patients died from CHF, and the systolic dysfunction improved in all patients after discontinuation of carfilzomib.

Prevalence of Monoclonal Gammopathy in Wild-Type Transthyretin Amyloidosis.
Geller HI, Singh A, Mirto TM, Padera R, Mitchell R, Laubach JP, Falk RH.
Mayo Clin Proc. 2017 Dec;92(12):1800-1805.
In this retrospective analysis, 113 patients with wild-type TTR amyloidosis were screened for the presence of monoclonal proteins, by SPEP, IFE, and FLC. Monoclonal gammopathy was found in 23% of cases. This is an important finding, because it shows that MGUS can coexist in patients with non-AL amyloidosis. These results underscore the possibility of misclassification of the amyloid type by laboratory test screening, and indicates the need for a precise amyloid typing by either IHC or (preferably) tandem mass spectrometry.



Giampaolo Talamo, MD