Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma.
N Engl J Med. 2016 Oct 6;375(14):1319-1331.
Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators.
This is a phase III trial which randomized 569 patients with relapsed myeloma in a group receiving RD (lenalidomide and dexamethasone) and another group receiving RD-daratumumab. At a mnedian follow-up of 13.5 months, the results favored the addition of daratumumab:
  - Response rate: 76.4% with RD (CR 19.2%) vs 92.9% with RD-daratumumab (CR 43.1%)
  - Progression-free survival at 12 months: 60.1% with RD vs 83.2% with RD-daratumumab (median PFS 18.4 months vs not reached)

Pentoxifylline and tocopherol in the management of cancer patients with medication-related osteonecrosis of the jaw: an observational retrospective study of initial case series.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2016 Oct;122(4):455-9.
Owosho AA, Estilo CL, Huryn JM, Yom SK.

Post-Transplant Outcomes in High-Risk Compared with Non-High-Risk Multiple Myeloma: A CIBMTR Analysis.
Biol Blood Marrow Transplant. 2016 Oct;22(10):1893-9.
Scott EC, Hari P, Sharma M, Le-Rademacher J, Huang J, Vogl D, Abidi M, Beitinjaneh A, Fung H, Ganguly S, Hildebrandt G, Holmberg L, Kalaycio M, Kumar S, Kyle R, Lazarus H, Lee C, Maziarz RT, Meehan K, Mikhael J, Nishihori T, Ramanathan M, Usmani S, Tay J, Vesole D, Wirk B, Yared J, Savani BN, Gasparetto C, Krishnan A, Mark T, Nieto Y, D'Souza A.
This is a retrospective study of 715 patients with mutliple myeloma who underwent an upfront autologous stem cell transplant (i.e., within 12 months of diagnosis). In 125 patients (17.5%), the myeloma had high-risk features at cytogenetic analysis/FISH, defined as 17p-, t(4;14), t(14;16), hypodiploidy (<45 chromosomes excluding -Y), or chromosome 1 abnormalities (1q+ or 1p-). The results showed that the response rates were similar after the transplant (evaluated at day 100): 59% in the high-risk group, and 61% in the other group. However, as expected, those responses were not sustained:
  - Progression-free survival at 3 years: 37% in the high-risk group, and 49% in the other group
  - Overall survival at 3 years: 72% in the high-risk group, and 85% in the other group

Identification of a new potential mechanism responsible for severe bleeding in myeloma: immunoglobulins bind the heparin binding domain of antithrombin activating this endogenous anticoagulant.
Haematologica. 2016 Oct;101(10):e423-e426.
Martínez-Martínez I, González-Porras JR, Cebeira MJ, de Arriba F, Espín S, Bohdan N, Corrales FJ, Corral J, Vicente V.

Outcomes in patients with multiple myeloma with TP53 deletion after autologous hematopoietic stem cell transplant.
Am J Hematol. 2016 Oct;91(10):E442-7.
Gaballa S, Saliba RM, Srour S, Lu G, Brammer JE, Shah N, Bashir Q, Patel K, Bock F, Parmar S, Hosing C, Popat U, Delgado R, Rondon G, Shah JJ, Manasanch EE, Orlowski RZ, Champlin R, Qazilbash MH.
This is a retrospective study that compared outcomes of an autologous stem cell transplant in 34 patients with high-risk disease due to 17p-, vs 111 control patients, with multiple myeloma but without 17p-.
  - Median progression-free survival: 8 months with 17p-, and 28 months without 17p-
  - Median overall survival: 21 months with 17p-, and 56 months without 17p-

Melphalan 200 mg/m2 in patients with renal impairment is associated with increased short-term toxicity but improved response and longer treatment-free survival.
Bone Marrow Transplant. 2016 Oct;51(10):1337-1341.
Sweiss K, Patel S, Culos K, Oh A, Rondelli D, Patel P.
This is a retrospective study of 46 patients with multiple myeloma and mild or moderate renal insufficiency (creatinine clearance 20-59), who underwent an autologous stem cell transplant. Their clinical outcomes were compared to a group of 103 patients with normal renal function (creatinine clearance 60). Of note, all patients received melphalan 200 mg/m2. Patients with creatinine clearance <60 had a greater rate of grade 4 mucositis (28% vs 16%), TPN use, grade 2-4 diarrhea, and infections. Although median "treatment-free survival" was longer in patients with normal renal function (37 vs 17 months), the overall survival was similar in the two groups.



Outcomes and management of lenalidomide-associated rash in patients with multiple myeloma.
Leuk Lymphoma. 2016 Nov;57(11):2510-5.
Barley K, He W, Agarwal S, Jagannath S, Chari A.

Elotuzumab in combination with thalidomide and low-dose dexamethasone: a phase 2 single-arm safety study in patients with relapsed/refractory multiple myeloma.
Br J Haematol. 2016 Nov;175(3):448-456.
Mateos MV, Granell M, Oriol A, Martinez-Lopez J, Blade J, Hernandez MT, Martín J, Gironella M, Lynch M, Bleickardt E, Paliwal P, Singhal A, San-Miguel J.
In this study, 40 patients with relapsed/refractory myeloma received the a combination of elotuzumab, thalidomide 50-200 mg daily, and dexamethasone 40 mg weekly. Cyclophosphamide 50 mg daily was added to the regimen if at least a partial response was not reached by cycle 5, or the myeloma progressed between cycles 2 and 5. The response rate was 38%, and the median progression-free survival was 3.9 months.

Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial.
Lancet Oncol. 2016 Nov;17(11):1569-1578.
Yee AJ, Bensinger WI, Supko JG, Voorhees PM, Berdeja JG, Richardson PG, Libby EN, Wallace EE, Birrer NE, Burke JN, Tamang DL, Yang M, Jones SS, Wheeler CA, Markelewicz RJ, Raje NS.
In this study, 38 patients with relapsed/refractory myeloma received treatment with lenalidomide, dexamethasone, and ricolinostat, an oral histone deacetylase (HDAC) inhibitor. Since it was a phase 1b trial, its goal was not to assess antitumor efficacy. However, a preliminary analysis of the data showed a response rate of 55%.

Randomized phase 2 trial of ixazomib and dexamethasone in relapsed multiple myeloma not refractory to bortezomib.
Blood. 2016 Nov 17;128(20):2415-2422.
Kumar SK, LaPlant BR, Reeder CB, Roy V, Halvorson AE, Buadi F, Gertz MA, Bergsagel PL, Dispenzieri A, Thompson MA, Crawley J, Kapoor P, Mikhael J, Stewart K, Hayman SR, Hwa YL, Gonsalves W, Witzig TE, Ailawadhi S, Dingli D, Go RS, Lin Y, Rivera CE, Rajkumar SV, Lacy MQ.
In this study, 70 patients with relapsed myeloma were given ixazomib 4 (35 patients) or 5.5 mg (35 patients) on days 1, 8, 15 every 28 days, along with dexamethasone 40 mg once a week. Results:
  - Response rate: 43% (95% CI: 31-55%)
  - Median event-free survival: 8.4 months
  - Event-free survival: 5.7 months in patients with prior bortezomib treatment, and 11 months in patients without prior bortezomib treatment
  - Patients treated with 5.5 mg had a higher response rate, but more toxicity

MMSET/WHSC1 enhances DNA damage repair leading to an increase in resistance to chemotherapeutic agents.
Oncogene. 2016 Nov 10;35(45):5905-5915.
Shah MY, Martinez-Garcia E, Phillip JM, Chambliss AB, Popovic R, Ezponda T, Small EC, Will C, Phillip MP, Neri P, Bahlis NJ, Wirtz D, Licht JD.



IAP antagonists induce anti-tumor immunity in multiple myeloma.
Nat Med. 2016 Dec;22(12):1411-1420.
Chesi M, Mirza NN, Garbitt VM, Sharik ME, Dueck AC, Asmann YW, Akhmetzyanova I, Kosiorek HE, Calcinotto A, Riggs DL, Keane N, Ahmann GJ, Morrison KM, Fonseca R, Lacy MQ, Dingli D, Kumar SK, Ailawadhi S, Dispenzieri A, Buadi F, Gertz MA, Reeder CB, Lin Y, Chanan-Khan AA, Stewart AK, Fooksman D, Bergsagel PL.
This is a study done in mouse models and patients with relapsed/refractory myeloma. The use of LCL161, a small-molecule IAP antagonist, led to anti-myeloma activity significant remission of the disease. cIAP = cellular inhibitors of apoptosis, 1 and 2.

Comparison of two dose levels of cyclophosphamide for successful stem cell mobilization in myeloma patients.
J Cancer Res Clin Oncol. 2016 Dec;142(12):2603-2610.
Winkelmann N, Desole M, Hilgendorf I, Ernst T, Sayer HG,3, Kunert C, Mügge LO, Hochhaus A, Scholl S.
This is a retrospective study which compared outcomes of stem cell collection in two groups of patients with multiple myeloma, one (48 patients) that received "intermediate-dose" cyclophosphamide, 2.5 g/m2, and another (53 patients) that received "high-dose" cyclophosphamide, 4 g/m2. Collection failure was define as the inability to collect more than 5 million CD34+ cells/Kg. Results:
  - Median time to apheresis: 11 days with 2.5 g/m2, and 12 days with 4 g/m2
  - Median CD34+ cells/Kg: 8.3 with 2.5 g/m2, and 7.6 with 4 g/m2
  - Neutropenic fever: 15% with 2.5 g/m2, and 34% with 4 g/m2 (p=0.08)
  - Collection failure: 10% with 2.5 g/m2, and 16% with 4 g/m2
The authors conclude that mobilization cyclophosphamide with 2.5 g/m2 is effective and safer than with 4 g/m2.

Outcome of Patients with Multiple Myeloma and CKS1B Gene Amplification after Autologous Hematopoietic Stem Cell Transplantation.
Biol Blood Marrow Transplant. 2016 Dec;22(12):2159-2164.
Bock F, Lu G, Srour SA, Gaballa S, Lin HY, Baladandayuthapani V, Honhar M, Stich M, Shah ND, Bashir Q, Patel K, Popat U, Hosing C, Korbling M, Delgado R, Rondon G, Shah JJ, Thomas SK, Manasanch EE, Isermann B, Orlowski RZ, Champlin RE, Qazilbash MH.
This is a retrospective study comparing post-transplant outcomes of patients with multiple myeloma with 1q21+ (gain/amplification of the CKS1B gene on the chromosome 1q21 region) (58 patients) vs those without it (58 patients). Median follow-up after the autolous stem cell transplant was 25.4 months. The results showed the adverse prognostic impact of 1q21+:
  - Median progression-free survival: 15 months with 1q21+, and 33 months without it (p=0.002)
  - Overall survival at 2 years: 62% with 1q21+, and 91% without it (p=0.02)

Survival Analyses and Prognosis of Plasma-Cell Myeloma and Plasmacytoma-Like Posttransplantation Lymphoproliferative Disorders.
Clin Lymphoma Myeloma Leuk. 2016 Dec;16(12):684-692.e3.
Rosenberg AS, Ruthazer R, Paulus JK, Kent DM, Evens AM, Klein AK.
These authors report 212 cases of "Myeloma/plasmacytoma-like post-transplantation lymphoproliferative disorder" (PTLD-MM), after solid organ transplantation. Extramedullary disease was present in 58% of cases. Median OS of the entire group was only 2.4 years (but many patients were treated with old chemotherapy regimens). Median OS of patients more recently diagnosed (2006-2010) was 44 months.

Prolonged survival with a longer duration of maintenance lenalidomide after autologous hematopoietic stem cell transplantation for multiple myeloma.
Cancer. 2016 Dec 15;122(24):3831-3837.
Mian I, Milton DR, Shah N, Nieto Y, Popat UR, Kebriaei P, Parmar S, Oran B, Shah JJ, Manasanch EE, Orlowski RZ, Shpall EJ, Champlin RE, Qazilbash MH, Bashir Q.
The optimal duration of maintenance therapy after an autologous stem cell transplant in patients with multiple myeloma is unknown. This retrospective study analyzed clinical outcomes of maintenance therapy with lenalidomide in 464 patients. In the overall group, median PFS was 38 months, and median OS 78 months. An additional 19% of patients achieved CR with the maintenance therapy. Revlimid maintenance had to be discontinued in 20% of patients, due to a variety of reasons, including progression (31%), cytopenias (32%), skin rash (14%), fatigue (9%), and GI toxicities (5%). Multivariate analysis showed that longer survival was observed in those patients who received maintenance for longer than 2 years (HR for PFS 0.13, and HR for OS 0.09), and the effect was seen even in those patients on maintenance for >3 years vs <3 years ((HR for PFS 0.02, and HR for OS 0.05). Secondary malignancies were observed in 3% of patients, and the most common malignancy was MDS. No association was found between incidence of secondary malignancies and duration of the Revlimid maintenance. The authors reminded us that the risk of death from relapsed myeloma is greater than the risk of death from secondary malignancies, and therefore the benefit/risk ratio of Revlimid maintenance vs observation is in favor of maintenance. The conclusion of the study, within the limitation of its retrospective nature, is that Revlimid maintenance should be continued indefinitely, until either disease progression or unacceptable toxicity. The optimal dose of Revlimid for post-transplant maintenance remains unknown. The authors used various doses, between 5 and 15 mg, at the discretion of the treating physician.

Phase II trial of nab-paclitaxel in patients with relapsed or refractory multiple myeloma.
Am J Hematol. 2016 Dec;91(12):E504-E505.
Jain T, Dueck AC, Kosiorek HE, Ginos BF, Mayo A, Reeder CB, Chesi M, Mikhael J, Keith Stewart A, Leif Bergsagel P, Fonseca R.
This was a trial with disappointing clinical results. Nab-paclitaxel was administered to 13 patients with relapsed/refractory myeloma, and only 2 patients (13%) responded to it. The study was terminated after the enrollment of the first cohort.

Differences between unselected patients and participants in multiple myeloma clinical trials in US: a threat to external validity.
Leuk Lymphoma. 2016 Dec;57(12):2827-2832.
Costa LJ1, Hari PN2, Kumar SK3.

Serum free light chains, not urine specimens, should be used to evaluate response in light-chain multiple myeloma.
Blood. 2016 Dec 22;128(25):2941-2948.
Dejoie T, Corre J, Caillon H, Hulin C, Perrot A, Caillot D, Boyle E, Chretien ML, Fontan J, Belhadj K, Brechignac S, Decaux O, Voillat L, Rodon P, Fitoussi O, Araujo C, Benboubker L, Fontan C, Tiab M, Godmer P, Luycx O, Allangba O, Pignon JM, Fuzibet JG, Legros L, Stoppa AM, Dib M, Pegourie B, Orsini-Piocelle F, Karlin L, Arnulf B, Roussel M, Garderet L, Mohty M, Meuleman N, Doyen C, Lenain P, Macro M, Leleu X, Facon T, Moreau P, Attal M, Avet-Loiseau H.
This is a study that prospectively compared results of serum and urine specimen in the context of the 2009 IFM myeloma trial. The authors showed that in 113 patients with light chain myeloma, serum free light chains (FLC) were superior to urine methods (UPEP and uIFE) in the monitoring the response to therapy. Serum FLC had superior sensitivity and prognostic value. At baseline, FLC were abnormal in 100% of patients, whereas a measurable urine M component (>200 mg/24 hours) by UPEP was observed in only 64% of cases. After 3 cycles of chemotherapy, serum FLC remained elevated in 46% of patients, and urine M only in 18% (and all patients with positive UPEP had elevated serum FLC). The authors concluded that urine tests underestimated the amount of FLC production, and overestimated the response to chemotherapy. Progression-free survival after 3 cycles of chemotherapy was shorter in patients with elevated serum FLC, but not with positive UPEP or uIFE. Serum FLC levels are preferred over urine FLC, which are more erratic, presumably because of the variable urine excretion rate of the FLC among different individuals. 

Obesity and the Transformation of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma: A Population-Based Cohort Study.
Chang SH, Luo S, Thomas TS, O'Brian KK, Colditz GA, Carlsson NP, Carson KR.
J Natl Cancer Inst. 2016 Dec 31;109(5).
These authors studied the outcomes of 7878 patients with MGUS after a median follow-up of about 5 years and a half. They concluded that obesity is a risk factor for progression to multiple myeloma. However, the difference was not high, because myeloma developed in 72 (3.5%) normal-weight patients, and in 113 (4.3%) obese patients. Black race was another risk factor to progression to multiple myeloma.



Giampaolo Talamo, MD