Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120).
Blood. 2014 Jan 2;123(1):78-85.
Dhodapkar MV, Sexton R, Waheed S, Usmani S, Papanikolaou X, Nair B, Petty N, Shaughnessy JD Jr, Hoering A, Crowley J, Orlowski RZ, Barlogie B.

DCEP for relapsed or refractory multiple myeloma after therapy with novel agents.
Ann Hematol. 2014 Jan;93(1):99-105.
Park S, Lee SJ, Jung CW, Jang JH, Kim SJ, Kim WS, Kim K.
DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) was administered as salvage chemotherapy to 59 patients with relapsed or refractory myeloma. Response rate was 45% (stable disease in 10 patients, minor response in 8, PR in 21, VGPR in 1, and CR in 1). Death secondary to chemotherapy occurred in 8 patients, and in 7 of them (12%), it was related to neutropenic fever. 

Heterogeneity of genomic evolution and mutational profiles in multiple myeloma.
Nat Commun. 2014 Jan 16;5:2997.
Bolli N1, Avet-Loiseau H2, Wedge DC3, Van Loo P4, Alexandrov LB3, Martincorena I3, Dawson KJ3, Iorio F5, Nik-Zainal S6, Bignell GR3, Hinton JW3, Li Y3, Tubio JM3, McLaren S3, O' Meara S3, Butler AP3, Teague JW3, Mudie L3, Anderson E3, Rashid N7, Tai YT7, Shammas MA8, Sperling AS7, Fulciniti M7, Richardson PG7, Parmigiani G9, Magrangeas F10, Minvielle S10, Moreau P11, Attal M12, Facon T13, Futreal PA14, Anderson KC7, Campbell PJ1, Munshi NC8.

Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells.
Science. 2014 Jan 17;343(6168):301-5.
Krönke J1, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C, Hartman E, Munshi N, Schenone M, Schreiber SL, Carr SA, Ebert BL.

The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins.
Science. 2014 Jan 17;343(6168):305-9.
Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, Wong KK, Bradner JE, Kaelin WG Jr.



Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse.
Haematologica. 2014 Feb;99(2):360-4.
Pour L, Sevcikova S, Greslikova H, Kupska R, Majkova P, Zahradova L, Sandecka V, Adam Z, Krejci M, Kuglik P, Hajek R.
Among 226 patients with relapsed myeloma, purely extramedullary disease was observed in 32 (14%). These patients had a poor prognosis, with median overall survival of 30 months from diagnosis.

IMWG consensus on risk stratification in multiple myeloma.
Leukemia. 2014 Feb;28(2):269-77.
Chng WJ, Dispenzieri A, Chim CS, Fonseca R, Goldschmidt H, Lentzsch S, Munshi N, Palumbo A, Miguel JS, Sonneveld P, Cavo M, Usmani S, Durie BG, Avet-Loiseau H.
The International Myeloma Working Group (IMWG) proposed the use a combination of ISS and FISH for risk stratification in multiple myeloma, according to the following categories:
  - Low risk      (20%): age <55, ISS I/II, FISH without 17p13 del, t(4;14), 1q21 gain
                         Median overall survival >10 years
  - Standard risk (60%): all others
                         Median overall survival   7 years
  - High risk     (20%): ISS II/III, FISH with 17p13 del, t(4;14)
                         Median overall survival   2 years

Sinonasal extramedullary plasmacytoma: a systematic review of 175 patients.
D'Aguillo C1, Soni RS, Gordhan C, Liu JK, Baredes S, Eloy JA.
Int Forum Allergy Rhinol. 2014 Feb;4(2):156-63.

Pattern of relapse and progression after autologous SCT as upfront treatment for multiple myeloma.
Bone Marrow Transplant. 2014 Feb;49(2):223-7.
Fernández de Larrea C, Jiménez R, Rosiñol L, Giné E, Tovar N, Cibeira MT, Fernández-Avilés F, Martínez C, Rovira M, Bladé J.
This is a study of 211 patients with multiple myeloma who underwent an autologous stem cell transplant and were followed at the time of disease progression/relapse. The authors describe findings that confirmed the practical knowledge of BMT centers following myeloma patients:
  - About half of the patients has an asymptomatic relapse/progression, with the only evidence of disease reactivation being a reappearance or increase of the myeloma markers
    ("serological relapse/progression");
  - Extramedullary disease was a frequent event at relapse/progression (24% of cases);
  - The treatment-free interval (= time spent without retreatment with chemotherapy) was longer in patients who had relapse from complete remission than in those with progression from partial remission;
  - The median overall survival was longer in patients who has an asymptomatic/serological relapse/progression than in those who were symptomatic.

Bendamustine-bortezomib-dexamethasone is an active and well-tolerated regimen in patients with relapsed or refractory multiple myeloma.
Blood. 2014 Feb 13;123(7):985-91.
Ludwig H, Kasparu H, Leitgeb C, Rauch E, Linkesch W, Zojer N, Greil R, Seebacher A, Pour L, Weißmann A, Adam Z.
In this study, 79 patients with relapsed/refractory myeloma received the following combination chemotherapy:
  - Bendamustine 70 mg/m2 IV on days 1, 4
  - Bortezomib 1.3 mg/m2 on days 1, 4, 8, 11
  - Dexamethasone 20 mg on days 1, 4, 8, 11
Cycles were repeated every 28 days x 8. Results:
  - Response rate: 61% (76% when including minor responses)
  - Median progression-free survival: 10 months
  - Median overall survival: 26 months

Evaluation of mortality among marines and navy personnel exposed to contaminated drinking water at USMC base Camp Lejeune: a retrospective cohort study.
Environ Health. 2014 Feb 19;13(1):10.
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 154,932 cases exposed to drinking the contaminated water, the mortality hazard ratio for multiple myeloma was elevated (1.68, 95% CI: 0.76-3.72).


MARCH 2014

Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients.
Leukemia. 2014 Mar;28(3):690-3.
Nooka AK, Kaufman JL, Muppidi S, Langston A, Heffner LT, Gleason C, Casbourne D, Saxe D, Boise LH, Lonial S.
A total of 45 patients with high-risk myeloma were treated with autologous stem cell transplant followed by VRD maintenance. High-risk was defined by the presence of primary plasma cell leukemia (>20% plasma cells in the peripheral blood at presentation), 17p-, t(4;14), t(14;16), and 1p deletion. VRD consisted of:
  - Bortezomib 1.3 mg/m2 SC/IV once a week
  - Lenalidomide 10 mg PO on days 1-21 every 28 days
  - Dexamethasone 40 mg PO once a week
After 3 years VRD, patients continued maintenance with single-agent lenalidomide.
Median follow-up was 26 months. The results were good, considering the high-risk nature of the patient population:
  - Median progression-free survival: 32 months
  - Overall survival at 3 years: 93%

Anti-epidermal growth factor receptor antibody cetuximab in refractory or relapsed multiple myeloma: a phase II prospective clinical trial.
Leuk Lymphoma. 2014 Mar;55(3):695-7.
von Tresckow B1, Boell B, Eichenauer D, Beschorner D, Knop S, Goebeler ME, Chemnitz JM, Hallek M, Engert A, Huebel K.
A total of 15 patients with relapsed/refractory myeloma were treated with cetuximab, a monoclonal antibody against EGFR (= epidermal growth factor receptor). EGFR is a protein expressed by malignant plasma cells and also by bone marrow stromal cells. Preclinical models previously indicated that cetuximab is able to induce apoptosis of myeloma cells. The results of the clinical trial, after 4 months of therapy, indicated an overall response rate of only 7% (1 partial remission). The "clinical benefit", defined by the percentage of patient in remission or with stable disease, was 47% (6 patients had stable disease). Of note, the majority of patients received dexamethasone as well.

Secondary monoclonal gammopathy of undetermined significance is frequently associated with high response rate and superior survival in patients with plasma cell dyscrasias.
Biol Blood Marrow Transplant. 2014 Mar;20(3):319-25.
Zou D, An G, Zhu G, Wang J, Shi L, Meng H, Xu Y, Sui W, Deng S, Zhan F, Qiu L.
Among 438 patients with either myeloma (409) or plasma cell leukemia (29), about 30% of patients after a stem cell transplant developed a secondary MGUS. Patients with secondary MGUS had a higher rate of complete remission (82% vs 22%), better median progression-free survival (52 vs 22.5 months), and better median overall survival ("not reached" vs 35 months).

Long-term disease control in patients with newly diagnosed multiple myeloma after suspension of lenalidomide therapy.
Am J Hematol. 2014 Mar;89(3):302-5.
Kourelis TV1, Kumar SK, Srivastava G, Gertz MA, Lacy MQ, Buadi FK, Hayman SR, Zeldenrust SR, Leung N, Kyle RA, Russell SJ, Dingli D, Lust JA, Lin Y, Kapoor P, Go R, Rajkumar SV, Dispenzieri A.
Among 131 patients with newly diagnosed myeloma treated with dexamethasone and lenalidomide, 31 discontinued the treatment for several reasons, while the myeloma was in remission. Median progression-free survival from the time of stopping the lenalidomide was 39 months in those patients who received lenalidomide for 1 year or more. This study shows that the so-called "drug holidays" are feasible in some patients with multiple myeloma. Of note, all patients who had progressive disease responded again to lenalidomide and dexamethasone. 



Giampaolo Talamo, MD