JULY 2015

Autologous Stem Cell Transplantation Is an Effective Salvage Therapy for Primary Refractory Multiple Myeloma.
Biol Blood Marrow Transplant. 2015 Jul;21(7):1330-4.
Parrish C, Rahemtulla A, Cavet J, Pearce RM, Kirkland K, Lee J, Cook M, Wilson K, Cook G; Clinical Trials Committee of the British Society for Blood and Marrow Transplantation.
In this study, 126 patients underwent an autologous stem cell transplant without achieving a partial remission after the induction chemotherapy. Despite the lack of initial response, the transplant was beneficial, because the response rate was 86% (CR 24%), and there were long term survivors. Progression-free survival (PFS) and overall survival (OS) at 5 years were 14% and 42%, respectively. Median PFS and OS were 18 and 51 months, respectively. The authors conclude that patients with primary refractory disease should not be excluded from an autologous transplant.

Clinical course and prognosis of non-secretory multiple myeloma.
Eur J Haematol. 2015 Jul;95(1):57-64.
Chawla SS, Kumar SK, Dispenzieri A, Greenberg AJ, Larson DR, Kyle RA, Lacy MQ, Gertz MA, Rajkumar SV.
This is an analysis of 124 patients with non-secretory myeloma. Their outcomes were compared to those of 6953 other myeloma patients. Interestingly, for the cohort of 36 patients diagnosed after 2001, the median overall survival of non-secretory myeloma was superior to that in patients with secretory myeloma (8.3 vs. 5.4 years, with a p=0.03).



Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations.
N Engl J Med. 2015 Aug 20;373(8):726-36.
Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E, Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J.

In this study, 122 patients with cancers positive for the BRAF V600 mutation received treatment with vemurafenib. Five of them had myeloma - no responses were observed.

Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma.
N Engl J Med. 2015 Aug 13;373(7):621-31.
Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators.
This is a phase 3 study which randomized patients with relapsed or refractory myeloma to either lenalidomide + dexamethasone (RD group, 325 patients) vs lenalidomide + dexamethasone + elotuzumab (RD-Elo group, 321 patients). Median follow-up was about 24 months. Results favored the RD-Elo group:
  - Response rate: 66% with RD vs 79% with RD-Elo
  - Median progression-free survival: 14.9 months with RD vs 19.4 months with RD-Elo
  - Progression-free survival at 2 years: 27% with RD vs 41% with RD-Elo 

NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma.
Nat Med. 2015 Aug;21(8):914-21.
Rapoport AP, Stadtmauer EA, Binder-Scholl GK, Goloubeva O, Vogl DT, Lacey SF, Badros AZ, Garfall A, Weiss B, Finklestein J, Kulikovskaya I, Sinha SK, Kronsberg S, Gupta M, Bond S, Melchiori L, Brewer JE, Bennett AD, Gerry AB, Pumphrey NJ, Williams D, Tayton-Martin HK, Ribeiro L, Holdich T, Yanovich S, Hardy N, Yared J, Kerr N, Philip S, Westphal S, Siegel DL, Levine BL, Jakobsen BK, Kalos M, June CH.
In this phase I/II trial, 20 patients with advanced myeloma were treated with engineered T cells 2 days after an autologous stem cell transplant. The engineered T cells expressed a T cell receptor (TCR) that recognized a peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. Clinical responses were observed in 16 patients (80%), and median progression-free survival was 19.1 months.

Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib.
Blood Cancer J. 2015 Aug 14;5:e338.
Kumar SK, LaPlant B, Roy V, Reeder CB, Lacy MQ, Gertz MA, Laumann K, Thompson MA, Witzig TE, Buadi FK, Rivera CE, Mikhael JR, Bergsagel PL, Kapoor P, Hwa L, Fonseca R, Stewart AK, Chanan-Khan A, Rajkumar SV, Dispenzieri A.
In this trial, 33 patients with relapsed myeloma, treated with a median of 2 prior therapies (range, 1-7), received ixazomib, 5.5 mg weekly for 3 of 4 weeks. Dexamethasone was added in 67% of patients. Response rate was 34%, and the median event-free survival was 11.5 months.



Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma.
N Engl J Med. 2015 Sep 10;373(11):1040-7.
Garfall AL, Maus MV, Hwang WT, Lacey SF, Mahnke YD, Melenhorst JJ, Zheng Z, Vogl DT, Cohen AD, Weiss BM, Dengel K, Kerr ND, Bagg A, Levine BL, June CH, Stadtmauer EA.
This is a case report of a patient with refractory myeloma who achieved a sustained complete response after treatment with autologous stem cell transplant followed by an infusion of CTL019 cells. Autologous T cells were transduced with an anti-CD19 chimeric antigen receptor using a lentiviral vector. The mechanism of action is not fully elucidated, because malignant plasma cells are generally negative for CD19.

Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma.
N Engl J Med. 2015 Sep 24;373(13):1207-19.
Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, Losic N, Lisby S, Basse L, Brun N, Richardson PG.
In the phase 2 of this trial, 72 patients with myeloma refractory to at least two prior lines of therapy were treated with daratumumab. These were heavily pretreated patients, because the median number of prior treatments was 4, and the median time since diagnosis was 5.7 years. 76% of patients had an autologous stem cell transplant, and 79% of them were refractory to the last line of therapy. Results:
  - Response rate: 36%
  - Median progression-free survival (with 16 mg/Kg): 5.6 months. 67% of the patients who responded did not have disease progression at 1 year.
  - Adverse reactions: infusion-related reactions (71% of patients, but of grade 3 in only 1%), thrombocytopenia, and pneumonia.

Paraproteinemic Keratopathy: The Expanding Diversity of Clinical and Pathologic Manifestations.
Ophthalmology. 2015 Sep;122(9):1748-56.
Milman T, Kao AA, Chu D, Gorski M, Steiner A, Simon CZ, Shih C, Aldave AJ, Eagle RC Jr, Jakobiec FA, Udell I.

Zoledronic acid as compared with observation in multiple myeloma patients at biochemical relapse: results of the randomized AZABACHE Spanish trial.
Haematologica. 2015 Sep;100(9):1207-13.
García-Sanz R, Oriol A, Moreno MJ, de la Rubia J, Payer AR, Hernández MT, Palomera L, Teruel AI, Blanchard MJ, Gironella M, Ribas P, Bargay J, Abellá E, Granell M, Ocio EM, Ribera JM, San Miguel JF, Mateos MV; Spanish Myeloma Group (GEM/PETHEMA).
In this study, 100 patients with multiple myeloma in relapse were randomized to receive either zoledronic acid 4 mg IV monthly (51 patients) or not (49 patients). Of note, patients had a biochemical relapse (as opposed to symptomatic relapse). The treatment with zoledronic acid did not have any antitumor effect (assessed by measuring the M component), but it was beneficial because it reduced the risk of progression to skeletal-related events (2 vs 14). Median time to symptoms was 16 vs 10 months, but the difference was not statistically significant (p=0.16).

Silent venous thromboembolism in multiple myeloma patients treated with lenalidomide.
Int J Hematol. 2015 Sep;102(3):271-7.

Isoda A, Sato N, Miyazawa Y, Matsumoto Y, Koumoto M, Ookawa M, Sawamura M, Matsumoto M.
In this study of 80 patients with relapsed/refractory myeloma, treatment with lenalidomide was associated with 18% rate of asymptomatic venous thromboembolism (VTE) of the lower extremities, despite prophylaxis with aspirin 100 mg daily. Patient were monitored with plasma D-dimer levels. VTE developed at a median time of 3 months after initiation of the lenalidomide therapy (range, 1-13 months).

BEAM Conditioning Regimen Has Higher Toxicity Compared With High-Dose Melphalan for Salvage Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma.
Clin Lymphoma Myeloma Leuk. 2015 Sep;15(9):531-5.
Veeraputhiran M, Jain T, Deol A, Ayash L, Kim S, Dyson G, Bhutani D, Lum LG, Ratanatharathorn V, Uberti JP, Abidi MH.

In this study, 43 patients with myeloma received a second autologous stem cell transplant at relapse after the first one. The conditioning regimen was high-dose melphalan with the first transplant, whereas it was either melphalan (19 patients) or BEAM (BCNU, etoposide, cytarabine, and melphalan) with the second one. The results favored melphalan:
  - The median progression free-survival was similar: 12.1 months with melphalan, and 7.7 months with BEAM (p=0.82)
  - BEAM was associated with higher toxicity, especially fever and infections (whereas melphalan was associated with a higher incidence of mucositis) 

Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma.
Blood. 2015 Sep 10;126(11):1294-301.
Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV.
This study published the results of the ECOG E1A06 protocol, which randomized 306 patients with newly diagnosed multiple myeloma into two groups: one treated with MPT (melphalan, prednisone, and thalidomide - 154 patients), and the second one with MPR (melphalan, prednisone, and lenalidomide - 152 patients). Patients were elderly (median age 76) and transplant-ineligible. Induction therapy consisted of:
  - Melphalan 9 mg/m2 (in the arm with thalidomide) or 5 mg/m2 (in the arm with lenalidomide) PO daily, on days 1-4 every 28 days
  - Prednisone 100 mg PO daily, on days 1-4 every 28 days
  - Thalidomide 100 mg PO daily continuously, or lenalidomide 10 mg daily on days 1-21, every 28 days
After 12 cycles, patients started maintenance therapy with either thalidomide 100 mg or lenalidomide 10 mg, to be continued indefinitely, until progression.
Median follow-up was 41 months. Clinical outcomes were similar, and neither regimen was well tolerated. Results favored the MPR arm, based on quality of life and toxicity profile (mainly neurotoxicity):
  - Response rate was similar: 64% with MPT, and 60% with MPR (p=0.56) (NB: this is lower than with other regimens used in the induction setting)
  - Median progression-free survival was similar: 21 months with MPT, and 19 with MPR (95% CI 0.64-1.09)
  - Median overall survival was similar: 53 months with MPT, and 48 months with MPR (p=0.48)
  - Toxicity of grade 3 or more: 73% with MPT vs 58% with MPR (NB: this is higher than with other regimens used in the induction setting)
  - Non-hematologic toxicities of grade 3 or more: 60% with MPT, and 40% with MPR (p=0.001)
  - Second malignancies: 18 patients with MPT, and 14 patients with MPR

Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma.
JAMA Oncol. 2015 Sep;1(6):746-54.
Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M, Tageja N, Kazandjian D, Mailankody S, Wu P, Morrison C, Costello R, Zhang Y, Burton D, Mulquin M, Zuchlinski D, Lamping L, Carpenter A, Wall Y, Carter G, Cunningham SC, Gounden V, Sissung TM, Peer C, Maric I, Calvo KR, Braylan R, Yuan C, Stetler-Stevenson M, Arthur DC, Kong KA, Weng L, Faham M, Lindenberg L, Kurdziel K, Choyke P, Steinberg SM, Figg W, Landgren O.

In this study, 45 patients with newly diagnosed myeloma were treated with CRD. Response rate was 98%, with 56% CR/sCR rate. Median time to CR was 5 cycles. The CRD regimen was well tolerated, and neuropathy of grade 3 or greater was not observed.

Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group.
J Clin Oncol. 2015 Sep 10;33(26):2863-9.
Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P, San Miguel J, Cavo M, Rajkumar SV, Moreau P.
The IMWG combined the data of 4,445 patients with newly diagnosed multiple myeloma enrolled in 11 international trials, and proposed a revised staging system for multiple myeloma (R-ISS). Median follow-up of these patients was 46 months. The revised system takes into account not only albumin and beta2-microglobulin, but also LDH and chromosomal abnormalities (CA) detected by FISH. Serum LDH was considered high if greater than the upper limit of normal range provided by the local laboratory. High-risk CA were defined by the presence of 17p-, t(4;14), or t(14;16).
The three new groups were defined as follows:
  - R-ISS   I (  871 pts): ISS I, normal LDH, and no high-risk CA    (5-year PFS 55%, 5-year OS 82%)
  - R-ISS  II (1,894 pts): Not R-ISS stage I or III                  (5-year PFS 36%, 5-year OS 62%)
  - R-ISS III (  295 pts): ISS III + either high LDH or high-risk CA (5-year PFS 24%, 5-year OS 40%)  

Pomalidomide-Induced Pulmonary Toxicity in Multiple Myeloma.
Am J Med Sci. 2015 Sep;350(3):241-2.
Modi D, Mamdani H, Vettese T.

Heavy/light chain specific immunoglobulin ratios provides no additional information than serum proteins electrophoresis and immunofixation for the diagnosis and the follow-up of intact immunoglobulin multiple myeloma patients.
Pathol Biol (Paris). 2015 Sep;63(4-5):215-21.
Beaumont-Epinette MP, Moreau C, Besnard S, Latute F, Collet N, Sebillot M, Grosbois B, Bendavid C, Guenet L, Decaux O.



Giampaolo Talamo, MD