APRIL 2016

Favorable long-term outcome of patients with multiple myeloma using a frontline tandem approach with autologous and non-myeloablative allogeneic transplantation.
Bone Marrow Transplant. 2016 Apr;51(4):529-35.
Ahmad I, LeBlanc R, Cohen S, Lachance S, Kiss T, Sauvageau G, Roy DC, Busque L, Delisle JS, Bambace N, Bernard L, Sabry W, Roy J.
In this study, 92 patients with newly diagnosed multiple myeloma younger than 65 were treated with an autologous stem cell transplant followed by a non-myeloablative allogeneic stem cell transplant, 2-3 months after the autologous one. The conditioning regimen for the allogeneic stem cell transplant consisted of fludarabine 30 mg/m2 IV and cyclophosphamide 300 mg/m2 IV, both of them for 5 days. The donors were 6/6 HLA-matched siblings. GVHD prophylaxis included tacrolimus and MMF. There was no maintenance therapy. Median follow-up was 8.8 years.
Despite the suboptimal induction chemotherapy (most patients received VAD, which was obsolete and considered inferior therapy at the time of the publication), the results were excellent, because the 10-year overall survival was 62%, and the 10-year progression-free survival was 41%, which suggested the potential for sure for a subset of patients treated with this approach. Unfortunately, the incidence of chronic GVHD was high (79%), but the non-relapsed mortality was low (10%).

Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma.
N Engl J Med. 2016 Apr 28;374(17):1621-34.
Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, Di Bacco A, Hui AM, van de Velde H, Richardson PG; TOURMALINE-MM1 Study Group.
This is a double-blind study of 722 patients with relapsed/refractory myeloma, randomized to receive lenalidomide 25 mg on days 1-21) + dexamethasone (40 mg on days 1, 8, 15, 22) + ixazomib (4 mg on days 1, 8, 15) vs lenalidomide + dexamethasone + placebo. After a median follow-up of about 15 months, the results were better in the ixazomib group:
  - Response rate was 78% in the ixazomib group, and 72% in the placebo group
  - CR + VGPR were 48% in the ixazomib group, and 39% in the placebo group
  - Median progression-free survival was 20.6 months in the ixazomib group, and 14.7 months in the placebo group
  - Median overall survival was not reached in either group
  - Adverse events: toxicities of at least grade 3 were observed in 74% of patients in the ixazomib group, and 69% of those in the placebo group; rash 36% vs 23%; peripheral neuropathy 27% vs 22%
Based on the results of this study, the FDA approved the use of ixazomib (in combination with lenalidomide and dexamethasone) for the treatment of patients with multiple myeloma who previously received at least one line of therapy.

A predictive tool particularly designed for elderly myeloma patients presenting with spinal cord compression.
BMC Cancer. 2016 Apr 25;16(1):292.
Rades D, Conde-Moreno AJ, Cacicedo J, Veninga T, Gebauer N, Bartscht T, Schild SE.
This is a retrospective study of 116 patients with spinal cord compression due to multiple myeloma.

Bortezomib-induced acute pancreatitis: Case report and review of the literature.
J Oncol Pharm Pract. 2016 Apr;22(2):332-4.
Talamo G, Sivik J, Pandey MK, Mir MA.


MAY 2016

VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial.
Blood. 2016 May 26;127(21):2569-74.
Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M.
In this study, 340 patients with newly diagnosed myeloma were randomized to receive either VTD (bortezomib, thalidomide, and dexamethasone), or VCD (bortezomib, cyclophosphamide, and dexamethasone, also called CyBorD). After 4 cycles of induction therapy, before an autologous stem cell transplant, the results were better with VDT: response rate was 92% with VTD, and 83% with VCD (p=0.01).

Distinct mechanisms account for acquired von Willebrand syndrome in plasma cell dyscrasias.
Ann Hematol. 2016 May;95(6):945-57.
Dicke C, Schneppenheim S, Holstein K, Spath B, Bokemeyer C, Dittmer R, Budde U, Langer F.

Cutaneous involvement in multiple myeloma (MM): A case series with clinicopathologic correlation.
J Am Acad Dermatol. 2016 May;74(5):878-84.
Malysz J, Talamo G, Zhu J, Clarke LE, Bayerl MG, Ali L, Helm KF, Chung CG.

Clinical characteristics and outcomes in biclonal gammopathies.
Am J Hematol. 2016 May;91(5):473-5.
Mullikin TC, Rajkumar SV, Dispenzieri A, Buadi FK, Lacy MQ, Lin Y, Dingli D, Go RS, Hayman SR, Zeldenrust SR, Russell SJ, Lust JA, Leung N, Kapoor P, Kyle RA, Gertz MA, Kumar SK.
These authors identified 539 patients with biclonal gammopathies. Of these, 393 had BGUS (biclonal gammopathy of undertermined significance), and 22 of this subset of patients progressed to a hematologic malignancy: symptomatic myeloma (11), smoldering myeloma (6), primary amyloidosis (3), or lymphoplasmacytic lymphoma (2). The rate of progression to hematologic malignancy was approximately 1% per year, which is similar to the rate of progression with MGUS. According to this study, the overall clinical significance of a BGUS is very similar to that of MGUS. 

Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma.
Blood. 2016 May 26;127(21):2561-8.
Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S.
This study evaluated the addition of cyclophosphamide to the standard combination of pomalidomide and dexamethasone in 80 patients with relapsed/refractory myeloma. In the randomized phase 2 portion of the study, 36 patients received Pom-Dex, and 34 patients Pom-Cy-Dex. Results were better with Pom-Cy-Dex:
  - Response rate: 39% with Pom-Dex, and 65% with Pom-Cy-Dex (p=0.035)
  - Median progression-free survival was 4.4 months with Pom-Dex, and 9.5 months with Pom-Cy-Dex (p=0.106)


JUNE 2016

Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial.
Br J Haematol. 2016 Jun;173(5):731-41.
Mai EK, Benner A, Bertsch U, Brossart P, Hänel A, Kunzmann V, Naumann R, Neben K, Egerer G, Ho AD, Hillengass J, Raab MS, Neubauer A, Peyn A, Ko YD, Peter N, Scheid C, Goldschmidt H.
This is a prospective study of 358 patients randomized to receive either a single transplant (188 patients) or tandem transplants (197 patients). Post-transplant maintenance was done with the use of interferon three times a week, a practice which was obsolete at the time of the publication. Of note, in the tandem arm, 26% of patients refused the second autologous transplant (p>0.05). In an intention-to-treat analysis, after a median follow-up of 134 months, results were as follows:
  - Response rate: 93% with single transplant, and 91% with tandem transplants
  - Median event-free survival: 25 months with single transplant, and 29 months with tandem transplants
  - Median overall survival: 73 months with single transplant, and 75 months with tandem transplants
  - 10-year overall survival: 34% with single transplant, and 33% with tandem transplants

TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström's macroglobulinemia.
Am J Hematol. 2016 Jun;91(4):400-5.
Ghobrial IM, Siegel DS, Vij R, Berdeja JG, Richardson PG, Neuwirth R, Patel CG, Zohren F, Wolf JL.
In this phase 1 study, 31 patients with relapsed/refractory myeloma received TAK-228, an oral TORC1/2 inhibitor. One patient had a minimal response, and 14 patients had stable disease.

A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma.
Leukemia. 2016 Jun;30(6):1320-6.
Larocca A, Bringhen S, Petrucci MT, Oliva S, Falcone AP, Caravita T, Villani O, Benevolo G, Liberati AM, Morabito F, Montefusco V, Passera R, De Rosa L, Omedé P, Vincelli ID, Spada S, Carella AM, Ponticelli E, Derudas D, Genuardi M, Guglielmelli T, Nozzoli C, Aghemo E, De Paoli L, Conticello C, Musolino C, Offidani M, Boccadoro M, Sonneveld P, Palumbo A.
In this study, 152 patients with newly diagnosed myeloma, 75 year-old and oler, received treatment with SC bortezomib in one of 3 regimens: bortezomib + prednisone (VP, 51 patients), bortezomib + prednisone + cyclophosphamide (VCP, 51 patients), and bortezomib + prednisone + melphalan (VMP, 50 patients). This was followed by maintenance therapy . Although VMP had slightly better results, it was more toxic, and the authors suggested that frail patients should be treated with a two-drug combination, followed by maintenance.
  - Response rate: 64% with VP, 67% with VCP, 86% with VMP
  - Median progression-free survival: 14 months with VP, 15.2 months with VCP, 17.1 months with VMP
 - Toxicity-related deaths at 6 months: 4% with VP, 4% with VCP, 8% with VMP

Central nervous system involvement by multiple myeloma: A multi-institutional retrospective study of 172 patients in daily clinical practice.
Am J Hematol. 2016 Jun;91(6):575-80.
Jurczyszyn A, Grzasko N, Gozzetti A, Czepiel J, Cerase A, Hungria V, Crusoe E, Silva Dias AL, Vij R, Fiala MA, Caers J, Rasche L, Nooka AK, Lonial S, Vesole DH, Philip S, Gangatharan S, Druzd-Sitek A, Walewski J, Corso A, Cocito F, Vekemans MC, Atilla E, Beksac M, Leleu X, Davila J, Badros A, Aneja E, Abildgaard N, Kastritis E, Fantl D, Schutz N, Pika T, Butrym A, Olszewska-Szopa M, Usnarska-Zubkiewicz L, Usmani SZ, Nahi H, Chim CS, Shustik C, Madry K, Lentzsch S, Swiderska A, Helbig G, Guzicka-Kazimierczak R, Lendvai N, Waage A, Andersen KT, Murakami H, Zweegman S, Castillo JJ.
This is a retrospective study conducted in 38 centers from 20 countries, and it included 172 patients with myeloma involving the CNS system. The median overall survival from the onset of CNS involvement was 7 months (2 months without treatment, and 8 months with treatment).

A phase II study of AT9283, an aurora kinase inhibitor, in patients with relapsed or refractory multiple myeloma: NCIC clinical trials group IND.191.
Leuk Lymphoma. 2016 Jun;57(6):1463-6.
Hay AE, Murugesan A, DiPasquale AM, Kouroukis T, Sandhu I, Kukreti V, Bahlis NJ, Lategan J, Reece DE, Lyons JF, Sederias J, Xu H, Powers J, Seymour LK, Reiman T.
AT9283 is a multi-targeted inhibitor of Aurora kinases A and B, as well as JAK2 and JAK3. The trial was closed due to slow accrual and toxicity (myelosuppression). The results were disappointing, because no responses were observed among the 8 patients enrolled.

Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM.
Blood. 2016 Jun 9;127(23):2833-40.
Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach J, Mohrbacher A, Carella AM, Singhal AK, Tsao LC, Lynch M, Bleickardt E, Jou YM, Robbins M, Palumbo A.
In this study, 152 patients with relapsed/refractory myeloma were randomized to receive either bortezomib + dexamethasone (VD) or bortezomib + dexamethasone + elotuzumab (E-VD). No significant increase of toxicities was observed in the arm receiving elotuzumab. Infusion reactions were uncommon (5%) and usually mild. The results favored the arm with the addition of elotuzumab. Response rate was 63% with VD and 66% with E-VD. Median progression-free survival 6.9 months with VD and 9.7 months with E-VD.

CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma.
Blood. 2016 Jun 30;127(26):3360-8.
Berenson JR, Cartmell A, Bessudo A, Lyons RM, Harb W, Tzachanis D, Agajanian R, Boccia R, Coleman M, Moss RA, Rifkin RM, Patel P, Dixon S, Ou Y, Anderl J, Aggarwal S, Berdeja JG.
In this study, 116 patients with relapsed/refractory myeloma were treated with carfilzomib once a week. After the phase I portion of the study, the regimen consisted of carfilzomib 70 mg/m2 IV over 30 minutes on days 1, 8, 15 every 28 days + dexamethasone 40 mg orally or IV on the same days. The response rate was 77%, and the median progression free survival 12.6 months.



Giampaolo Talamo, MD