APRIL 2017

Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma.
N Engl J Med. 2017 Apr 6;376(14):1311-1320.
Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM 2009 Study.
The aim of this study, IFM 2009, was to establish whether the autologous transplant was still the best approach in the treatment of newly diagnosed myeloma, or combinations of novel chemotherapy agents could supplant or delay its use. 700 patients were randomized to receive either VRD (bortezomib, lenalidomide, and dexamethasone) for 8 cycles (VRD group, 350 patients), or VRD for 3 cycles followed by an autologous stem cell transplant, then 2 cycles of VRD (transplant group, 350 patients). Stem cells were collected with cyclophosphamide and G-CSF. In both groups, patients received 1 year of maintenance therapy with lenalidomide 10-15 mg. After a median follow-up of about 3 and a half years, transplant prolonged remission, but it did not improve overall survival. Results:
  - Rate of complete remission: 48% in the VRD group, and 59% in the transplant group
  - Median progression-free survival: 36 months in the VRD group, and 50 months in the transplant group
  - Overall survival at 4 years: 82% in the VRD group, and 81% in the transplant group
Interestingly, stem cells were collected with cyclophosphamide. Although this was not the intent of the trial, the survival results suggest that chemotherapy for mobilization purposes only does not seem to be necessary in these patients.
It has to be noted that many (79%) of the patients who were assigned to the VRD group did receive a "salvage" transplant at the time of disease progression. Therefore, the conclusion of this study should not be that transplant is not necessary any more, but that it can be delayed until disease progression. Unfortunately, since there is no apparent plateau in the survival curves, it seems that even with the best currently available regimens, the majority of patients with myeloma do not achieve a definitive cure.

Prolonged Use of Zoledronic Acid (4 Years) Did Not Improve Outcome in Multiple Myeloma Patients.
Clin Lymphoma Myeloma Leuk. 2017 Apr;17(4):207-210.
Avilès A, Nambo MJ, Huerta-Guzmàn J, Cleto S, Neri N.
A total of 170 patients with newly diagnosed myeloma were divided in two groups, one treated with zoledronic acid for 2 years (standard group), and the other for 4 years. Overall survival at 5 years was the same (68% in both groups), but the rate of skeletal events was reduced (21% in the 2-year group, and 43% in the 4-year group (p<0.001).

Absence of spontaneous response improvement beyond day +100 after autologous stem cell transplantation in multiple myeloma.
Bone Marrow Transplant. 2017 Apr;52(4):567-569.
Fernández de Larrea C, Dávila J, Isola I, Ocio EM, Rosiñol L, García-Sanz R, Cibeira MT, Tovar N, Rovira M, Mateos MV, Miguel JS, Bladé J.
Among 144 patients with myeloma who did not achieve complete response after an autologous stem cell transplant, 74 (51%) did not receive any maintenance therapy. Improvement of response after day +100 is exceedingly rare, because only 1 of these patients achieved CR.


MAY 2017

Circulating tumour DNA sequence analysis as an alternative to multiple myeloma bone marrow aspirates.
Nat Commun. 2017 May 11;8:15086.
Kis O, Kaedbey R, Chow S, Danesh A, Dowar M, Li T, Li Z, Liu J, Mansour M, Masih-Khan E, Zhang T, Bratman SV, Oza AM, Kamel-Reid S, Trudel S, Pugh TJ.
These authors used a methods of "liquid biopsy" sequencing, in which they sampled circulating cell-free DNA for molecular analysis of myeloma-related mutations. The test was done in 53 patients, and it seemed to have high accuracy in identifying those mutations, and the results reflected those obtained from the bone marrow aspirates.

Triplet versus doublet combination regimens for the treatment of relapsed or refractory multiple myeloma: A meta-analysis of phase III randomized controlled trials.
Crit Rev Oncol Hematol. 2017 May;113:249-255.
Sun Z, Zheng F, Wu S, Liu Y, Guo H, Liu Y.
This is a meta-analysis of 3197 patients with relapsed/refractory myeloma enrolled in clinical trials comparing triplet versus doublet combination regimens. The results showed that triplet combinations led to superior clinical outcomes (improved response rates, CR rates, progression-free survival, and overall survival), at the expense of increased toxicities.

A phase 2 safety study of accelerated elotuzumab infusion, over less than 1 h, in combination with lenalidomide and dexamethasone, in patients with multiple myeloma.
Am J Hematol. 2017 May;92(5):460-466.
Berenson J, Manges R, Badarinath S, Cartmell A, McIntyre K, Lyons R, Harb W, Mohamed H, Nourbakhsh A, Rifkin R.

G-CSF improves safety when you start the day after autologous transplant in multiple myeloma.
Leuk Lymphoma. 2017 May 16:1-5.
Sborov DW, Cho YK, Cottini F, Hade EM, Lamprecht M, Tackett K, Sharma N, Williams N, Li J, Devine S, Poi M, Phelps MA, Hofmeister CC.
This study analyzed outcomes of three different schedules of G-CSF given after an autologous stem cell transplant for multiple myeloma: started on day +1 (43 patients), +5 (75 patients), or +7 (103 patients). Although starting G-CSF on day -7 leads to some cost savings, the administration on day +1 leads to:
  - Shorter duration of severe neutropenia: median number of days to ANC >500 was 10.2, instead of 11.3 with day +5, and 11.8 with day +7
  - Reduced incidence of neutropenic fever: 28%, instead of 49% with day +5, and 91% with day +7
  - Reduced incidence of grade 2-3 mucositis: 2%, instead of 4% with day +5, and 18% with day +7


JUNE 2017

High-dose gemcitabine, busulfan, and melphalan for autologous stem-cell transplant in patients with relapsed or refractory myeloma: a phase 2 trial and matched-pair comparison with melphalan.
Lancet Haematol. 2017 Jun;4(6):e283-e292.
Nieto Y, Valdez BC, Pingali SR, Bassett R, Delgado R, Nguyen J, Shah N, Popat U, Jones RB, Andersson BS, Gulbis A, Ahmed S, Bashir Q, Parmar S, Patel K, Myers A, Rondon G, Orlowski RZ, Champlin R, Qazilbash M.
This is a phase II trial of 74 patients with relapsed/refractory myeloma, treated with an autologous stem cell transplant. They used a conditioning regimen with gemcitabine, busulfan, and melphalan instead of the standard single agent melphalan. Results were compared to those of 184 patients who received melphalan alone. Despite similar post-transplant maintenance, the progression-free survival was better with the three drugs instead of one (15 vs 9 months). There were 3 deaths (4%), 2 due to sepsis and 1 due to a cardiac event.

Pharmacokinetics and safety of carfilzomib in patients with relapsed multiple myeloma and end-stage renal disease (ESRD): an open-label, single-arm, phase I study.
Cancer Chemother Pharmacol. 2017 Jun;79(6):1067-1076.
Quach H, White D, Spencer A, Ho PJ, Bhutani D, White M, Inamdar S, Morris C, Ou Y, Gyger M.
In this study, carfilzomib was administered to 11 patients with renal failure on dialysis. No dose modifications seemed to be necessary.

Phase II study of the c-MET inhibitor tivantinib (ARQ 197) in patients with relapsed or relapsed/refractory multiple myeloma.
Ann Hematol. 2017 Jun;96(6):977-985.
Baljevic M, Zaman S, Baladandayuthapani V, Lin YH, de Partovi CM, Berkova Z, Amini B, Thomas SK, Shah JJ, Weber DM, Fu M, Cleeland CS, Wang XS, Stellrecht CM, Davis RE, Gandhi V, Orlowski RZ.
This is a phase II study of tivantinib, a c-MET inhibitor, in 16 patients with relapsed/refractory myeloma. There was no response, but 4 of 11 evaluable patients (36%) had stable disease.

Outcomes of newly diagnosed myeloma patients requiring dialysis: renal recovery, importance of rapid response and survival benefit.
Blood Cancer J. 2017 Jun 16;7(6):e571.
Dimopoulos MA, Roussou M, Gavriatopoulou M, Fotiou D, Ziogas DC, Migkou M, Panagiotidis I, Eleutherakis-Papaiakovou E, Kanellias N, Psimenou E, Marinaki S, Bacharaki D, Mparmparoussi D, Matsouka C, Giannouli S, Terpos E, Kastritis E.

This is an interesting study, that analyzed outcomes of patients with multiple myeloma with renal failure, and in particular those who required hemodialysis at the time of diagnosis (52 patients). Of note, after response to chemotherapy, 26 (50%) patients had an improvement of their renal function to the point that they could discontinued dialysis, even without the use of special filters.

An Ex Vivo Platform for the Prediction of Clinical Response in Multiple Myeloma.
Cancer Res. 2017 Jun 15;77(12):3336-3351.
Silva A, Silva MC, Sudalagunta P, Distler A, Jacobson T, Collins A, Nguyen T, Song J, Chen DT, Chen L, Cubitt C, Baz R, Perez L, Rebatchouk D, Dalton W, Greene J, Gatenby R, Gillies R, Sontag E, Meads MB, Shain KH.
These authors at the H. Lee Moffitt Cancer Center and Research Institute (Tampa, FL) developed an assay, called EMMA (Ex vivo Mathematical Myeloma Advisor) able to predict the sensitivity of myeloma cells to specific chemotherapy agents. Its accuracy, tested in 52 patients, was very high.

The role of initial clinical presentation, comorbidity and treatment in multiple myeloma patients on survival: a detailed population-based cohort study.
Eur J Clin Pharmacol. 2017 Jun;73(6):771-778.
Oortgiesen BE, van Roon EN, Joosten P, Kibbelaar RE, Storm H, Hovenga S, van Rees B, Woolthuis G, Veeger N, de Waal EG, Hoogendoorn M.
This is a population-based study of clinical outcomes in 225 patients who were diagnosed with symptomatic multiple myeloma in Friesland, a province of the Netherlands. This study is interesting even because it indicates that among patients (15) who decided not to receive any treatment, the median overall survival was only 3 months, as compared to 43 months in those who received treatment.

Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR.
Leukemia. 2017 Jun;31(6):1368-1374.
Chng WJ, Goldschmidt H, Dimopoulos MA, Moreau P, Joshua D, Palumbo A, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Feng S, Aggarwal S, Hájek R.
This is an analysis of the data from the Endeavor Trial, a phase 3 randomized trial which compared outcomes of 785 patients with relapsed/refractory myeloma treated with either bortezomib + dexamethasone (VD group) or carfilzomib + dexamethasone (KD). The results were analyzed according to the cytogenetic analysis, standard-risk (575 patients, 73%) vs high-risk (210 patients, 27%). The results favored the KD group:
  - Response rate in standard risk myeloma: 66% with VD, and 79% with KD (CR: 8 vs 13%)
  - Response rate in high-risk myeloma: 58% with VD, and 72% with KD (CR: 4 vs 15%)
  - Median PFS in standard risk myeloma: 10 months with VD, and not reached with KD
  - Median PFS in high-risk myeloma: 6 months with VD, and about 9 months with KD  

Prognostic impact of circulating plasma cells in patients with multiple myeloma: implications for plasma cell leukemia definition.
Haematologica. 2017 Jun;102(6):1099-1104.
Granell M, Calvo X, Garcia-Guiñón A, Escoda L, Abella E, Martínez CM, Teixidó M, Gimenez MT, Senín A, Sanz P, Campoy D, Vicent A, Arenillas L, Rosiñol L, Sierra J, Bladé J, de Larrea CF; GEMMAC (Grup per l’estudi del mieloma i l’amiloïdosi de Catalunya).
In this study, 482 patients with newly diagnosed myeloma were stratified into 4 groups, based on the review of the peripheral blood smear:
  - 0% circulating plasma cells (382 patients, 79%). Median survival was 47 months.
  - 1-4% circulating plasma cells (83 patients, 17%). Median survival was 50 months.
  - 5-20% circulating plasma cells (12 patients, 2.5%). Median survival was 6 months.
  - >20% circulating plasma cells (5 patients, 1%). This group represents those patients who are traditionally diagnosed with plasma cell leukemia. Median survival was 14 months.
 Of note, the prognosis of patients with 5-20% circulating plasma cells was similar to that of patients with plasma cell leukemia (i.e., >20%). Instead, the presence of 1-4% circulating plasma cells had no adverse impact on prognosis. 

A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma.
Blood. 2017 Jun 22;129(25):3294-3303.
Martin T, Baz R, Benson DM, Lendvai N, Wolf J, Munster P, Lesokhin AM, Wack C, Charpentier E, Campana F, Vij R.
Isatuximab is a monoclonal antibody against CD38, like daratumumab. In this trial, 57 patients with heavily pretreated relapsed/refractory myeloma were given isatuximab + lenalidomide and dexamethasone. Among 52 evaluable patients, response rate was 56%, and median progression-free survival was 8.5 months. Of note, 83% of enrolled patients were previously refractory to lenalidomide.



Giampaolo Talamo, MD