JULY 2013

In a high-dose melphalan setting, palifermin compared with placebo had no effect on oral mucositis or related patient's burden.
Bone Marrow Transplant. 2013 Jul;48(7):966-71.
Blijlevens N, de Château M, Krivan G, Rabitsch W, Szomor A, Pytlik R, Lissmats A, Johnsen HE, de Witte T, Einsele H, Ruutu T, Niederwieser D; CLWP of the EBMT.

Metronomic therapy is an effective salvage treatment for heavily pre-treated relapsed/refractory multiple myeloma.
Haematologica. 2013 Jul;98(7):1147-53.
Papanikolaou X, Szymonifka J, Rosenthal A, Heuck CJ, Mitchell A, Johann D Jr, Keller J, Waheed S, Usmani SZ, Van Rhee F, Bailey C, Petty N, Hoering A, Crowley J, Barlogie B.
The term metronomic refers to the administration of chemotherapy at low continuous doses. The authors used bortezomib, dexamethasone, thalidomide, cisplatin, and doxorubicin at low doses. The results were modest (median overall survival was 11 months, and progression-free survival 3.6 months - with 25% of patients subsequently treated with salvage autologous stem cell transplant), but we need to keep in mind that many of those patients were heavily pretreated and with end-stage myeloma, i.e., hospice candidates.

Autologous retransplantation for patients with recurrent multiple myeloma: a single-center experience with 200 patients.
Cancer. 2013 Jul 1;119(13):2438-46.
Sellner L, Heiss C, Benner A, Raab MS, Hillengass J, Hose D, Lehners N, Egerer G, Ho AD, Goldschmidt H, Neben K.
In this study of 200 patients with myeloma previously treated with an upfront autologous stem cell transplantation, and subsequently treated with a second autologous transplant as salvage therapy, the median  progression-free survival was 15 months. Median overall survival was 42 months.

Incidence, clinical features, laboratory findings and outcome of patients with multiple myeloma presenting with extramedullary relapse.
Leuk Lymphoma. 2013 Jul;54(7):1459-64.
Papanikolaou X, Repousis P, Tzenou T, Maltezas D, Kotsopoulou M, Megalakaki K, Angelopoulou M, Dimitrakoloulou E, Koulieris E, Bartzis V, Pangalis G, Panayotidis P, Kyrtsonis MC.
In this retrospective series of 303 myeloma patients, there were 28 cases (9%) of relapse with extramedullary disease. These patients had a poor outcome, and their median overall survival was significantly less than in other patients (38 vs 59 months, p<0.01).

Pomalidomide is nonteratogenic in chicken and zebrafish embryos and nonneurotoxic in vitro.
Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12703-8.
Mahony C, Erskine L, Niven J, Greig NH, Figg WD, Vargesson N.



Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma.
N Engl J Med. 2013 Aug 1;369(5):438-47.
Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF.
This is the first clinical trials which showed a survival advantage in the treatment of smoldering myeloma. 119 patients with high-risk smoldering myeloma were randomized to either observation (the historical standard of care) vs treatment with lenalidomide + dexamethasone.
High-risk myeloma was defined as:
  1- Plasma cells 10% in bone marrow
  2- IgG 3000 mg/dL or IgA 2,000 mg/dL or urine M >1000 mg/24 hours
  3- Only one of the two criteria above + at least 95% phenotypically aberrant plasma cells in the bone marrow aspirate
       and >25% reduction in one or two uninvolved immunoglobulins
The treatment was divided into:
  - Induction phase: lenalidomide 25 mg on days 1-21 and dexamethasone 20 mg on days 1-4 and 12-15 every 28 days, x 9 cycles
  - Maintenance phase: lenalidomide 10 mg on days 1-21 every 28 days, for 2 years
Median follow-up was 40 months.
  - Response rate: 79% in the induction phase, and 90% in the maintenance phase
  - Progression-free survival at 3 years: 30% in the observation group, and 77% in the treatment group
  - Overall survival at 3 years: 80% in the observation group, and 94% in the treatment group
There are 4 aspects that could be criticized: 1) the definition of high-risk myeloma as used in this trial is arbitrary/controversial; 2) the trial compared Len-Dex upfront vs observation, but we do not know the outcome of Len-Dex upfront vs Len-Dex delayed; 3) only 28% of patients received autologous stem cell transplantation at progression; 4) in a world with limited resources, the use of a drug with a cost exceeding 10,000$ a month in asymptomatic persons (and with risk of side effects like rash, thrombosis, and second malignancies) is debatable.
A published comment by Dr. Gertz explained in detail the reasons why patients with smoldering myeloma should not receive lenalidomide, outside of the context of clinical trials [Gertz MA. Chemoprevention for smoldering multiple myeloma: not ready for prime time. Leuk Lymphoma, 2013; 54:2331-2].

Pseudo-autologous hematopoietic SCT as treatment for a patient with multiple myeloma who relapsed following an allogeneic hematopoietic SCT.
Bone Marrow Transplant. 2013 Aug;48(8):1138.
Palfreyman E, Song K, Nantel S.
The authors described the case of a myeloma patient previously treated with an allogeneic stem cell transplant. At disease relapse, they decided to collect her stem cells, and use them after high-dose melphalan. The term pseudo-autologous refers to the original allogeneic source of patient's stem cells: while the "usual" sequence of transplant in myeloma is autologous, possibly followed by an allogeneic transplant, in this case the sequence is reversed, and it involved an allogeneic followed by an autologous transplant.

Central nervous system multiple myeloma--potential roles for intrathecal therapy and measurement of cerebrospinal fluid light chains.
Br J Haematol. 2013 Aug;162(3):371-5.
Lee D, Kalff A, Low M, Gangatharan S, Ho P, Bajel A, Ritchie D, Grigg A, Spencer A.
The authors report 17 cases of myeloma involving the CNS. Interesting findings:
  - In 3 of 5 tested patients, free light chains in the CSF were found to be elevated.
  - Cytology of CSF became negative in 4 of 11 patients treated with intratechal chemotherapy.
  - Median overall survival from the diagnosis of CNS involvement was only 4 months.
  - Overall survival was better in 7 patients who received intratechal chemotherapy than in 10 patients who did not received it (20 vs 2 months, p=00.2).

Central nervous system involvement with multiple myeloma: long term survival can be achieved with radiation, intrathecal chemotherapy, and immunomodulatory agents.
Br J Haematol. 2013 Aug;162(4):483-8.
Chen CI, Masih-Khan E, Jiang H, Rabea A, Cserti-Gazdewich C, Jimenez-Zepeda VH, Chu CM, Kukreti V, Trudel S, Tiedemann R, Tsang R, Reece DE.
The authors report 37 cases of myeloma with CNS involvement, either at diagnosis (24%) or at progression (76%). There was a high incidence of plasma cell leukemia (40%). Median overall survival was 4.6 months. Nine patients received a combination of intratechal chemotherapy (hydrocortisone, methotrexate/cytarabine), radiotherapy (cranial and/or spinal), and thalidomide/lenalidomide, and had a median OS of 17.1 months. The administration of D-PACE chemotherapy did not seem to improve survival. Of note, there is no evidence that bortezomib can cross the blood-brain barrier, but thalidomide certainly does, even because it is associated with sedative effects and CNS toxicity.

Early versus delayed autologous stem cell transplant in patients receiving novel therapies for multiple myeloma.
Leuk Lymphoma. 2013 Aug;54(8):1658-64.
Dunavin NC, Wei L, Elder P, Phillips GS, Benson DM Jr, Hofmeister CC, Penza S, Greenfield C, Rose KS, Rieser G, Merritt L, Ketcham J, Heerema N, Byrd JC, Devine SM, Efebera YA.
The authors compared clinical outcomes of 102 myeloma patients who received an "early" autologous transplant (= within 12 months of diagnosis) and 65 patients who received a "late" transplant. The 5 year survival rate was similar in both groups (63%). However, I am not convinced that this study demonstrates that "late" transplant has the same benefit than upfront transplant, and that it can be safely delayed in all patients until conventional therapies fail: the median time to transplant in the "late" group was 18 months, which means that 50% of patients received it within 18 months of diagnosis (this is not really "late", in my point of view).



Identification of a novel t(7;14) translocation in multiple myeloma resulting in overexpression of EGFR.
Genes Chromosomes Cancer. 2013 Sep;52(9):817-22.
Walker BA, Wardell CP, Ross FM, Morgan GJ.

Sequence of novel agents in multiple myeloma: an instrumental variable analysis.
Leuk Res. 2013 Sep;37(9):1077-82.
Baz R, Miladinovic B, Patel A, Ho VQ, Shain KH, Alsina M, Nishihori T, Ochoa-Bayona JL, Sullivan DM, Dalton WS, Djulbegovic B.
In this retrospective analysis, outcomes were not affected by the sequence of therapy chosen (lenalidomide vs bortezomib): 97 patients treated with lenalidomide-based regimens first had a similar survival to that of 111 patients treated with a bortezomib-containing regimen first. Patients with renal insufficiency seemed to benefit more from the use of bortezomib-based therapy upfront.

Implications of continued response after autologous stem cell transplantation for multiple myeloma.
Blood. 2013 Sep 5;122(10):1746-9.
Gonsalves WI, Gertz MA, Dispenzieri A, Lacy MQ, Lin Y, Singh PP, Gupta V, Hayman SR, Buadi FK, Dingli D, Kapoor P, McCurdy AR, Kumar SK.
Most transplant centers assess the disease response to the transplant 3 months later, at approximately day 100. In this study of 430 patients who underwent an autologous transplant upfront (= within 12 months of diagnosis), the authors found that 39% of patients had a continued response (i.e., a decline in the M component in the serum and/or urine) after day 100, without additional therapy. Compared with the other patients, these patients had a better progression-free survival (35 vs 13 months) and overall survival (96 vs 57 months). The prognostic value of the continued response was maintained after a multivariable analysis.

Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials.
J Clin Oncol. 2013 Sep 10;31(26):3279-87.
Sonneveld P, Goldschmidt H, Rosiñol L, Bladé J, Lahuerta JJ, Cavo M, Tacchetti P, Zamagni E, Attal M, Lokhorst HM, Desai A, Cakana A, Liu K, van de Velde H, Esseltine DL, Moreau P.
This meta-analysis includes 1,572 myeloma patients who underwent autologous stem cell transplantation. 787 were treated with bortezomib-based induction therapy, and 785 treated with a non-bortezomib based induction chemotherapy. Results favored the first group:
  - Rate of nCR + CR: 38% in the bortezomib group and 24% in the non-bortezomib group
  - Median progression-free survival: 36 months in the bortezomib group and 29 months in the non-bortezomib group
  - 3-year overall survival: 80% in the bortezomib group and 75% in the non-bortezomib group



Giampaolo Talamo, MD