Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma.
Blood. 2015 Jan 15;125(3):443-8.
Kumar SK, LaPlant B, Chng WJ, Zonder J, Callander N, Fonseca R, Fruth B, Roy V, Erlichman C, Stewart AK; Mayo Phase 2 Consortium.
Dinaciclib is a small molecule inhibitor of several cyclin-dependent kinases (CDK1, CDK2, CDK5, and CDK9). Among 27 patients with relapsed myeloma, single agent dinaciclib showed a clinical benefit rate of 19% (3 PR and 2 minor responses.

Efficacy, toxicity and mortality of autologous SCT in multiple myeloma patients with dialysis-dependent renal failure.
Bone Marrow Transplant. 2015 Jan;50(1):95-9.
St Bernard R, Chodirker L, Masih-Khan E, Jiang H, Franke N, Kukreti V, Tiedemann R, Trudel S, Reece D, Chen CI.
In this retrospective study, the authors analyzed the outcomes of 33 patients with mutliple myeloma who underwent an autologous stem cell transplant while on hemodialysis (in Toronto, Canada, 1998-2012). The coinditioning regimen consisted of high-dose melphalan 200 mg/m2 (61%), 140 mg/m2 (36%), or 160 mg/m2 + TBI (3%). Dose were reduced at the treating physician discretion. Results:
  - Median overall survival: 5.6 years (comparable to that of non-dialysis patients)
  - 7 (25%) patients became dialysis-independent
  - Toxicities: increased risk of mucositis, atrial arrhythmias, hemorrhages, and altered mental status
  - Transplant-related mortality was 15% (primarily septic shock), higher than that seen in previous reports of dialysis-dependent patients (3-12%)

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.
N Engl J Med. 2015 Jan 8;372(2):142-52.
Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosińol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; ASPIRE Investigators.
This is a large study of 792 patients withg relapsed multiple myeloma, randomized to therapy with either lenalidomide and dexamethasone, or CRD (carfilzomib, lenalidomide, and dexamethasone). CRD was given as follows:
  - Carfilzomib 27 mg/m2 (20 mg/m2 on days 1 and 2 of cycle #1) IV in days 1,2, 8,9, 15,16 every 28 days for 18 cycles
  - Lenalidomide 25 mg PO on days 1-21 every 28 days
  - Dexamethasone 40 mg PO on days 1, 8 , 15, 22
Results favored the carfilzomib group:
  - Response rate: 67% in the control group, and 87% in the CRD group
  - Complete response rate: 9% in the control group, and 32% in the CRD group
  - Median progression free survival: 17.6 months in the control group, and 26.3 months in the CRD group
  - Overall survival at 2 years: 65% in the control group, and 73.3% in the CRD group
  - Toxicities: the CRD group experienced a higher rate of fever, cough, diarrhea, and hypertension

Phase 2 study of carfilzomib, thalidomide, and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma.
Blood. 2015 Jan 15;125(3):449-56.
Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H.

Retrospective matched-pairs analysis of bortezomib plus dexamethasone versus bortezomib monotherapy in relapsed multiple myeloma.
Haematologica. 2015 Jan;100(1):100-6.
Dimopoulos MA, Orlowski RZ, Facon T, Sonneveld P, Anderson KC, Beksac M, Benboubker L, Roddie H, Potamianou A, Couturier C, Feng H, Ataman O, van de Velde H, Richardson PG.
This is a retrospective analysis of 109 matched pairs of patients with relapsed myeloma, treated in 3 clinical trials with either single agent bortezomib (V group) or the combination dexamethasone + bortezomib (VD group). Median dose of bortezomib and treatment duration were similar in the two groups. The results favored the addition of dexamethasone to bortezomib:
  -  Response rate: 41% in the V group, and 75% in the VD group
  -  Median progression-free survival: 6.4 months in the V group, and 11.9 months in the VD group
  - Toxicity rates and treatment-related mortality were similar in the two groups (2 patients died in each group)



t(14;16)-positive multiple myeloma shows negativity for CD56 expression and unfavorable outcome even in the era of novel drugs.
Blood Cancer J. 2015 Feb 27;5:e285.
Narita T, Inagaki A, Kobayashi T, Kuroda Y, Fukushima T, Nezu M, Fuchida S, Sakai H, Sekiguchi N, Sugiura I, Maeda Y, Takamatsu H, Tsukamoto N, Maruyama D, Kubota Y, Kojima M, Sunami K, Ono T, Ri M, Tobinai K, Iida S.
This is a retrospective study of 35 myeloma patients with the rare 14;16 translocation.

Current role of radiation therapy for multiple myeloma.
Front Oncol. 2015 Feb 18;5:40.
Talamo G, Dimaio C, Abbi KK, Pandey MK, Malysz J, Creer MH, Zhu J, Mir MA, Varlotto JM.
Retrospective study of 449 consecutive myeloma patients. Treatment with RT was indicated in 149 (34%) of them. Most common indications for RT:
  - Palliation of bone pain (109 pts, 42%)
  - Prevention/treatment of pathological fractures (73 pts, 28%)
  - Spinal cord compression (26 pts, 10%)
  - Involvement of vital organs or extramedullary disease (25 pts, 10%)

Role of magnetic resonance imaging in the management of patients with multiple myeloma: a consensus statement.
J Clin Oncol. 2015 Feb 20;33(6):657-64.
Dimopoulos MA, Hillengass J, Usmani S, Zamagni E, Lentzsch S, Davies FE, Raje N, Sezer O, Zweegman S, Shah J, Badros A, Shimizu K, Moreau P, Chim CS, Lahuerta JJ, Hou J, Jurczyszyn A, Goldschmidt H, Sonneveld P, Palumbo A, Ludwig H, Cavo M, Barlogie B, Anderson K, Roodman GD, Rajkumar SV, Durie BG, Terpos E.

Impact of pretransplant therapy and depth of disease response before autologous transplantation for multiple myeloma.
Biol Blood Marrow Transplant. 2015 Feb;21(2):335-41.
Vij R, Kumar S, Zhang MJ, Zhong X, Huang J, Dispenzieri A, Abidi MH, Bird JM, Freytes CO, Gale RP, Kindwall-Keller TL, Kyle RA, Landsburg DJ, Lazarus HM, Munker R, Roy V, Sharma M, Vogl DT, Wirk B, Hari PN.
This retrospective study aimed at clarifying whether the use of a second-line different chemotherapy is beneficial in those patient who have a suboptimal response (i.e., less than partial response) to the first-line induction therapy before an autologous stem cell transplant. 539 patients with a suboptimal response to the first-line induction chemotherapy were divided into 2 groups: the group who proceeded directly to the autologous stem cell transplant (group A, 215 patients), and the group who received a second induction therapy (group B, 324 patients). In group B, the second-line chemotherapy was able to deepen the responses in 68% of patients (PR 60%, CR 8%), but there was no difference in progression-free survival or overall survival in the 2 groups. The authors concluded that additional induction chemotherapy in patients with a suboptimal response to first-line chemotherapy deepens the response, but it does not lead to a prolonged remission or a prolonged survival after the stem cell transplant.

Patterns of cardiac toxicity associated with irreversible proteasome inhibition in the treatment of multiple myeloma.
J Card Fail. 2015 Feb;21(2):138-44.
Grandin EW, Ky B, Cornell RF, Carver J, Lenihan DJ.
The authors describe 6 cases of significant cardiac toxicity due to carfilzomib. Patients had dyspnea and left ventricular systolic or diastolic dysfunction.

Bortezomib-based induction therapy followed by intravenous busulfan-melphalan as conditioning regimen for patients with newly diagnosed multiple myeloma.
Leuk Lymphoma. 2015 Feb;56(2):415-9.
Blanes M, González JD, Lahuerta JJ, Ribas P, Lorenzo I, Boluda B, Sanz MA, de la Rubia J.


MARCH 2015

A pooled analysis of cigarette smoking and risk of multiple myeloma from the international multiple myeloma consortium.
Cancer Epidemiol Biomarkers Prev. 2015 Mar;24(3):631-4.
Andreotti G, Birmann BM, Cozen W, De Roos AJ, Chiu BC, Costas L, de Sanjosé S, Moysich K, Camp NJ, Spinelli JJ, Pahwa P, Dosman JA, McLaughlin JR, Boffetta P, Staines A, Weisenburger D, Benhaim-Luzon V, Brennan P, Costantini AS, Miligi L, Campagna M, Nieters A, Becker N, Maynadié M, Foretová L, Zheng T, Tricot G, Milliken K, Krzystan J, Steplowski E, Baris D, Purdue MP.
This epidemiologic study confirmed that smoking is not a risk factor for multiple myeloma.

Comparative effectiveness on survival of zoledronic acid versus pamidronate in multiple myeloma.
Leuk Lymphoma. 2015 Mar;56(3):615-21.
Sanfilippo KM, Gage B, Luo S, Weilbaecher K, Tomasson M, Vij R, Colditz G, Carson K.
This study is a retrospective comparison of pamidronate vs zoledronic acid in 1018 patients with multiple myeloma. Median follow-up was 27 months. The authors believe that zoledronic acid should be the preferred bisphosphonate for patients with multiple myeloma, because it was associated with a 25% reduction in skeletal-related events, and a 22% reduction in risk of death compared to pamidronate.

Chromosome 8q24.1/c-MYC abnormality: a marker for high-risk myeloma.
Leuk Lymphoma. 2015 Mar;56(3):602-7.
Glitza IC, Lu G, Shah R, Bashir Q, Shah N, Champlin RE, Shah J, Orlowski RZ, Qazilbash MH.
The oncogene c-MYC is rearranged in about 15% of patients with multiple myeloma. In this study, 23 patients with myeloma and c-MYC rearrangement had an aggressive clinical course, because of the high incidence of plasma cell leukemia and/or extramedullary disease either at diagnosis or upon progression (12 patients, 52%), and a short median survival (only 20 months).

Phase 1/2 study of CDK4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma.
Leuk Lymphoma. 2015 Mar 27:1-21.
Niesvizky R, Badros AZ, Costa LJ, Ely SA, Singhal SB, Stadtmauer EA, Haideri NA, Yacoub A, Hess G, Lentzsch S, Spicka I, Chanan-Khan AA, Raab MS, Tarantolo S, Vij R, Zonder JA, Huang X, Jayabalan D, DiLiberto M, Huang X, Jiang Y, Kim ST, Randolph S, Chen-Kiang S.
Palbociclib is a specific inhibitor of the cyclin-dependent kinase (CDK) 4/6. In the phase 2 portion of this study, response rate was 20%, and disease stability was observed in 44% of patients.

BRAF V600E mutation in early-stage multiple myeloma: good response to broad acting drugs and no relation to prognosis.
Blood Cancer J. 2015 Mar 20;5:e299.
Rustad EH, Dai HY, Hov H, Coward E, Beisvag V, Myklebost O, Hovig E, Nakken S, Vodák D, Meza-Zepeda LA, Sandvik AK, Wader KF, Misund K, Sundan A, Aarset H, Waage A.
In this study, the BRAF V600E mutation was detected in 11 (5%) of 209 patients with multiple myeloma. Its presence was not associated with an adverse prognosis.

Minimal residual disease in myeloma by flow cytometry: independent prediction of survival benefit per log reduction.
Blood. 2015 Mar 19;125(12):1932-5.
Rawstron AC, Gregory WM, de Tute RM, Davies FE, Bell SE, Drayson MT, Cook G, Jackson GH, Morgan GJ, Child JA, Owen RG.
The authors assessed the presence of minimal residual disease (MDR) by flow cytometry in 397 patients with multiple myeloma, treated in the Medical Research Council Myeloma IX study (this included autologous stem cell transplant). They found that median overall survival increased for each log depletion in the MDR level:
  -     >10%  : 1    year
  -    1-10%  : 4    years
  -  0.1-1%   : 5.9  years
  - 0.01-0.1% : 6.8  years
  -     <0.01%: >7.5 years



Giampaolo Talamo, MD