International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100).
Leukemia. 2009 Oct;23(10):1904-12.
Giralt S, Stadtmauer EA, Harousseau JL, Palumbo A, Bensinger W, Comenzo RL, Kumar S, Munshi NC, Dispenzieri A, Kyle R, Merlini G, San Miguel J, Ludwig H, Hajek R, Jagannath S, Blade J, Lonial S, Dimopoulos MA, Einsele H, Barlogie B, Anderson KC, Gertz M, Attal M, Tosi P, Sonneveld P, Boccadoro M, Morgan G, Sezer O, Mateos MV, Cavo M, Joshua D, Turesson I, Chen W, Shimizu K, Powles R, Richardson PG, Niesvizky R, Rajkumar SV, Durie BG; IMWG.

Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma.
J Clin Oncol. 2009 Oct 20;27(30):5008-14.
Lacy MQ, Hayman SR, Gertz MA, Dispenzieri A, Buadi F, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Kyle RA, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV.
This is the first phase II trial of pomalidomide + dexamethasone in patients with relapsed or refractory. 60 patients received pomalidomide 2 mg PO daily on days 1-28 + dexamethasone 40 mg PO daily on days 1, 8, 15, and 22, with cycles repeated every 28 days. Patients received aspirin 325 mg PO qd for thromboprophylaxis. Results:
  - RR: 63%, CR: 5%. Responses were observed even in patients refractory to lenalidomide (40%) and thalidomide (37%).
  - Median progression-free survival time was 11.6 months.
  - Main toxicity was myelosuppression. Venous thromboembolism was observed in 1 patient (1.6%).

Short-term thalidomide incorporated into double autologous stem-cell transplantation improves outcomes in comparison with double autotransplantation for multiple myeloma.
J Clin Oncol. 2009 Oct 20;27(30):5001-7.
Cavo M, Di Raimondo F, Zamagni E, Patriarca F, Tacchetti P, Casulli AF, Volpe S, Perrone G, Ledda A, Ceccolini M, Califano C, Bigazzi C, Offidani M, Stefani P, Ballerini F, Fiacchini M, de Vivo A, Brioli A, Tosi P, Baccarani M.
The Bologna 2002 study utilized thalidomide 200 mg PO qhs from diagnosis until the second stem cell transplant. Results compared favorably with those of the Bologna 96 study, which used VAD in the induction therapy. RR: 68%, PFS at 4 years: 51%, OS at 5 years: 69% (53% in the control group, p= 0.07).

Kyphoplasty for patients with multiple myeloma is a safe surgical procedure: results from a large patient cohort.
Clin Lymphoma Myeloma. 2009 Oct;9(5):375-80.
Huber FX, McArthur N, Tanner M, Gritzbach B, Schoierer O, Rothfischer W, Krohmer G, Lessl E, Baier M, Meeder PJ, Kasperk C.
This study evaluates the outcomes of 190 kyphoplasty procedures in 76 patients with multiple myeloma. The authors observed one case of pulmonary embolism, due to leakage of the bone cement.

An open-label, phase 2 trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma.
Am J Hematol. 2009 Oct;84(10):650-6.
Vij R, Horvath N, Spencer A, Taylor K, Vadhan-Raj S, Vescio R, Smith J, Qian Y, Yeh H, Jun S.
The RANKL inhibitor denosumab was administered in patients with myeloma, either relapsed or in a plateau phase. No CR and no PR were observed in this phase II trial.

Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma.
J Clin Oncol. 2009 Oct 20;27(30):5015-22.
Jakubowiak AJ, Kendall T, Al-Zoubi A, Khaled Y, Mineishi S, Ahmed A, Campagnaro E, Brozo C, Braun T, Talpaz M, Kaminski MS.
This is a phase II trial with VDD in 40 patients with newly diagnosed multiple myeloma:
  - Velcade 1.3 mg/m2 IV on days 1, 4, 8, 11
  - Doxil 30 mg/m2 IV on day 4
  - Dexamethasone 20-40 mg
Cycles were repeated every 21 days, x 6.
Results: RR was 85.0%, CR/nCR 37.5%. 30 patients proceeded with stem cell transplant. 1-year OS 97.5%, 1-year PFS 92.5%.



Impact of prior therapies on the relative efficacy of bortezomib compared with dexamethasone in patients with relapsed/refractory multiple myeloma.
Br J Haematol. 2009 Nov;147(4):531-4.
Vogl DT, Stadtmauer EA, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Facon T, Harousseau JL, Boral A, Neuwirth R, Anderson KC.

Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma.
Leukemia. 2009 Nov;23(11):2147-52.
Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM.
This is an update analysis of 2 large randomized trials, MM-009 and MM-010, including 704 patients with relapsed/refractory myeloma treated with lenalidomide + dexamethasone vs placebo + dexamethasone. Results:
  - Overall response was 61% in the lenalidomide group and 22% in the placebo group
  - CR was 15% in the lenalidomide group and 2% in the placebo group
  - Median time to progression was 13.4 months in the lenalidomide group and 4.6 months in the placebo group
  - Median overall survival was 38 months in the lenalidomide group and 31.6 months in the placebo group (p= 0.045) (cross-over: 48%)

Bortezomib plus dexamethasone is highly effective in relapsed and refractory myeloma patients but responses are short-lived.
Eur J Haematol. 2009 Nov;83(5):449-54.
Corso A, Varettoni M, Mangiacavalli S, Zappasodi P, Pica GM, Algarotti A, Pascutto C, Lazzarino M.
70 MM patients were treated with bortezomib, with or without dexamethasone. Bortezomib was found to be highly effective in inducing a therapeutic response (RR: 59%, including 7% CR), but the duration of response was short: the median time to progression was 5.6 months (7.3 months in patients achieving CR/VGPR, and 3.8 months in patients achieving PR).

Phase II trial of temsirolimus in patients with relapsed or refractory multiple myeloma.
Leuk Res. 2009 Nov;33(11):1475-80.
Farag SS, Zhang S, Jansak BS, Wang X, Kraut E, Chan K, Dancey JE, Grever MR.
This is a phase II trial of temsirolimus (25mg IV weekly) in patients with relapsed or refractory myeloma. The activity of temsirolimus was modest: only 1 PR (RR 6%) and 5 minor responses among 16 patients. The median time to progression was about 4.6 months.

DSMM XI study: dose definition for intravenous cyclophosphamide in combination with bortezomib/dexamethasone for remission induction in patients with newly diagnosed myeloma.
Ann Hematol. 2009 Nov;88(11):1125-30.
Kropff M, Liebisch P, Knop S, Weisel K, Wand H, Gann CN, Berdel WE, Einsele H; Deutsche Studiengruppe Multiples Myelom, DSMM.
This is a clinical trial in 30 patients with newly diagnosed myeloma, who received combination chemotherapy with cyclophosphamide, bortezomib, and dexamethasone as induction therapy before stem cell transplantation. Patients received 3 cycles of:
  - Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11
  - Dexamethasone 40 mg on the day of bortezomib and the day after
  - Cyclophosphamide at various doses, 900-1,500 mg/m2 IV on day 1
The maximum tolerated dose of cyclophosphamide was 900 mg/m2. At this dose level, RR was 92%.

Triple MEL100 therapy in multiple myeloma.
Transplant Proc. 2009 Nov;41(9):3863-7.
Berz D, Colvin GA, McCormack EM, Winer ES, Karwan P, Colvin L, Rathore R, Lum LG, Elfenbein GJ, Quesenberry PJ.
In this study, 13 patients with multiple myeloma underwent triple transplant using melphalan 100 mg/m2 every 3 weeks. The average hospital stay for the 3 transplants was 18 days, and 3 patients were managed entirely as outpatients. Median progression-free survival was about 28 months, overall survival not reached.

Patterns of hematologic malignancies and solid tumors among 37,838 first-degree relatives of 13,896 patients with multiple myeloma in Sweden.
Kristinsson SY, Björkholm M, Goldin LR, Blimark C, Mellqvist UH, Wahlin A, Turesson I, Landgren O.
Int J Cancer. 2009 Nov 1;125(9):2147-50.
In order to elucidate the impact of genetic factors in the pathogenesis of multiple myeloma, these authors assessed the risk for hematologic malignancies and solid tumors among first-degree relatives of myeloma patients. The analysis included:
  - 13,896 patients with MM
  - 54,365 matched controls
  - 37,838 first-degree relatives of patients with MM
  - 151,068 first-degree relatives of matched controls
When compared with first-degree relatives of matched controls, first-degree relatives of patients with MM had an increased risk of developing multtiple myeloma (RR 2.1), MGUS (RR 2.1), acute lymphoblastic leukemia (RR 2.1), and bladder cancer (RR 1.3). These findings support a role for a shared susceptibility that predisposes to MM, MGUS, acute lymphoblastic leukemia, and bladder cancer. It cannot be established whether the shared susceptibility involves only genetic factors, shared environmental factors, or both.



Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma.
J Clin Oncol. 2009 Dec 1;27(34):5713-9.
Richardson PG, Weller E, Jagannath S, Avigan DE, Alsina M, Schlossman RL, Mazumder A, Munshi NC, Ghobrial IM, Doss D, Warren DL, Lunde LE, McKenney M, Delaney C, Mitsiades CS, Hideshima T, Dalton W, Knight R, Esseltine DL, Anderson KC.
In this phase I study of 38 patients with relapsed/refractory myeloma, the maximum-tolerated dose of lenalidomide + bortezomib was found to be lenalidomide 15 mg + bortezomib 1.0 mg/m2. Cytopenias were the most common toxicity. At least minimal response was observed in 61% of cases, and 83% of patients had stable disease or better. Median overall survival: 37 months.

Retrospective comparison of mobilization methods for autologous stem cell transplantation in multiple myeloma.
Am J Hematol. 2009 Dec;84(12):809-14.
Nakasone H, Kanda Y, Ueda T, Matsumoto K, Shimizu N, Minami J, Sakai R, Hagihara M, Yokota A, Oshima K, Tsukada Y, Tachibana T, Nakaseko C, Fujisawa S, Yano S, Fujita H, Takahashi S, Kanamori H, Okamoto S; Kanto Study Group of Cell Therapy.
This retrospective study in 146 myeloma patients compared 3 different strategies of stem cell collection. The median number of CD34+ million cells/Kg was:
  - 2.0 with G-CSF alone
  - 5.27 with cyclophosphamide 2-4 g/m2 + G-CSF
  - 13.85 with etoposide 500 mg/m2/day days 1-3 + G-CSF
There was no difference in progression-free survival among the 3 regimens, therefore the antimyeloma effect of cyclophosphamide and etoposide is questionable.

Idiotype-pulsed antigen-presenting cells following autologous transplantation for multiple myeloma may be associated with prolonged survival.
Am J Hematol. 2009 Dec;84(12):799-802.
Lacy MQ, Mandrekar S, Dispenzieri A, Hayman S, Kumar S, Buadi F, Dingli D, Litzow M, Wettstein P, Padley D, Kabat B, Gastineau D, Rajkumar SV, Gertz MA.
This is a phase II trial of an idiotype vaccine, given after autologous SCT in 27 patients with multiple myeloma. The median overall survival was 5.3 years, better than that seen in a control group who underwent the transplant but did not receive the vaccine (3.4 years).

Primary plasma cell leukemia: a Surveillance, Epidemiology, and End Results database analysis between 1973 and 2004.
Cancer. 2009 Dec 15;115(24):5734-9.
Ramsingh G, Mehan P, Luo J, Vij R, Morgensztern D.
This is a case series of 291 patients with PCL. Median age was 67 years (range, 19-98 years). Median overall survival was 4 months. The long-term outcome was poor: the 2-year survival was 14%, and the 5-year survival was 6.4%.

Abnormal serum free light chain ratio in patients with multiple myeloma in complete remission has strong association with the presence of oligoclonal bands: implications for stringent complete remission definition.
Blood. 2009 Dec 3;114(24):4954-6.
de Larrea CF, Cibeira MT, Elena M, Arostegui JI, Rosiñol L, Rovira M, Filella X, Yagüe J, Bladé J.
Despite the status of CR in 34 myeloma patients after stem cell transplantation, the FLC ratio was abnormal in 14 of them (41%). This was related to the presence of oligoclonal bands, which are commonly seen after SCT, and usually indicate a good outcome. These results have important implications for the definition of "stringent" CR, which includes normalization of the FLC ratio.



Giampaolo Talamo, MD