APRIL 2012

Efficacy of bendamustine in relapsed/refractory myeloma patients: results from the French compassionate use program.
Leuk Lymphoma. 2012 Apr;53(4):632-4.
Damaj G, Malard F, Hulin C, Caillot D, Garidi R, Royer B, Marit G, Stoppa AM, Banos A, Morineau N, Moreau P, Fitoussi O, Tiab M, Moreau P.
Bendamustine was given to 110 patients with relapsed/refractory multiple myeloma. Results:
  - Response rate: 30%
  - Complete response rate: 2%
  - Median progression-free survival: 9.3 months
  - Median overall survival: 12.4 months


MAY 2012

Second autologous stem cell transplantation as salvage therapy for multiple myeloma: impact on progression-free and overall survival.
Biol Blood Marrow Transplant. 2012 May;18(5):773-9.
Jimenez-Zepeda VH, Mikhael J, Winter A, Franke N, Masih-Khan E, Trudel S, Chen C, Kukreti V, Reece DE.
In this study, 81 patients with myeloma underwent a second autologous stem cell transplantation as a salvage therapy, for relapsed myeloma. The median time to relapse after the second transplant was 19 months. The benefit of second transplant was observed especially in those patients who experienced relapse >24 months after the first transplant (median PFS was 9.8 months and 17.3 months in patients who experienced relapse <24 and >24 months after the first autologous transplant, respectively).

Continuous lenalidomide treatment for newly diagnosed multiple myeloma.
N Engl J Med. 2012 May 10;366(19):1759-69.
Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jędrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators.
This is a double-blind, placebo-controlled, randomized trial comparing three regimen for the treatment of 459 patients with newly diagnosed multiple myeloma and ineligible for stem cell transplantation:
  - MP (melphalan 0.18 mg/Kg and prednisone 2 mg/Kg on days 1-4 every 28 days x 9 cycles) (154 patients)
  - MPR (MP and lenalidomide 10 mg on days 1-21) (153 patients)
  - MPR-R (MPR x 9 cycles, followed by lenalidomide maintenance) (152 patients)
Patients received aspirin 75-100 mg for thromboprophylaxis during induction therapy. Aspirin was optional during maintenance.
  - Response rate: 50% with MP, 68% with MPR, 77% with MPR-R
  - Median progression-free survival: 13 months with MP, 14 months with MPR, 31 months with MPR-R
    The benefit of MPR, as compared with MP, occurred in patients 65-75 years of age and not in those older than 75 years of age.
    The benefit of lenalidomide maintenance was observed even in patients older than 75 (median PFS with MPR-R: 19 months).
  - 3-year overall survival rate: 66% with MP, 62% with MPR, 70% with MPR-R
    Of note, the influence of maintenance therapy on overall survival was unclear, because median follow-up period was only 30 months.
  - The most frequent grade 4 toxicity was neutropenia.
  - 3-year rate of second cancers: 3% with MP, 7% with MPR, 7% with  MPR-R

Lenalidomide after stem-cell transplantation for multiple myeloma.
N Engl J Med. 2012 May 10;366(19):1770-81.
McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, Van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Qazilbash MH, Levitan D, McClune B, Schlossman R, Hars V, Postiglione J, Jiang C, Bennett E, Barry S, Bressler L, Kelly M, Seiler M, Rosenbaum C, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Anderson KC, Linker C.
In this double-blinded, placebo-controlled trial, 460 patients with myeloma treated with autologous stem cell transplantation were randomized to receive either lenalidomide 5-15 mg daily (231 patients) or placebo (229 patients). Maintenance therapy was started 100-110 days after transplant, and continued indefinitely, until disease progression. Induction therapy lasted 2-12 months, and it included no more than 2 regimens. Median follow-up period was 34 months.
  - Median time to progression: 27 months with placebo, and 46 months with lenalidomide
  - 3-year overall survival rate: 80% with placebo, and 88% with lenalidomide
  - Median survival was not reached in either group
  - Rate of second cancers: 3% with placebo, and 8% with lenalidomide (p=0.008)
Of note, benefits of maintenance lenalidomide were observed despite the crossover of patients receiving placebo to lenalidomide therapy.

Lenalidomide maintenance after stem-cell transplantation for multiple myeloma.
N Engl J Med. 2012 May 10;366(19):1782-91.
Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, Stoppa AM, Hulin C, Benboubker L, Garderet L, Decaux O, Leyvraz S, Vekemans MC, Voillat L, Michallet M, Pegourie B, Dumontet C, Roussel M, Leleu X, Mathiot C, Payen C, Avet-Loiseau H, Harousseau JL; IFM Investigators.
This is a placebo-controlled trial of 614 patients with myeloma treated with autologous stem cell transplantation, randomized to receive either lenalidomide 10-15 mg daily (307 patients) or placebo (307 patients). Patients were offered a second autologous transplant if they did not achieve CR or VGPR after the first one. Before starting maintenance, most patients received 2 cycles of post-transplant consolidation therapy with lenalidomide 25 mg daily on days 1-21 every 28 days. Maintenance was started within 6 months from the transplant, and it was continued indefinitely, until disease progression. Thromboprophylaxis was not used. Median follow-up period was 45 months.
  - Median progression-free survival: 23 months with placebo, and 41 months with lenalidomide
  - 3-year progression free-survival rate: 35% with placebo, and 59% with lenalidomide
  - 4-year overall survival rate: 75% with placebo, and 73% with lenalidomide
  - Median survival was not reached in either group
  - Thromboembolic events: 2% with placebo, and 6% with lenalidomide (p=0.01)
    Based on these results, the authors recommend aspirin prophylaxis with lenalidomide therapy.
  - Patients with second cancers: 4% with placebo, and 8% with lenalidomide
The benefit of lenalidomide seemed to persist despite the risk of second cancers, because the median event-free survival, which included second cancers as events, was 23 months with placebo, and 40 months with lenalidomide.

Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma.
Blood. 2012 May 10;119(19):4375-82.
Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV.
This study compared three regimens in 140 patients with newly diagnosed multiple myeloma:
  - VDR = Velcade, Dexamethasone, Revlimid
  - VDC = Velcade, Dexamethasone, Cyclophosphamide
  - VDCR = Velcade, Dexamethasone, Cyclophosphamide, Revlimid
All combinations were highly active, with high response rates. The 4-drug combination regimen induced more toxicities, especially myelosuppression, and it did not provide a significant advantage over the 3-drug combinations.


JUNE 2012

Effect of acute and chronic GVHD on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma.
Bone Marrow Transplant. 2012 Jun;47(6):831-7.
Ringdén O, Shrestha S, da Silva GT, Zhang MJ, Dispenzieri A, Remberger M, Kamble R, Freytes CO, Gale RP, Gibson J, Gupta V, Holmberg L, Lazarus H, McCarthy P, Meehan K, Schouten H, Milone GA, Lonial S, Hari PN.
This study analyses outcomes of 177 myeloma patients treated with non-myeloablative allogeneic stem cell transplant. The authors found that chronic GVHD was associated with improved progression-free survival, but this advantage did not translate into an overall survival advantage.

Multiple myeloma shows no intra-disease clustering of immunoglobulin heavy chain genes.
Haematologica. 2012 Jun;97(6):849-53.
Ferrero S, Capello D, Svaldi M, Boi M, Gatti D, Drandi D, Rossi D, Barbiero S, Mantoan B, Mantella E, Zanni M, Ghione P, Larocca A, Passera R, Bertoni F, Gattei V, Forconi F, Laurenti L, Del Poeta G, Marasca R, Cortelazzo S, Gaidano G, Palumbo A, Boccadoro M, Ladetto M.
This study analyzed 345 immunoglobulin sequences of multiple myeloma and investigated for stereotyped receptor clusters. The findings did not support a pathogenetic role for antigen selection in multiple myeloma.

Long-term analysis of the IFM 99 trials for myeloma: cytogenetic abnormalities [t(4;14), del(17p), 1q gains] play a major role in defining long-term survival.
J Clin Oncol. 2012 Jun 1;30(16):1949-52.
Avet-Loiseau H, Attal M, Campion L, Caillot D, Hulin C, Marit G, Stoppa AM, Voillat L, Wetterwald M, Pegourie B, Voog E, Tiab M, Banos A, Jaubert J, Bouscary D, Macro M, Kolb B, Traulle C, Mathiot C, Magrangeas F, Minvielle S, Facon T, Moreau P.

An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma.
Blood. 2012 Jun 14;119(24):5661-70.
Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK, Kukreti V, Jagannath S, McDonagh KT, Alsina M, Bahlis NJ, Reu FJ, Gabrail NY, Belch A, Matous JV, Lee P, Rosen P, Sebag M, Vesole DH, Kunkel LA, Wear SM, Wong AF, Orlowski RZ, Siegel DS.
This is a phase 2 study of 129 patients with relapsing/refractory myeloma (but not previously treated with bortezomib), who received carfilzomib IV. Results:
  - Response rate: 52%
  - PFS at 9 months: 54%
  - Most common adverse events: fatigue (62%) and nausea (49%).
  - Peripheral neuropathy was seen in 17% of patients (only 1 with grade 3 neuropathy, and no grade 4). Of note, more than two thirds of patients had neuropathy at baseline.

Donor versus no-donor comparison of newly diagnosed myeloma patients included in the HOVON-50 multiple myeloma study.
Blood. 2012 Jun 28;119(26):6219-25.
Lokhorst HM, van der Holt B, Cornelissen JJ, Kersten MJ, van Oers M, Raymakers R, Minnema MC, Zweegman S, Janssen JJ, Zijlmans M, Bos G, Schaap N, Wittebol S, de Weerdt O, Ammerlaan R, Sonneveld P.
This is a prospective study of 260 patients with newly diagnosed myeloma. After a single autologous transplant, patients were divided into 2 groups, based on the availability of a HLA-identical sibling donor for allogeneic stem cell transplant: 138 patients did not have a sibling donor, and 122 patients had a donor. After a median follow-up of 77 months, complete remission, progression-free survival, and overall survival were similar:
  - PFS at 6 years: 22% in the no-donor group, and 28% in the donor group (p=0.19)
  - Overall survival at 6 years (from the autologous transplant): 55% in both groups
In the group of 99 patients who underwent the allogeneic transplant, the incidence of relapse was lower, but the nonrelapse mortality was higher. Therefore, the prologation of PFS did not translate into a survival benefit. This study suggests that mini-allogeneic stem cell transplant should not be routinely offered as part of frontline therapy in patients with multiple myeloma. The different outcomes and conclusion of this study compared to those of the Italian and EBMT trials are likely due to the worse outcomes of the no-donor group in those two trials.

Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma.
J Clin Oncol. 2012 Jun 1;30(16):1953-9.
Lonial S, Vij R, Harousseau JL, Facon T, Moreau P, Mazumder A, Kaufman JL, Leleu X, Tsao LC, Westland C, Singhal AK, Jagannath S.
This is a phase I study of elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed or refractory myeloma. Response rate was 82%. After a median follow-up of 16 months, median time to progression was not reached. These results are better than those historically seen with lenalidomide and dexamethasone alone. Infusion reactions were only mild or moderate in the majority of patients.

Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma.
J Clin Oncol. 2012 Jun 1;30(16):1960-5.
Jakubowiak AJ, Benson DM, Bensinger W, Siegel DS, Zimmerman TM, Mohrbacher A, Richardson PG, Afar DE, Singhal AK, Anderson KC.

Comparable outcomes between unrelated and related donors after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation in patients with high-risk multiple myeloma.
Eur J Haematol. 2012 Jun;88(6):497-503.
El-Cheikh J, Crocchiolo R, Boher JM, Furst S, Stoppa AM, Ladaique P, Faucher C, Calmels B, Castagna L, Lemarie C, De Colella JM, Coso D, Bouabdallah R, Chabannon C, Blaise D.
These authors compared results of mini-allogeneic stem cell transplant from MRD (matched related donor) (17 patients) vs MUD (matched unrelated donor) (23 patients) in multiple myeloma. Results:
  - Acute GVHD, grade II-IV: 17% with MRD and 47% with MUD
  - Chronic GVHD: 30% with MRD and 24% with MUD
  - Treatment-related mortality at 2 years: 22% with MRD and 12% with MUD
  - Progression-free survival at 2 years: 44% with MRD and 42% with MUD
  - Overall survival at 2 years: 66% with MRD and 59% with MUD



Giampaolo Talamo, MD