JULY 2008

Systemic lupus erythematosus and multiple myeloma: an uncommon association. Two cases and literature review.
Clin Exp Rheumatol. 2008 Jul-Aug;26(4):667-70.
Maamar M, Tazi Mezalek Z, Harmouche H, Adnaoui M, Aouni M, Maaouni A.
The coexistence of systemic lupus erythematosus and multiple myeloma is very rare. Authors report two cases of SLE and MM, and review the literature on this subject. Two female patients of 50 and 35 years old developed MM 7 and 3 years respectively after the diagnosis of SLE. In the second case, SLE was associated to monoclonal gammopathy.

Familial myeloma.
N Engl J Med. 2008 Jul 10;359(2):152-7.
Lynch HT, Ferrara K, Barlogie B, Coleman EA, Lynch JF, Weisenburger D, Sanger W, Watson P, Nipper H, Witt V, Thomé S.
Authors describe a family with 5 cases of multiple myeloma, 3 cases of MGUS, and 5 cases of prostate cancer in two generations.

Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma.
Blood. 2008 Jul 1;112(1):196-207.
Qiang YW, Chen Y, Stephens O, Brown N, Chen B, Epstein J, Barlogie B, Shaughnessy JD Jr.
MM cell-derived DKK1 disrupts Wnt3a-regulated OPG and RANKL expression in osteoblasts. Wnt3a-induced OPG expression is reduced in osteoblasts cocultured with DKK1-expressing MM cell lines or primary MM cells. DKK1 induces osteolysis by inhibiting Wnt-regulated differentiation of osteoblasts, and by promoting osteoclastogenesis after increase of the RANKL/OPG ratio.

Wnt3a signaling within bone inhibits multiple myeloma bone disease and tumor growth.
Blood. 2008 Jul 15;112(2):374-82.
Qiang YW, Shaughnessy JD Jr, Yaccoby S.
These authors studied the effect of Wnt3a on bone disease and growth of MM cells. Wnt3a activated canonical signaling in MM cell lines, but it had no effect on MM cell growth in vitro. Expression of Wnt3a in MM cells conferred no growth advantage in vitro. SCID-hu mice with MM treated with recombinant Wnt3a had increased bone formation and decreased MM growth.

Low efficacy of thalidomide in improving response after induction in multiple myeloma patients who are candidates for high-dose therapy.
Leuk Res. 2008 Jul;32(7):1085-90.
Corso A, Mangiacavalli S, Barbarano L, Montalbetti L, Mazzone A, Fava S, Varettoni M, Zappasodi P, Morra E, Lazzarino M.
This is a retrospective study of 74 myeloma patients treated with VAD induction therapy, followed by 3 months of thalidomide + dexamethasone (TD), in the attempt of achieving a deeper remission before stem cell transplantation. Results:
  - CR rate was 6% after VAD and 11% after TD
  - VGPR rate was 40% after VAD and 39% after TD
  - PR rate was 23% after VAD and 17% after TD
  - Progressive disease rate was 8% after VAD and 24% after TD
In view of the above results, and the presence of additional toxicities with TD, the authors concluded that intensification therapy with TD after VAD is not a useful therapeutic strategy.

Complete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma.
Cancer. 2008 Jul 15;113(2):355-9.
Barlogie B, Anaissie E, Haessler J, van Rhee F, Pineda-Roman M, Hollmig K, Alsayed Y, Epstein J, Shaughnessy JD Jr, Crowley J.
Data from 3 clinical trials were reviewed, and sustained CR -for 3 years after the beginning of treatment- was found to be a superior surrogate for prolonged survival than the simple achievement of CR.

VTD combination therapy with bortezomib-thalidomide-dexamethasone is highly effective in advanced and refractory multiple myeloma.
Leukemia. 2008 Jul;22(7):1419-27.
Pineda-Roman M, Zangari M, van Rhee F, Anaissie E, Szymonifka J, Hoering A, Petty N, Crowley J, Shaughnessy J, Epstein J, Barlogie B.
This is a phase I/II trial of the VTD regimen in 85 patients with refractory multiple myeloma.
  - Velcade, started at 1.0 mg/m2 IV days 1, 4, 8, 11, increased to 1.3 mg
  - Thalidomide, started at 50 mg and increased to a maximum dose of 200 mg, added from cycle 2
  - Dexamethasone, added with cycle 4 in the absence of PR
Cycles were repeated every 21 days.
  - MTD was reached at Velcade 1.3 mg/m2 and Thalidomide 50 mg
  - Partial response rate: 63% (nCR 22%)
  - Event-free survival at 4 years: 6%
  - Overall survival at 4 years: 23%

Phase I, pharmacokinetic and pharmacodynamic study of the anti-insulinlike growth factor type 1 Receptor monoclonal antibody CP-751,871 in patients with multiple myeloma.
J Clin Oncol. 2008 Jul 1;26(19):3196-203.
Lacy MQ, Alsina M, Fonseca R, Paccagnella ML, Melvin CL, Yin D, Sharma A, Enriquez Sarano M, Pollak M, Jagannath S, Richardson P, Gualberto A.
CP-751,871 is an anti-insulin-like growth factor 1 receptor (IGF-IR) monoclonal antibody. It blocks ligand binding of IGF-1and IGF-2, and it down-regulates IGF-1R. 47 patients with relapsed/refractory myeloma. Dexamethasone and rapamycin could be added in patients with less than a partial response. There were 9 responses in 27 patients treated with CP-751,871 + dexamethasone.

Stem cell mobilization with cyclophosphamide overcomes the suppressive effect of lenalidomide therapy on stem cell collection in multiple myeloma.
Biol Blood Marrow Transplant. 2008 Jul;14(7):795-8.
Mark T, Stern J, Furst JR, Jayabalan D, Zafar F, LaRow A, Pearse RN, Harpel J, Shore T, Schuster MW, Leonard JP, Christos PJ, Coleman M, Niesvizky R.
In this study, 28 patients with newly diagnosed myeloma were were treated with clarithromycin, lenalidomide, and dexamethasone (BIRD), and they underwent stem cell collection with either G-CSF or cyclophosphamide + G-CSF. All patients mobilized with cyclophosphamide + G-CSF collected sufficient stem cells for 2 autologous stem cell transplants, whereas only 33% of patients mobilized with G-CSF alone reached the same goal. No correlation was found between duration of prior lenalidomide therapy and success of stem cell collection.



Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma: a phase 2 trial of the Minnie Pearl Cancer Research Network.
Cancer. 2008 Aug 15;113(4):765-71.
Hainsworth JD, Spigel DR, Barton J, Farley C, Schreeder M, Hon J, Greco FA.
40 patients with myeloma in relapse/progression after 1-2 lines of therapy received bortezomib 1.6 mg/m2 IV weekly for 4 weeks, followed by 1 week without therapy. Results:
  - Response rate: 55%
  - Median progression-free survival: 9.6 months
  - 1-year progression-free survival: 39%
  - 1-year overall survival: 75%
  - 2-year overall survival: 51%
  - Grade 3-4 neuropathy: 10%
Response rate and duration of disease remission seemed similar to those observed with twice-weekly bortezomib.

Current status of autologous hematopoietic stem cell transplantation in myeloma.
Bone Marrow Transplant. 2008 Aug;42 Suppl 1:S28-S34.
Mehta J, Singhal S.

MAGE-C1/CT7 is the dominant cancer-testis antigen targeted by humoral immune responses in patients with multiple myeloma.
Leukemia. 2008 Aug;22(8):1646-8.
Curioni-Fontecedro A, Knights AJ, Tinguely M, et al.

Association of thyroid disease and thyroid autoimmunity with multiple myeloma risk: a case-control study.
Leuk Lymphoma. 2008 Aug;49(8):1545-52.
Dalamaga M, Karmaniolas K, Papadavid E, Pelecanos N, Migdalis I.
This study explored whether thyroid disease and autoimmune thyroid disease (ATD) are associated with MM risk. 73 patients with MM and 73 controls were studied between 2001 and 2007. The prevalence of clinical thyroid disease in MM patients was significantly higher than in controls, and ATD was associated with increased risk of MM. A person with any thyroid disease >10 years has about 2.41 times higher risk to develop MM than an individual without any thyroid disease (95% CI: 1.35-4.29). A familial history of thyroid disease was associated with increased risk of MM (OR = 3.23, 95% CI: 1.25-8.31).

The role of vertebral augmentation in multiple myeloma: International Myeloma Working Group Consensus Statement.
Leukemia. 2008 Aug;22(8):1479-84.
Hussein MA, Vrionis FD, Allison R, Berenson J, Berven S, Erdem E, Giralt S, Jagannath S, Kyle RA, LeGrand S, Pflugmacher R, Raje N, Rajkumar SV, Randall RL, Roodman D, Siegel D, Vescio R, Zonder J, Durie BG; International Myeloma Working Group.

Risk factors for symptomatic hypocalcaemia complicating treatment with zoledronic acid.
Intern Med J. 2008 Aug;38(8):635-7.
Chennuru S, Koduri J, Baumann MA.
This study reviews the data from 120 patients who received a total of 546 infusions of zoledronic acid. Hypocalcemia developed after 55 infusions (10%) in 42 patients (35%). Symptomatic hypocalcaemia requiring IV replacement occurred in 10 patients (8%). All patients with hypocalcemia had hypomagnesaemia as well. Therefore, hypocalcemia is a common side effect of zoledronic acid. Hypomagnesemia may increase the risk of symptomatic hypocalcemia by blunting the compensatory increase in PTH secretion.

Clinical impact of discordance in serum albumin measurements on myeloma international staging system.
J Clin Oncol. 2008 Aug 20;26(24):4051-2.
Kapoor P, Snozek CL, Colby C, Larson DR, Katzmann JA, Rajkumar SV, Greipp PR.
Serum albumin level, necessary for ISS staging, can be measured either by serum protein electrophoresis or by the bromcresol assay, as part of the chemistry panel. These authors show that the two methods provide equivalent results. They recommend using the albumin level obtained by SPEP for convenience, in order to avoid missing data in clinical trials, because SPEP is always ordered at the time of diagnosis of multiple myeloma.

Bortezomib and the increased incidence of herpes zoster in patients with multiple myeloma.
Clin Lymphoma Myeloma. 2008 Aug;8(4):237-40.
Kim SJ, Kim K, Kim BS, Lee HJ, Kim H, Lee NR, Nam SH, Kwon JH, Kim HJ, Sohn SK, Won JH, Lee JH, Suh C, Yoon SS, Kim HJ, Kim I, Do YR, Lee WS, Joo YD, Shin HJ; Korean Multiple Myeloma Working Party.
This is a retrospective analysis of 282 myeloma patients treated with bortezomib-containing regimens. The incidence of herpes zoster was 11% (31 of 282 patients) without bortezomib, but after treatment with bortezomib, the incidence increased to 22% (63 of 282 patients). In the vast majority of cases, herpes zoster developed during the the first 3 cycles of bortezomib.

Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma.
N Engl J Med. 2008 Aug 28;359(9):906-17.
San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG; VISTA Trial Investigators.
This is a phase III study (VISTA trial - Velcade as Initial Standard Therapy in multiple myeloma)) comparing MP (melphalan + prednisone) (338 pts) vs MPV (MP + bortezomib) (344 pts) in newly diagnosed multiple myeloma who were ineligible for stem cell transplant.
  - Melphalan 9 mg/m2 PO days 1-4
  - Prednisone 60 mg/m2 PO on days 1-4
  - Bortezomib 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, 32 during cycles 1-4 and on days 1, 8, 22, and 29 during cycles 5-9
Cycles were repeated every 6 weeks, x9.
MPV gave superior results:
  - Response rate was 35% with MP and 71% with MPV
  - CR rate was 4% with MP and 30% with MPV
  - Time to progression was 16.6 months with MP and 24 months with MPV
  - Treatment-related mortality was similar (1-2%)
An updated follow-up of the VISTA trial [J Clin Oncol, 2010; 28:2259] found that VMP was more beneficial than therapy with conventional agents followed by bortezomib-based regimens at relapse. Another report on the Vista study showed that patients achieving complete response had superior clinical outcomes [Blood, 2010; 116::3743].

Impact of additional cytoreduction following autologous SCT in multiple myeloma.
Bone Marrow Transplant. 2008 Aug;42(4):259-64.
Kumar S, Dingli D, Dispenzieri A, Lacy M, Hayman SR, Buadi F, Rajkumar S, Litzow M, Gertz M.

Autologous stem cell transplantation in patients of 70 years and older with multiple myeloma: Results from a matched pair analysis.
Am J Hematol. 2008 Aug;83(8):614-7.
Kumar SK, Dingli D, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK, Rajkumar SV, Litzow MR, Gertz MA.
This study analyzes outcomes of high-dose chemotherapy and autologous stem cell transplantation in older patients with multiple myeloma, with age 70 or older. 33 older patients (range: 70-75.8 years) were matched to a group of 60 myeloma patients younger than 65. Among the older patients, 23 patients received melphalan 200 mg/m2, and 10 patients received melphalan 140 mg/m2. Hematologic recovery and toxicities of the transplant were comparable to younger patients. 1 patient in the older group died, vs no deaths in the younger group, but the difference was not statistically significant. Response rates, ttime to progression, and overall survival were similar. Therefore, the authors conclude that older patients with multiple myeloma should not be excluded from transplant based only on their chronological age.

Restrictive usage of monoclonal immunoglobulin lambda light chain germline in POEMS syndrome.
Blood. 2008 Aug 1;112(3):836-9.
Abe D, Nakaseko C, Takeuchi M, Tanaka H, Ohwada C, Sakaida E, Takeda Y, Oda K, Ozawa S, Shimizu N, Masuda S, Cho R, Nishimura M, Misawa S, Kuwabara S, Saito Y.



Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein.
Blood. 2008 Sep 15;112(6):2489-99.
Oerlemans R, Franke NE, Assaraf YG, Cloos J, van Zantwijk I, Berkers CR, Scheffer GL, Debipersad K, Vojtekova K, Lemos C, van der Heijden JW, Ylstra B, Peters GJ, Kaspers GL, Dijkmans BA, Scheper RJ, Jansen G.
These authors found that resistance of cells to bortezomib involved an Ala49Thr mutation located in the PSMB5 protein (the bortezomib-binding pocket of the proteasome beta5-subunit), and overexpression of PSMB5.

Cellular immunotherapy for multiple myeloma.
Best Pract Res Clin Haematol. 2008 Sep;21(3):559-77.
Rosenblatt J, Avigan D.

A cohort mortality study of chemical laboratory workers at Department of Energy Nuclear Plants.
Am J Ind Med. 2008 Sep;51(9):656-67.
Kubale T, Hiratzka S, Henn S, Markey A, Daniels R, Utterback D, Waters K, Silver S, Robinson C, Macievic G, Lodwick J.
This study evaluates the mortality experience of 6,157 chemical laboratory workers employed at the US Department of Energy facilities, to assess the relation between chemical exposure and mortality risk due to cancer. There was a statistically higher occurrence of deaths due to MM among females (number of observed deaths: 7), lung cancer, and leukemia among workers employed 20+ years (possibly due to radiation and benzene exposure).

Analysis of clonotypic switch junctions reveals multiple myeloma originates from a single class switch event with ongoing mutation in the isotype-switched progeny.
Blood. 2008 Sep 1;112(5):1894-903.
Taylor BJ, Kriangkum J, Pittman JA, Mant MJ, Reiman T, Belch AR, Pilarski LM.
Authors found that myeloma cells have a single, unchanging clonotypic switch junction that persists over time. They suggest that post-switch plasma cells arise from a single clonogenic IgM cell, and that MM-PC progenitors reside in the post-switch population. They also found that aggressive clones that evolve throughout the course of MM are associated with new mutations upstream of the switch junction, often targeting the intronic enhancer, a key control region in IgH expression.

MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis.
Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):12885-90.
Pichiorri F, Suh SS, Ladetto M, Kuehl M, Palumbo T, Drandi D, Taccioli C, Zanesi N, Alder H, Hagan JP, Munker R, Volinia S, Boccadoro M, Garzon R, Palumbo A, Aqeilan RI, Croce CM.
MicroRNAs (miRNAs) are small noncoding RNAs which target mRNAs and regulate gene expression. To assess the possible role of miRNAs in the malignant transformation of plasma cells, these authors studied miRNA expression in 49 MM-derived cell lines, 16 MM patients, 6 patients with MGUS, and 6 normal donors. They identified and described a MM miRNA signature, with miRNAs that modulate the expression of proteins critical to the pathogenesis of MM.

Incorporation of the bone marker carboxy-terminal telopeptide of type-1 collagen improves prognostic information of the International Staging System in newly diagnosed symptomatic multiple myeloma.
Leukemia. 2008 Sep;22(9):1767-72.
Jakob C, Sterz J, Liebisch P, Mieth M, Rademacher J, Goerke A, Heider U, Fleissner C, Kaiser M, von Metzler I, Müller C, Sezer O.
This study evaluated several prognostic markers for the identification of high-risk myeloma among 100 patients with newly diagnosed symptomatic multiple myeloma. Significant prognostic factors included beta2-microglobulin, albumin, transplantation, monosomy 13, and also the carboxy-terminal telopeptide of type-1 collagen (ICTP), a marker of bone resorption. After multivariate analysis, ICTP was the most powerful prognostic factor. After incorporation of ICTP in the ISS, the combined ICTP-ISS score separated 4 groups, with a 5-year overall survival rate of 95%, 64%, 46% and 22%.

Evaluation of minimal residual disease in multiple myeloma patients by fluorescent-polymerase chain reaction: the prognostic impact of achieving molecular response.
Br J Haematol. 2008 Sep;142(5):766-74.
Martínez-Sánchez P, Montejano L, Sarasquete ME, García-Sanz R, Fernández-Redondo E, Ayala R, Montalbán MA, Martínez R, García Laraña J, Alegre A, Hernández B, Lahuerta JJ, Martínez-López J.
Fluorescent PCR (F-PCR) of DHJ and light chain rearrangements was used for the detection of minimal residual disease after stem cell transplantation in 53 patients with multiple myeloma. The results of F-PCR were similar to those of flow cytometry. Molecular response by PCR had prognostic value. PCR could identify a subset of patients with better prognosis, even amongst patients in CR by IFE.

Thalidomide-Related Eosinophilic Pneumonia: A case report and brief literature review.
Cases J. 2008 Sep 8;1(1):143.
Tilluckdharry L, Dean R, Farver C, Ahmad M.

Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature.
Blood. 2008 Sep 1;112(5):1593-9.
Argyriou AA, Iconomou G, Kalofonos HP.

Impact of early relapse after auto-SCT for multiple myeloma.
Bone Marrow Transplant. 2008 Sep;42(6):413-20.
Kumar S, Mahmood ST, Lacy MQ, Dispenzieri A, Hayman SR, Buadi FK, Dingli D, Rajkumar SV, Litzow MR, Gertz MA.
Without maintenance therapy, nearly a fifth of myeloma patients relapse within a year of autologous stem cell transplant. In a study of 494 patients who underwent transplant within 12 months after the diagnosis of myeloma, early relapse (<12 months from transplant) was observed in 120 patients (24%). This group had a significantly shorter overall survival (median 26.6 months, vs 90.7 months for the rest of the patients, calculating survival from the time of diagnosis). Multivariate analysis found 3 factors predicting for early relapse:
  - Failure to achieve complete remission
  - >1 treatment regimen prior to transplant
  - Labeling index >1%
Patients who relapse within 12 months of an autologous transplant have a poor outcome.

Allogeneic transplantation in multiple myeloma.
Haematologica. 2008 Sep;93(9):1295-300.
Gahrton G, Björkstrand B.

Erythropoiesis-stimulating agents are associated with reduced survival in patients with multiple myeloma.
Am J Hematol. 2008 Sep;83(9):697-701.
Katodritou E, Verrou E, Hadjiaggelidou C, Gastari V, Laschos K, Kontovinis L, Kapetanos D, Constantinou N, Terpos E, Zervas K.
In this study, 323 patients with MM found reduced overall survival and progression-free survival in patients treated with EPO. After a median follow-up of 31 months (range: 1-238):
  - Median survival: 31 months in patients treated with EPO, and 67 months in patients not treated with EPO (p < 0.001)
  - Median PFS: 14 months in patients treated with EPO, and 30 months in patients not treated with EPO (p < 0.001)



Giampaolo Talamo, M.D.