Zdenek Adam

Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma

We compared thalidomide-dexamethasone (TD) with melphalan-prednisolone (MP) in 289 elderly patients with multiple myeloma (MM). Patients received either thalidomide 200 mg plus dexamethasone 40 mg, days 1 to 4 and 15 to 18 on even cycles and days 1 to 4 on odd cycles, during a 28-day cycle or to melphalan 0.25 mg/kg and prednisolone 2 mg/kg orally on days 1 to 4 during a 28- to 42-day cycle. Patients achieving stable disease or better were randomly assigned to maintenance therapy with either thalidomide 100 mg daily and 3 MU interferon alpha-2b thrice weekly or to 3 MU interferon alpha-2b thrice weekly only. TD resulted in a higher proportion of complete and very good remissions (26% vs 13%; P= .006) and overall responses (68% vs 50%; P= .002) compared with MP. Time to progression (21.2 vs 29.1 months; P= .2), and progression-free survival was similar (16.7 vs 20.7 months; P= .1), but overall survival was significantly shorter in the TD group (41.5 vs 49.4 months; P= .024). Toxicity was higher with TD, particularly in patients older than 75 years with poor performance status. The study was registered at ClinicalTrials.gov as NCT00205751.

Light Chain–Induced Acute Renal Failure Can Be Reversed by Bortezomib-Doxorubicin-Dexamethasone in Multiple Myeloma: Results of a Phase II Study

PURPOSE To assess the efficacy of bortezomib-doxorubicin-dexamethasone (BDD) therapy in patients with multiple myeloma with light chain-induced acute renal failure. PATIENTS AND METHODS Sixty-eight patients with light chain-induced acute renal failure and glomerular filtration rate (GFR) less than 50 mL/min received bortezomib (1.0 mg/m(2) on days 1, 4, 8, and 11), doxorubicin (9 mg/m(2) on days 1 and 4), and dexamethasone (40 mg on days 1, 4, 8, and 11); if well tolerated after two cycles, bortezomib could be increased to 1.3 mg/m(2) and doxorubicin administered on days 1, 4, 8, and 11. RESULTS By intent-to-treat analysis a myeloma response was obtained in 72% of 18 previously and 50 not previously treated patients (complete response [CR]/near CR [nCR], 38%; very good partial response [VGPR], 15%; partial response [PR], 13%; minor response [MR], 6%). Renal response was achieved in 62% of patients (renal CR, 31%; renal PR, 7%; renal MR, 24%). Median GFR increased from 20.5 to 48.4 mL/min. GFR improvement correlated with tumor response; the greatest increase to 59.6 mL/min was seen in the group of patients with CR/nCR/VGPR. Median progression-free survival was 12.1 months. One- and 2-year survival rates were 72% and 58%, respectively. Survival did not differ between patients with and without renal response but was inferior in previously treated patients (P < .001). In multivariate analysis, baseline GFR and tumor response correlated with renal response, and pretreatment status, lactate dehydrogenase, and myeloma response correlated with survival. The most common grade 3 or 4 toxicities were infection (19.1%), thrombocytopenia (14.7%), neutropenia (14.7%), fatigue/weakness (10.3%), and polyneuropathy (8.8%). CONCLUSION BDD induced a high rate of myeloma and renal responses, and treatment was well tolerated.

Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma

Background Thalidomide maintenance therapy after stem cell transplantation resulted in increased progression-free survival and overall survival in a few trials, but its role in non-transplant eligible patients with multiple myeloma remains unclear. This study assessed the impact of thalidomide-interferon in comparison to interferon maintenance therapy in elderly patients with multiple myeloma. Design and Methods Of 289 elderly patients with multiple myeloma who were randomized to thalidomide-dexamethasone or melphalan-prednisolone induction therapy, 137 finally completed 9 cycles of induction therapy with stable disease or better and thereby qualified for maintenance treatment. Of these, 128 have been randomized to either thalidomide-interferon or interferon alone. Primary study endpoints were progression-free survival and response rates; secondary endpoints were overall survival, toxicity and quality of life. Results Thalidomide-interferon maintenance therapy led to a significantly longer progression-free survival compared to interferon (27.7 vs. 13.2 months, P=0.0068), but overall survival was similar in both groups (52.6 vs. 51.4 months, P=0.81) and did not differ between patients aged 75 years or older, or younger patients (P=0.39). Survival after disease progression tended to be shorter in patients on thalidomide-interferon maintenance therapy (P=0.056). Progression-free survival and overall survival tended to be shorter in patients with adverse cytogenetic (FISH) findings compared to the standard risk group but differences were not significant (P=0.084 and P=0.082, respectively). Patients on thalidomide-interferon presented with more neuropathy (P=0.0015), constipation (P=0.0004), skin toxicity (P=0.0041) and elevated creatinine (P=0.026). Conclusions Thalidomide plus interferon maintenance therapy increased progression-free survival but not overall survival and was associated with slightly more toxicity than maintenance with interferon alone. (ClinicalTrials.gov Identifier: NCT00205751).

Circulating serum microRNAs as novel diagnostic and prognostic biomarkers for multiple myeloma and monoclonal gammopathy of undetermined significance

Multiple myeloma still remains incurable in the majority of cases prompting a further search for new and better prognostic markers. Emerging evidence has suggested that circulating microRNAs can serve as minimally invasive biomarkers for multiple myeloma and monoclonal gammopathy of undetermined significance. In this study, a global analysis of serum microRNAs by TaqMan Low Density Arrays was performed, followed by quantitative real-time PCR. The analyses revealed five deregulated microRNAs: miR-744, miR-130a, miR-34a, let-7d and let-7e in monoclonal gammopathy of undetermined significance, newly diagnosed and relapsed multiple myeloma when compared to healthy donors. Multivariate logistical regression analysis showed that a combination of miR-34a and let-7e can distinguish multiple myeloma from healthy donors with a sensitivity of 80.6% and a specificity of 86.7%, and monoclonal gammopathy of undetermined significance from healthy donors with a sensitivity of 91.1% and a specificity of 96.7%. Furthermore, lower levels of miR-744 and let-7e were associated with shorter overall survival and remission of myeloma patients. One-year mortality rates for miR-744 and let-7e were 41.9% and 34.6% for the ‘low’ expression and 3.3% and 3.9% for the ‘high’ expression groups, respectively. Median time of remission for both miR-744 and let-7e was approximately 11 months for the ‘low’ expression and approximately 47 months for the ‘high’ expression groups of myeloma patients These data demonstrate that expression patterns of circulating microRNAs are altered in multiple myeloma and monoclonal gammopathy of undetermined significance and miR-744 with let-7e are associated with survival of myeloma patients.

Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse

Even in the era of new drugs, multiple myeloma patients with extramedullary relapse have a poor prognosis. Our goal was to analyze the frequency and outcome of extramedullary relapse occurring in relapsed multiple myeloma patients. In total, we analyzed the prognosis of 226 relapsed multiple myeloma patients treated between 2005 and 2008 and evaluated them for presence of extramedullary relapse. We found evidence of extramedullary relapse in 24% (55 of 226) of relapsed multiple myeloma patients. In 14% (32 of 226) of patients, the lesions were not adjacent to the bone, while extramedullary relapse adjacent to the bone was documented in 10% (23 of 226) of cases. Patients without extramedullary relapse had significantly longer overall survival than patients with extramedullary relapse (109 vs. 38 months; P<0.001). Moreover, patients with soft tissue-related extramedullary relapse had significantly poorer overall survival compared to bone-related extramedullary relapse patients (30 vs. 45 months; P=0.022). Also, overall survival from diagnosis was as low as five months for soft tissue-related extramedullary relapse patients when compared to 12 months overall survival for bone-related extramedullary relapse. This is the first study that shows a significant difference in prognosis for different types of extramedullary relapse. If the extramedullary myeloma infiltration was not bone-related, overall survival after relapse was extremely short (5 months).

Gain of 1q21 Is an Unfavorable Genetic Prognostic Factor for Multiple Myeloma Patients Treated with High-Dose Chemotherapy

The prognostic significance of 1q21 gain, del(13)(q14), del(17)(p13), t(4;14)(p16.3;q32), and t(11;14)(q13;q32) detected by interphase fluorescein in situ hybridization (FISH) was studied in a cohort of 91 patients with newly diagnosed multiple myeloma (MM). 1q21 gain was detected in 37 of 91 patients (40.7%). In comparison with patients lacking 1q21 gain, patients with 1q21 gain had significantly shorter progression-free survival (PFS) (14.9 versus 27.4 months; P = .044) and worse 4-year overall survival (OS) (40.1% versus 76.2% of patients; P = <.001). PFS or OS were not influenced by the presence or absence of the other studied chromosomal abnormalities. Although the occurrence of 1q21 gain correlated with deletion of 13q14, the presence of 1q21 gain can be considered an independent prognostic factor, as no impact of del(13)(q14) as an isolated chromosomal abnormality on either PFS or OS has been observed. In comparison with patients lacking 1q21 gain, patients with 1q21 gain were significantly more likely to discontinue the preplanned treatment protocol because of disease progression or death. We conclude that 1q21 gain defines a prognostically unfavorable group of MM patients.

Varicella-Zoster Virus Prophylaxis with Low-Dose Acyclovir in Patients with Multiple Myeloma Treated with Bortezomib

BACKGROUND Varicella-zoster virus (VZV) reactivation is a common complication in patients with multiple myeloma (MM) treated with bortezomib, with an incidence rate of 10%-60%. The aim of our study was to analyze the effect of acyclovir prophylaxis in this patient population. PATIENTS AND METHODS We studied 98 consecutive patients with relapsed MM treated with bortezomib. Bortezomib 1.3 mg/m2 was given on days 1, 4, 8, and 11 of a 21-day cycle. At first, patients did not receive any VZV prophylaxis, but because of the high incidence of VZV reactivation, VZV prophylaxis with acyclovir was implemented subsequently. RESULTS A total of 11 patients treated with bortezomib did not have any VZV prophylaxis, and 4 of these 11 patients (36%) developed VZV reactivation in the form of herpes zoster. No VZV reactivations were observed in the 32 patients who received acyclovir 400 mg 3 times daily or the 55 patients who received acyclovir in a dose reduced to 400 mg once daily during bortezomib treatment. CONCLUSION Varicellazoster virus reactivation is a common and serious adverse effect of bortezomib treatment. Acyclovir 400 mg once daily is sufficient to protect from VZV reactivation in patients with MM treated with bortezomib.

Complex karyotype and translocation t(4;14) define patients with high-risk newly diagnosed multiple myeloma: results of CMG2002 trial

Abstract The prognostic impact of chromosomal abnormalities was evaluated by fluorescence in situ hybridization with cytoplasmic immunoglobulin light chain staining (cIg-FISH) and by classical metaphase cytogenetics in a cohort of 207 patients with newly diagnosed multiple myeloma who were treated with high-dose therapy followed by autologous stem cell transplantation in the CMG2002 clinical trial. The incidence of chromosomal abnormalities detected by FISH was as follows: 52.7% for del(13)(q14), 6.5% for del(17)(p13), 18.6% for t(11;14)(q13;q32), 22.8% for t(4;14)(p16;q32) and 45.7% for gain(1)(q21). Metaphase cytogenetic analysis revealed a complex karyotype in 19.1% and hyperdiploidy in 21.7% of patients. The overall response rate was not influenced by the presence of any studied chromosomal abnormality. Patients with a complex karyotype, those with translocation t(4;14) and those with gain of the 1q21 locus had a shorter time to progression (TTP) and overall survival (OS). Other genomic changes such as translocation t(11;14) and del(13q) had less impact on TTP and OS. In multivariate analysis, complex karyotype, translocation t(4;14) and β2-microglobulin level > 2.5 mg/L were independent prognostic factors associated with poor overall survival. Their unfavorable prognostic impact was even more pronounced if they were present in combination. Patients with t(4;14) present together with a complex karyotype had the worst prognosis, with a median OS of only 13.2 months, whereas patients with a normal karyotype or karyotype with ≤ 2 chromosomal changes had the best outcome, with 3-year OS of 85.9%. In conclusion, complex karyotype, gain of 1q21 region and translocation t(4;14) are major prognostic factors associated with reduced survival of patients with newly diagnosed multiple myeloma treated with autologous stem cell transplantation.

Levels of angiogenic factors in patients with multiple myeloma correlate with treatment response

Angiogenesis plays a significant role in the pathogenesis of multiple myeloma (MM). We have measured concentrations of angiogenesis activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and hepatocyte growth factor (HGF), and inhibitors, including endostatin, thrombospondin-1 (TSP-1), and angiostatin in the peripheral and bone marrow blood of MM patients at diagnosis and after high-dose chemotherapy. We have analyzed 96 patients with secretory MM. Serial measurements of angiogenesis factors/inhibitors were analyzed in the plasma by subgroups based on the best treatment response. Concentrations of angiogenic factors were determined in the peripheral blood and bone marrow plasma. There were significant decreases of VEGF and HGF levels and a significant increase in TSP-1 concentrations in the bone marrow plasma of patients who achieved complete or very good partial response in contrast to those who had partial or no response. VEGF and HGF levels decrease but those of TSP-1 increase after successful treatment for MM, indicating a reduction in the rate of angiogenesis.

Subcutaneous Bortezomib in Multiple Myeloma Patients Induces Similar Therapeutic Response Rates as Intravenous Application But It Does Not Reduce the Incidence of Peripheral Neuropathy

Objective Subcutaneous (SC) application of bortezomib has been recently introduced as a new application route in multiple myeloma (MM) patients. We performed an analysis to compare the outcomes of bortezomib-based therapy in multiple myeloma (MM) patients treated using either intravenous (IV) or subcutaneous (SC) route of administration. Patients and methods During January 2012 through December 2013, we performed a retrospective analysis of 446 patients with MM treated with bortezomib-based regimens (either once weekly – 63% or twice weekly – 27%) in both, the first line setting, and in relapse, with separate analysis of patients undergoing autologous stem cell transplantation. We assessed the response rates and toxicity profiles in both, IV and SC route of bortezomib administration. Results The response rates in both IV and SC arm were similar with overall response rate 71.7% vs 70.7%, complete remissions in 13.9% vs 8.6%, very good partial remissions in 30.8% vs 34.5% and partial remissions in 27% vs 27.6%. The most frequent grade ≥3 toxicities were anemia, thrombocytopenia and neutropenia, with no significant differences between IV and SC group. There were no significant differences in the rate of peripheral neuropathy (PN). PN of any grade was present in 48% in the IV arm and in 41% in the SC arm. PN grade ≥2 was present in 20% vs 18% and PN grade ≥3 was present in 6% vs 4%. Conclusions We conclude that subcutaneous application of bortezomib has similar therapeutic outcomes and toxicity profile as intravenous route of application. In our cohort there was no difference in the incidence of PN, suggesting that PN is dose dependent and might be reduced by lower intensity schemes rather than by the route of administration.