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Intensive upfront therapy in newly-diagnosed multiple myeloma (MM) including induction therapy (IT), high-dose melphalan (MEL200), and autologous blood stem cell transplantation (ASCT) followed by consolidation and/or maintenance is mostly restricted to patients up to 65 years of age. Prospective phase III trial data in the era of novel agents for patients up to 70 years of age are not available. The GMMG-MM5 trial included 601 patients between 18 and 70 years of age, divided in three groups for the present analysis: ≤60 years (S1, n = 353), 61–65 years (S2, n = 107) and 66–70 years (S3, n = 141). Treatment consisted of a bortezomib-containing IT, MEL200/ASCT, consolidation, and maintenance with lenalidomide. Adherence to treatment was similar among patients of the three age groups. Overall toxicity during all treatment phases was increased in S2 and S3 compared to S1 (any adverse event/any serious adverse event: S1:81.7/41.8% vs. S2:90.7/56.5% vs. S3:87.2/68.1%, p = 0.05/p = 0.73), overall survival (log-rank p = 0.54) as well as time-to-progression (Gray’s p = 0.83) and non-relapse mortality (Gray’s p = 0.25), no differences were found between the three age groups. Our results imply that an intensive upfront therapy with a bortezomib-containing IT, MEL200/ASCT, lenalidomide consolidation, and maintenance should be applied to transplant-eligible MM patients up to 70 years of age.

The MM5 trial aimed at demonstrating a progression-free survival (PFS) difference in continued vs. response-adapted (in case of complete response, CR) lenalidomide (LEN) maintenance therapy (MT) in newly diagnosed, transplant-eligible multiple myeloma (MM). Patients were equally randomized to receive induction therapy with PAd (bortezomib/doxorubicin/dexamethasone) or VCD (bortezomib/cyclophosphamide/dexamethasone), high-dose melphalan and autologous blood stem cell transplantation, and LEN consolidation, followed by either LEN MT for a fixed duration of 2 years (LEN-2Y) or until achievement of CR (LEN-CR, intention-to-treat population n = 502): arms A1:PAd + LEN-2Y (n = 125), B1:PAd + LEN-CR (n = 126), A2:VCD + LEN-2Y (n = 126), B2:VCD + LEN-CR (n = 125). In the LEN-CR group (B1 + B2), n = 88/17.5% patients did not start or discontinued LEN MT due to CR. There was no PFS (p = 0.60, primary endpoint) nor overall survival (OS) (p = 0.15) difference between the four study arms. On pooled LEN MT strategies, OS (hazard ratio, hazard ratio [HR] = 1.42, p = 0.03) but not PFS (HR = 1.15, p = 0.20) was shorter in LEN-CR (B1 + B2) vs. LEN-2Y (A1 + A2) groups. PFS was shortened on landmark analyses from the start of LEN MT in patients being in CR in the LEN-CR group (LEN-CR vs. LEN-2Y, HR = 1.84, p = 0.02). OS from first progression was shortened in the LEN-CR vs. LEN-2Y group (HR = 1.60, p = 0.01). LEN MT should be applied beyond CR for at least 2 years.

Here we describe the results of an interlaboratory test for RT-PCR-based BCR/ABL analysis. The test was organized in two parts. The number of participating laboratories in the first and second part was 27 and 20, respectively. In the first part samples containing various concentrations of plasmids with the ela2, b2a2 or b3a2 BCR/ABL transcripts were analyzed by PCR. In the second part of the test, cell samples containing various concentrations of BCR/ABL-positive cells were analyzed by RT-PCR. Overall PCR sensitivity was sufficient in approximately 90% of the tests, but a significant number of false positive results were obtained. There were significant differences in sensitivity in the cell-based analysis between the various participants. The results are discussed, and proposals are made regarding the choice of primers, controls, conditions for RNA extraction and reverse transcription.

We compared the biological effects of the CXC chemokine SDF-1alpha on immunomagnetically purified CD34+ cells isolated from human normal bone marrow (NBM), leukapheresis products (LP) and patients with chronic myeloid leukaemia (CML). LP CD34+ cells showed a significantly stronger migration response to SDF-1alpha (100 ng/ml) than CD34+ cells isolated from the peripheral blood (PB) of CML patients (P0.05). The chemotactic response to SDF-1alpha was also reduced in CML BM CD34+ cells in comparison to NBM CD34+ cells but the observed differences were not statistically significant. In analogy to normal CD34+ cells circulating CML PB CD34+ cells were less responsive to SDF-1alpha than their BM counterparts (P0.05). Furthermore, SDF-1alpha elicited similar concentration-dependent growth suppressive effects on normal and CML CD34+ cells (P0.05) in colony-forming cell assays. We then demonstrated that SDF-1alpha triggers intracellular calcium increases in CD34+ cells and there were no differences in the time course and dose response characteristics of normal and CML CD34+ cells. The reduced migration response to SDF-1alpha in CML CD34+ cells was not due to a down-regulation of the SDF-1alpha receptor CXCR-4 as flow cytometric analysis revealed similar CXCR-4 expression levels on NBM, LP, CML PB and CML BM CD34+ cells (P0.05). Finally, no differences in the modulation of CXCR-4 levels in response to SDF-1alpha and serum were observed in CML and normal CD34+ cells. Our data suggest that the impaired chemotactic response of CML CD34+ cells to SDF-1alpha is not caused by a lack or complete uncoupling of CXCR-4, but may be due to an intracellular signalling defect downstream of the receptor.