Conventional induction treatments do not influence overall survival in multiple myeloma.

A retrospective analysis was performed on two subsequent myeloma patient series treated with the same conventional induction treatments, melphalan and prednisone or alternating VMCP/VBAP: 273 were enrolled in the multicentre M83 trial (M83 trial group) from 1983 to 1986; 160 were referred to a single institution (Haemat. To group) from 1986 to 1994. Response to treatment was very similar in the two groups (53% v 50.3%). Remission duration curves merely overlapped (median 20 v 21 months). However, overall survival was significantly longer in the Haemat. To group (43.2 v 33 months, P < 0.04). This difference was due to a prolonged period from relapse or progression to death (21 v 8 months, P < 0.01; 20.8 v 7 months, P < 0.009). Prolonged survival was also observed in poor-prognosis patients with a serum beta2-microglobulin level > 3 mg/l, in the Haemat. To group (31.8 v 24.2 months, P < 0.04). The same induction treatments produced almost identical response rate and remission duration in both groups, but overall survival was 10 months longer for one group. However, it could be argued that treatment salvage modalities and support therapies have been improved in a decade. Lastly, induction treatments did not influence overall survival.

Multicyclic, dose-intensive chemotherapy supported by hemopoietic progenitors in refractory myeloma patients.

Attempts to increase dose intensity have been hampered by hematologic toxicity. To address this issue, we designed a study to determine whether the reinfusion of PBPC significantly reduces the toxicity of multicyclic dose-intensive chemotherapy. Thirty refractory patients, median age 63, received CY 3 g/m2 plus melphalan 60 mg/m2 followed by PBPC and G-CSF (CM regimen). CY (at day 0) and G-CSF were used to mobilize PBPC harvested by a single leukapheresis at day 10. Melphalan was infused at day 11. PBPC were kept unprocessed at 4 degrees C for 48 h and reinfused at day 12. This regimen was repeated three times every 6 months. Outcomes were compared with those of 30 similar patients treated with melphalan 30 mg/m2 followed by G-CSF only, and repeated every 2 months for a total of six cycles. In patients receiving CY plus melphalan followed by PBPC reinfusion, the median duration of neutropenia (ANC < 500/microliters) and thrombocytopenia (platelets < 2500 microliters) was only 5 and 2 days respectively, and did not increase after the subsequent courses. Hematologic toxicity was quite similar to that observed after melphalan 30 mg/m2 plus G-CSF. The CM regimen was followed by 30% complete remission and 86% response > 50%, melphalan 30 mg/m2 by no complete remissions and 38% response > 50%. Patients receiving CM regimen showed a longer progression-free survival (22 vs 10 months, P < 0.01). The dose intensity of melphalan can be doubled by reinfusing PBPC without increasing toxicity. The combination of CY and melphalan followed by PBPC improves response rate and outcome when compared to low-dose melphalan.

Role of chemotherapy and GM-CSF on hemopoietic progenitor cell mobilization in multiple myeloma.

Circulating hemopoietic progenitors were evaluated in 19 multiple myeloma patients at diagnosis. Eleven patients received either high-dose cyclophosphamide (7 g/m2, 8 patients) or etoposide (2 g/m2, 3 patients) followed by GM-CSF administration; the remaining 8 patients received intermediate-dose cyclophosphamide (1.2 g/m2 on days 1 and 3), 4 of them with GM-CSF support. The highest levels of circulating progenitor cells were observed among patients in the high-dose chemotherapy group (median CFU-GM peak value of 6432 per ml), while in patients receiving intermediate-dose, with or without GM-CSF, median peak values were 2588 and 462 per ml, respectively. In all groups a remarkable heterogeneity in the yield of circulating progenitors was observed; this was particularly pronounced in the high-dose group, where CFU-GM peak values ranged between 200 and 38,070 per ml. At variance with the effect observed in previously untreated patients with lymphoma or breast cancer, the degree of mobilization in myeloma patients was rather unpredictable. The only pre-treatment characteristic correlating to some extent with a poor expansion of the circulating progenitor pool was heavy BM infiltration with plasma cells. The mobilizing effect was not restricted to the myeloid lineage, as demonstrated by the rise of BFU-E; CD34+ cells were increased as well. Indeed, a simultaneous evaluation of CFU-GM and CD34+ cells was carried out and a highly significant correlation (r = 0.9) was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Interferon plus glucocorticoids as intensified maintenance therapy prolongs tumor control in relapsed myeloma.

Interferon-alpha-2b (IFN) has been demonstrated to prolong remission duration and survival in responding multiple myeloma (MM) patients. The aim of this study was to intensity maintenance therapy adding glucocorticoids (GLU) to the standard IFN therapy. Twenty-eight relapsed MMs with stable disease or response after conventional chemotherapy received IFN+GLU. The treatment included 3 megaunits of IFN 3 times a week continuously until relapse, plus 4 days pulsed high-dose dexamethasone (40 mg/day for 4 days every 28 days for 6 consecutive months every 12 months) in patients < 70 years, or oral prednisone (PDN, 50 mg 3 times a week) in patients > 70 years, both until relapse. Conventional chemotherapy induced a response in 12/28 MMs. For all patients the actuarial median progression-free survival from relapse was 24 months and the survival from relapse 42 months with no difference between responding and nonresponding patients. The first duration of tumor control, i.e. the interval from diagnosis to first relapse, was shorter than the period between first and second relapse in 11/28 patients (40%). Toxicity was mild and oral PDN significantly increased the subjective tolerability of IFN. These findings indicate that IFN+GLU after induction chemotherapy may prolong the duration of tumor control in relapsed MM.

Multiple independent immunoglobulin class-switch recombinations occurring within the same clone in myeloma.

Multiple myeloma (MM) is characterized by the expansion of terminally differentiated plasma cells. It is still uncertain whether the clonogenic fraction is confined to the plasma cell or pre-plasma cell compartment. We examined the immunoglobulin (Ig) rearrangement of myeloma heavily infiltrated bone marrow cells with a probe from the heavy chain J region (JH) and the BamHI, EcoRI and HindIII restriction enzymes which are appropriate for the detection of clonal VDJ recombination. In 23/39 MMs, clonal Ig gene rearrangement was detected with BamHI, EcoRI and HindIII enzymes. Unexpectedly, in 14/39 patients both BamHI and EcoRI failed to detect Ig rearrangement, whereas HindIII consistently demonstrated VDJ recombination. The 5' sites of BamHI, EcoRI and HindIII restriction fragments are precisely defined by the VDJ rearrangement. Since the 3' ends of BamHI and EcoRI restriction fragments are downstream from the switch mu region and change in size during switch recombination, the absence of rearranged bands is determined by several autonomous recombinations affecting the switch region. By contrast, the 3' ends of HindIII restriction fragments are upstream, their size does not vary during isotype switch allowing the constant detection of clonality. Accordingly, in 35% of patients the clonogenic fraction seems to originate from a pre-switch B cell. This B cell will differentiate to a mature plasma cell developing multiple independent switch recombinations, as the variable mechanism of switch recombination suggests.

Multiple myeloma: intensified maintenance therapy with recombinant interferon-alpha-2b plus glucocorticoids.

Interferon-alpha-2b has been demonstrated to prolong remission duration and survival in responding multiple myeloma patients. The aim of this study was to evaluate intensification of this maintenance therapy through the addition of glucocorticoids. Eighteen myeloma patients at diagnosis received six-12 courses of conventional chemotherapy and then interferon + glucocorticoids. This treatment included 3 megaunits of interferon three times a week, plus 4 days of pulsed high-dose dexamethasone (40 mg/d for 4 d every 28 d for 6 months/year) in patients < 70 yr old, or oral prednisone (50 mg three times a wk) in patients > 70 yr old. Conventional chemotherapy induced an objective response in 13/18 patients and a further reduction of the M component (> 50%) was achieved during interferon + glucocorticoids treatment in 7/13. 4/18 patients relapsed with a median follow-up of 22 months (range 13-40). These findings indicate that interferon + glucocorticoids, after inductional chemotherapy, further reduces tumor burden and may prolong remission.

Increased serum neopterin concentration as indicator of disease severity and poor survival in multiple myeloma.

In this study we investigated serum neopterin levels in 73 multiple myeloma (MM) patients (63 determinations at diagnosis, 58 in remission, and 35 at relapse), in 56 monoclonal gammopathies of undetermined significance (MGUS), and in 70 normal controls. Median neopterin level was 5.3 nmol/l in normal controls, 6.8 nmol/l in MGUS, and 10.7 nmol/l in MM patients. In comparison to healthy subjects, significantly higher levels were observed in MM patients (p less than 0.0001). A statistical difference was observed between MGUS and MM patients at diagnosis (p less than 0.007). Compared to diagnosis, a further increase was noticed during relapse, suggesting a correlation between neopterin and disease activity. The prognostic significance of raised neopterin levels was confirmed by a survival analysis. Median survival for patients with high values was 20 months, whereas it was 63.9 months for those with low values (log-rank test p less than 0.003). Serum neopterin concentrations also correlated to beta 2 microglobulin levels and the percentage of CD38+ circulating lymphocytes, indicating a link between neopterin and other myeloma prognostic factors.

Consolidation treatment with dexamethasone and alpha-2B recombinant interferon further reduces the M-component level in multiple myeloma patients responding to conventional induction chemotherapy.

Three patients with symptomatic multiple myeloma who had achieved an objective response after conventional induction chemotherapy were treated with alpha-2b-interferon plus intermittent high-dose dexamethasone as consolidation therapy. This treatment included three mega units of alpha-2b-interferon three times a week, plus 4 days pulsed high-dose dexamethasone every 28 days for 6 months. Toxicity was limited to a mild flu-like syndrome. A further and significant M-component reduction (50%), obtained after conventional chemotherapy, suggests the value of intermittent high-dose dexamethasone plus interferon as consolidation therapy.

Multiple myeloma: increased circulating lymphocytes carrying plasma cell-associated antigens as an indicator of poor survival.

In multiple myeloma (MM) an increase in circulating lymphocytes expressing plasma cell-associated antigens (PCAA) has been described. Its prognostic significance was evaluated in this study. The immunologic phenotype of peripheral blood lymphocytes was analyzed with a panel of monoclonal antibodies specific for B, T, natural killer lymphocytes, and PCAA (CD38, PCA1) in 52 MM patients at diagnosis, remission, and during relapse, 18 monoclonal gammopathy of undetermined significance (MGUS), and 25 normal controls. No significant phenotypic alteration was observed in MGUS. In MM, the number of B lymphocytes was in the normal range at diagnosis and during the subsequent phases. A CD4/CD8 ratio decrease, during relapse, was due to both a CD4+ reduction and to an expansion of a subset of CD8+ activated suppressor lymphocytes. CD38+ and PCA1+ lymphocytes at diagnosis were significantly higher than in MGUS, and a further increase was observed during relapse, suggesting a correlation between PCAA expression and disease activity. The prognostic significance of increased PCAA was confirmed by a survival analysis of 32 patients evaluated at diagnosis using a CD38 cutoff of 0.45 x 10(9)/L positive lymphocytes. Median survival for patients with high values was only 14 months, whereas it was not reached at 32 months by those with low values (P less than .0007).

Multiple myeloma: beta-2-microglobulin is not a useful follow-up parameter.

Serum beta-2-microglobulin (beta 2M) has been suggested as the most powerful prognostic factor in multiple myeloma (MM). This paper investigates its ability to detect remission and relapse in individual patients. A correlation analysis was carried out between beta 2M and M component determinations, at diagnosis and monthly during follow-up in 21 consecutive MM patients with normal renal function. A statistically significant correlation was observed in 52.4% only. The lack of correlation in the remaining cases was due to low beta 2M production at diagnosis, or independent fluctuation of these 2 parameters. Serum beta 2M proved a much less reliable parameter for the detection of tumour variations than simpler M-component determination.