Mervi Putkonen

Low-dose or intermediate-dose cyclophosphamide plus granulocyte colony-stimulating factor for progenitor cell mobilisation in patients with multiple myeloma.

Summary:Cyclophosphamide (CY) combined with granulocyte colony-stimulating factor (G-CSF) is commonly used to mobilise blood progenitor cells to support high-dose therapy in patients with multiple myeloma (MM). The optimal dose of CY in this setting is unknown. We have retrospectively analysed mobilisation efficiency and need for supportive care in 57 patients with newly diagnosed myeloma previously treated with VAD±local radiotherapy. The patients were mobilised either with low-dose CY (LD-CY, 1.2–2 g/m2) (n=25) or intermediate-dose CY (ID-CY, 4 g/m2) (n=32) plus G-CSF. Both regimens proved to be effective in the progenitor cell mobilisation. At least 2×106/kg CD34+ cells were collected from 88% and 84% of the patients with a single apheresis, respectively. Only one patient in the LD-CY group (4%) failed to mobilise vs none in the ID-CY group. Patients mobilised with LD-CY plus G-CSF had less toxicity: fewer hospital days during the mobilisation and apheresis procedures (5 vs 9 days, P<0.001), lower frequency of fever (20 vs 73%, P<0.001) and less need for supportive care including platelet transfusions (0 vs 24%, P=0.004) and days on parenteral antibiotics (0 vs 4 days, P<0.001). While these regimens seem to be equally effective in terms of progenitor cell mobilisation in newly diagnosed patients with MM, LD-CY+G-CSF is preferential because of more optimal resource utilisation and more favourable toxicity profile.

Depth of response assessed by quantitative ASO-PCR predicts the outcome after stem cell transplantation in multiple myeloma

Achievement of complete response (CR) is a new goal of therapy for multiple myeloma (MM). By sensitive methods, the depth of response can be measured even among the patients in CR. We used a sensitive real‐time quantitative polymerase chain reaction by allele‐specific primers (qASO‐PCR) to assess the level of minimal residual disease (MRD) in bone marrow of 37 patients with myeloma who had achieved CR/near‐to‐CR after autologous or allogeneic stem cell transplantation (SCT). Allele‐specific primers could be successfully designed for 86% of patients. Three to six months after autotransplantation, the PCR target was not detectable in 53% of patients (16/30 patients), and the respective figure after allotransplantation was 71% (5/7 patients); the median sensitivity of PCR assay was <0.002%. The proportion of patients without detectable PCR target was 22% of all autotransplanted patients. A threshold level of 0.01% in the qASO‐PCR assay 3–6 months after SCT was found to be a useful cut‐off limit to divide the patients into two prognostic groups: MRD low/negative vs. MRD high. Low/negative MRD after SCT was a significant predictive factor for the prolongation of progression free (70 vs. 19 months; P = 0.003) and suggestively also for overall survival. We conclude that not only CR but also its depth is important for the long‐term outcome in MM.

Autologous stem cell transplantation versus novel drugs or conventional chemotherapy for patients with relapsed multiple myeloma after previous ASCT

High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) is the most common first-line treatment for patients with multiple myeloma (MM) under 65 years of age. A second ASCT at first relapse is frequently used but is challenged by the use of novel drugs. We retrospectively studied the outcome of second-line treatment in MM patients from the Nordic countries with relapse after first-line HDT and ASCT. Patients that underwent a second ASCT (n=111) were compared with patients re-treated with conventional cytotoxic drugs only (n=91) or with regimens including novel drugs (proteasome inhibitors and/or immunomodulatory drugs) (n=362) without a second ASCT. For patients receiving a second ASCT median overall survival was 4.0 years compared with 3.3 years (P<0.001) for the group treated with novel drugs and 2.5 years (P<0.001) for those receiving conventional cytotoxic drugs only. A second ASCT also resulted in a significantly longer second time to progression and a significantly longer time to next treatment. We conclude that, irrespective of the addition of novel drugs, MM patients in first relapse after ASCT still appear to benefit from a second ASCT. A second ASCT should be considered for all physically fit patients.

Comparative analysis of minimal residual disease detection by multiparameter flow cytometry and enhanced ASO RQ-PCR in multiple myeloma

Multiparameter flow cytometry (MFC) and allele-specific oligonucleotide real-time quantitative PCR (ASO RQ-PCR) are the two most sensitive methods to detect minimal residual disease (MRD) in multiple myeloma (MM). We compared these methods in 129 paired post-therapy samples from 22 unselected, consecutive MM patients in complete/near complete remission. Appropriate immunophenotypic and ASO RQ-PCR-MRD targets could be detected and MRD analyses constructed for all patients. The high PCR coverage could be achieved by gradual widening of the primer sets used for clonality detection. In addition, for 13 (55%) of the patients, reverse orientation of the ASO primer and individual design of the TaqMan probe improved the sensitivity and specificity of ASO RQ-PCR analysis. A significant nonlinear correlation prevailed between MFC-MRD and PCR-MRD when both were positive. Discordance between the methods was found in 32 (35%) paired samples, which were negative by MFC-MRD, but positive by ASO RQ-PCR. The findings suggest that with the described technique, ASO RQ-PCR can be constructed for all patients with MM. ASO RQ-PCR is slightly more sensitive in MRD detection than 6−10-color flow cytometry. Owing to technical demands ASO RQ-PCR could be reserved for patients in immunophenotypic remission, especially in efficacy comparisons between different drugs and treatment modalities.

A randomized phase II study of stem cell mobilization with cyclophosphamide+G-CSF or G-CSF alone after lenalidomide-based induction in multiple myeloma.

The most common means of mobilizing autologous stem cells is G-CSF alone or combined with cyclophosphamide (CY) to obtain sufficient CD34+ cells for one to two transplants. There are few prospective, randomized studies investigating mobilization regimens in multiple myeloma (MM), especially after lenalidomide-based induction. We designed this prospective, randomized study to compare low-dose CY 2 g/m2+G-CSF (arm A) and G-CSF alone (arm B) after lenalidomide-based up-front induction in MM. Of the 80 initially randomized patients, 69 patients were evaluable, 34 and 35 patients in arms A and B, respectively. The primary end point was the proportion of patients achieving a yield of ⩾3 × 106/kg CD34+ cells with 1−2 aphereses, which was achieved in 94% and 77% in arms A and B, respectively (P=0.084). The median number of aphereses needed to reach the yield of ⩾3 × 106/kg was lower in arm A than in arm B (1 vs 2, P=0.035). Two patients needed plerixafor in arm A and five patients in arm B (P=0.428). Although CY-based mobilization was more effective, G-CSF alone was successful in a great majority of patients to reach the defined collection target after three cycles of lenalidomide-based induction.

Assessment of molecular remission rate after bortezomib plus dexamethasone induction treatment and autologous stem cell transplantation in newly diagnosed multiple myeloma patients

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Autologous stem cell transplantation in patients with high-risk plasmacytoma

Abstract:  Although autologous stem cell transplantation (ASCT) is considered standard treatment in patients with multiple myeloma (MM), limited experience is available on this approach in patients with plasmacytoma (PC). Twelve patients with high‐risk PC received ASCT in Finland 1994–2002. There were nine males and three females with a median age of 50 yr (32–64). Ten patients had a PC of bone, whereas two patients had extramedullary PCs. The median time from the diagnosis to ASCT was 9 months (5–100). At the time of ASCT six patients were in first complete remission (CR) or partial remission (PR), in four patients the disease was refractory to the first line therapy and two patients had relapsed. High‐dose therapy consisted of melphalan (MEL)200 (n = 7), MEL200 × 2 (n = 3) or total body irradiation (TBI)‐MEL140 (n = 2). No transplant‐related deaths occurred. After ASCT eight patients (67%) were in CR, one patient in very good PR and one patient in PR; two patients were non‐responders. With a median follow‐up of 48 months from ASCT, 11 patients (92%) are alive. Six patients (50%) have relapsed or progressed 3–81 months from ASCT. ASCT is feasible in this patient population resulting in promising overall survival. A randomised trial is needed to assess the real value of ASCT when compared with other treatment options in patients with high‐risk PC.

Autologous stem cell transplantation in patients with primary amyloidosis: a nation-wide survey.

Due to poor prognosis with conventional therapy, high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is considered for treatment in patients with primary amyloidosis (AL). Only single centre series are available on the feasibility and efficacy of this approach. Altogether 20 AL patients (11 males, 9 females, median age 54 years) were included in HDT protocols in 5 Finnish transplant centres between 1997 and 2003. Twelve patients were mobilized with granulocyte colony-stimulating factor (G-CSF) alone and 8 patients with a combination of cyclophosphamide and G-CSF. Sixteen patients (80%) went on to high-dose melphalan. Early transplant-related mortality was 25%. Nine out of 11 evaluable patients showed improvement or stabilization of AL. The overall survival of the transplanted patients is 69% (median follow-up 13 months). After a median follow-up of 26 months for the living patients, only 2 patients (18%) have shown progression of AL. This retrospective nation-wide analysis shows that HDT with ASCT leads to improvement or stabilization of AL in the majority of the patients who survive the immediate posttransplant period. A randomized multicentre trial is needed to show whether ASCT is superior to conventional therapy in patients with AL.

Blood graft cellular composition and posttransplant outcomes in myeloma patients mobilized with or without low‐dose cyclophosphamide: a randomized comparison

Autologous stem cell transplantation is a standard treatment in multiple myeloma (MM). Blood grafts are usually collected after mobilization with granulocyte–colony‐stimulating factor (G‐CSF) alone or in a combination with cyclophosphamide (CY). There is limited knowledge of the possible effects of different mobilization regimens on blood graft characteristics and posttransplant outcomes.

Early CD8+-recovery independently predicts low probability of disease relapse but also associates with severe GVHD after allogeneic HSCT

In this single-center study we retrospectively evaluated the impact of early reconstitution of different lymphocyte subsets on patient outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that CD8+ T-cell counts exceeding 50x106/l as early as on day 28 post-transplantation correlated significantly with decreased relapse risk, with three-year relapse rates of 17.0% and 55.6% (P = 0.002), but were also associated with severe acute and chronic GVHD. Incidence of grade III-IV acute GVHD was 30.5% for those with early CD8+ T-cell recovery compared to 2.1% for those with lower CD8+ T-cell counts on day 28 post-transplant (HR = 20.24, P = 0.004). Early CD8+ T-cell reconstitution did not, however, affect the overall survival. Multivariate analysis showed that slow CD8+ T-cell reconstitution was strongly associated with increased risk of relapse (HR = 3.44, P = 0.026). A weaker correlation was found between CD4+ reconstitution and relapse-risk, but there was no such association with CD19+ B-cells or NK-cells. In conclusion, the early CD8+ T-cell recovery on day 28 post-transplant is associated with the lower risk of relapse but also predicts the impending severe GVHD, and thus could be useful in guiding timely treatment decisions.