Joan Bargay

Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial

BACKGROUND Bortezomib plus melphalan and prednisone (VMP) is significantly better than melphalan plus prednisone alone for elderly patients with untreated multiple myeloma; however, toxic effects are high. We investigated a novel and less intensive bortezomib-based regimen to maintain efficacy and to reduce toxic effects. METHODS Between March, 2006, and October, 2008, 260 patients with untreated multiple myeloma, 65 years and older, from 63 Spanish centres, were randomly assigned to receive six cycles of VMP (n=130) or bortezomib plus thalidomide and prednisone (VTP; n=130) as induction therapy, consisting of one cycle of bortezomib twice per week for 6 weeks (1·3 mg/m² on days 1, 4, 8, 11, 22, 25, 29, and 32), plus either melphalan (9 mg/m² on days 1-4) or daily thalidomide (100 mg), and prednisone (60 mg/m² on days 1-4). The first cycle was followed by five cycles of bortezomib once per week for 5 weeks (1·3 mg/m² on days 1, 8, 15, and 22) plus the same doses of melphalan plus prednisone and thalidomide plus prednisone. 178 patients completed the six induction cycles and were randomly assigned to maintenance therapy with bortezomib plus prednisone (n=87) or bortezomib plus thalidomide (n=91), consisting of one conventional cycle of bortezomib for 3 weeks (1·3 mg/m² on days 1, 4, 8, and 11) every 3 months, plus either prednisone (50 mg every other day) or thalidomide (50 mg per day), for up to 3 years. Treatment codes were generated with a computerised random number generator, and neither participants nor study personnel were masked to treatment. The primary endpoint was response rate in induction and maintenance phases. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00443235. FINDINGS In the induction phase, 105 (81%) patients in the VTP group and 104 (80%) in the VMP group achieved partial responses or better (p=0·9), including 36 (28%) and 26 (20%) complete remissions, respectively (p=0·2). Treatment with VTP resulted in more serious adverse events (40 [31%] vs 20 [15%], p=0·01) and discontinuations (22 [17%] vs 15 [12%], p=0·03) than did treatment with VMP. The most common toxicities (grade 3 or worse) were infections (one [1%] in the VTP group vs nine [7%] in the VMP group), cardiac events (11 [8%] vs 0), and peripheral neuropathy (nine [7%] vs 12 [9%]). After maintenance therapy, the complete remission rate was 42% (40 [44%] patients in complete remission in the bortezomib plus thalidomide group, 34 [39%] in the bortezomib plus prednisone group). No grade 3 or worse haematological toxicities were recorded during maintenance therapy; two (2%) patients in the bortezomib plus prednisone group and six (7%) in the bortezomib plus thalidomide group developed peripheral neuropathy. INTERPRETATION Reduced-intensity induction with a bortezomib-based regimen, followed by maintenance, is a safe and effective treatment for elderly patients with multiple myeloma. FUNDING Pethema (Spanish Program for the Treatment of Hematologic Diseases).

Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma.

BACKGROUND For patients with smoldering multiple myeloma, the standard of care is observation until symptoms develop. However, this approach does not identify high-risk patients who may benefit from early intervention. METHODS In this randomized, open-label, phase 3 trial, we randomly assigned 119 patients with high-risk smoldering myeloma to treatment or observation. Patients in the treatment group received an induction regimen (lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone at a dose of 20 mg per day on days 1 to 4 and days 12 to 15, at 4-week intervals for nine cycles), followed by a maintenance regimen (lenalidomide at a dose of 10 mg per day on days 1 to 21 of each 28-day cycle for 2 years). The primary end point was time to progression to symptomatic disease. Secondary end points were response rate, overall survival, and safety. RESULTS After a median follow-up of 40 months, the median time to progression was significantly longer in the treatment group than in the observation group (median not reached vs. 21 months; hazard ratio for progression, 0.18; 95% confidence interval [CI], 0.09 to 0.32; P<0.001). The 3-year survival rate was also higher in the treatment group (94% vs. 80%; hazard ratio for death, 0.31; 95% CI, 0.10 to 0.91; P=0.03). A partial response or better was achieved in 79% of patients in the treatment group after the induction phase and in 90% during the maintenance phase. Toxic effects were mainly grade 2 or lower. CONCLUSIONS Early treatment for patients with high-risk smoldering myeloma delays progression to active disease and increases overall survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00480363.).

Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)]

Most patients with acute myeloid leukemia (AML) and t(8;21) or inv(16) have a good prognosis with current anthracycline- and cytarabine-based protocols. Tandem analysis with flow cytometry (FC) and real-time RT-PCR (RQ-PCR) was applied to 55 patients, 28 harboring a t(8;21) and 27 an inv(16), including one case with a novel CBFbeta/MYH11 transcript. A total of 31% (n=17) of CR patients relapsed: seven with t(8;21) and 10 with inv(16). The mean amount of minimal residual disease (MRD) detected by FC in relapsed and nonrelapsed patients was markedly different: 0.3 vs 0.08% (P=0.002) at the end of treatment. The mean number of fusion transcript copies/ABLx104 also differed between relapsed and non-relapsed patients: 2385 vs 122 (P=0.001) after induction, 56 vs 7.6 after intensification (P=0.0001) and 75 vs 3.3 (P=0.0001) at the end of chemotherapy. Relapses were more common in patients with FC MRD level >0.1% at the end of treatment than in patients with ⩽0.1%: cumulative incidence of relapse (CIR) was 67 and 21% (P=0.03), respectively. Likewise, using RQ-PCR, a cutoff level of >10 copies at the end of treatment correlated with a high risk of relapse: CIR was 75% for patients with RQ-PCR >10 compared to 21% for patients with RQ-PCR levels ⩽10 (P=0.04). Combined use of FC and RQ-PCR may improve MRD detection, and provide useful clinical information on relapse kinetics in AML patients.

Allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: results of a prospective multicentre study

Reduced‐intensity conditioning (RIC) regimens for allogeneic haematopoietic stem cell transplantation (SCT) have been shown to lead to engraftment of donor stem cells without the severe extra‐haematological toxicities of traditional myeloablative transplants. Between December 1998 and December 2000, 76 patients underwent a RIC peripheral blood SCT in a prospective multicentre study. The median age was 53 years, and 57 patients were beyond the early phase of their disease. The conditioning regimens consisted of fludarabine (150 mg/m2) plus melphalan (140 mg/m2) or busulphan (10 mg/kg). Graft‐versus‐host disease (GVHD) prophylaxis consisted of cyclosporin A plus short‐course methotrexate. The preparative regimens were well tolerated. All patients experienced severe pancytopenia, but haematological recovery was prompt in all but two cases (early deaths). The 100‐d probability of developing grade II–IV acute GVHD was 32% (10% grade III–IV), and the 1‐year probability of developing chronic extensive GVHD was 43%. Early complete donor chimaerism was observed in 52/68 patients, and 16 evaluable patients were in complete chimaerism 1 year post transplant. With a median follow‐up of 283 d (355 in 48 survivors), the 1‐year probability of transplant‐related mortality was 20%, and the 1‐year overall and progression‐free survivals were 60% and 55% respectively. In conclusion, RIC regimens lead to low early toxicity after allografting, with stable donor haematopoietic engraftment, with an apparent low risk of acute GVHD. Chronic GVHD, however, develops in a significant proportion of patients.

Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to post-remission therapy

Risk associated to FLT3 internal tandem duplication (FLT3-ITD) in patients with acute myeloid leukemia (AML) may depend on mutational burden and its interaction with other mutations. We analyzed the effect of FLT3-ITD/FLT3 wild-type (FLT3wt) ratio depending on NPM1 mutation (NPM1mut) in 303 patients with intermediate-risk cytogenetics AML treated with intensive chemotherapy. Among NPM1mut patients, FLT3wt and low ratio (<0.5) subgroups showed similar overall survival, relapse risk, and leukemia-free survival, whereas high ratio (≥0.5) patients had a worse outcome. In NPM1wt AML, FLT3-ITD subgroups showed a comparable outcome, with higher risk of relapse and shortened overall survival than FLT3wt patients. Allogeneic stem cell transplantation in CR1 was associated with a reduced relapse risk in all molecular subgroups with the exception of NPM1mut AML with absent or low ratio FLT3-ITD. In conclusion, effect of FLT3 burden is modulated by NPM1 mutation, especially in patients with a low ratio.

Analysis of factors associated with low peripheral blood progenitor cell collection in normal donors

BACKGROUND: Predictive factors of the response to rHuG–CSF in normal donors have not been extensively studied.

Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression

Novel therapeutic agents have become available for patients with multiple myeloma in the last few years. This study conducted by the Spanish PETHEMA and GEM groups investigated the effect of bortezomib plus melphalan and prednisone in elderly patients with newly diagnosed multiple myeloma. Treatment was highly active and well tolerated, with 85% of patients alive at 3 years. Background New treatment options offering enhanced activity in elderly, newly diagnosed patients with multiple myeloma are required. One strategy is to combine melphalan and prednisone with novel agents. We previously reported an 89% response rate, including 32% complete responses and 11% near complete responses, in our phase 1/2 study of bortezomib plus melphalan and prednisone (VMP) in 60 newly diagnosed multiple myeloma patients with a median age of 75 years. Here, we report updated time-to-events data and the impact of poor prognosis factors on outcome. Design and Methods Updated analyses of time to biochemical progression and overall survival with VMP were conducted, and compared with those of historical controls treated with melphalan and prednisone. A univariate analysis was performed to evaluate the influence of known prognostic factors on the time to progression. Results After a median follow-up of 26 months, the median time to progression with VMP was 27.2 months, compared with 20.0 months with melphalan plus prednisone. The median overall survival with VMP was not reached versus 26 months with melphalan and prednisone; the survival rate at 38 months was 85% versus 38%, respectively. Time to progression was not significantly affected by elevated β2-microglobulin or lactate dehydrogenase levels, advanced age, or cytogenetic abnormalities, but was shorter in patients with albumin <3 g/dL, Karnofsky performance status ≤70%, bone marrow plasma cell infiltration ≥40%, and, particularly, high plasma cell proliferative activity (≥2.5% S-phase cells). Conclusions VMP is highly active and well tolerated in elderly patients with newly diagnosed muktiple myeloma, with 85% of patients alive at 3 years. Moreover, VMP may overcome the poor prognostic impact of various factors, particularly cytogenetic abnormalities.

Chronic graft-versus-host disease after allogeneic peripheral blood progenitor cell or bone marrow transplantation from matched related donors. A case-control study

We retrospectively compared the incidence and clinical characteristics of cGVHD in 37 allo-PBT recipients transplanted between July 1994 and October 1996 and 37 historical control allo-BMT recipients in a case- control study. All patients received a first unmanipulated transplant, graft from an HLA-identical sibling donor, with CsA-MTX GVHD prophylaxis and survived more than 100 days after transplant. PBT and BMT groups were well matched for age, grade of acute GVHD, male patients grafted from female donors, and phase of disease. The median CD34+ and CD3+ cell numbers infused in the PBT group were 5.2 × 106/kg and 307 × 106/kg, respectively. The median time to an ANC greater than 0.5 × 109/l was 16 days (range 11–22) after PBT and 22 days (range 14–36) after BMT (P < 0.001). the median time to a platelet count greater than 20 × 109/l was 15 days (range 6–43) after PBT and 28 days (range 12–68) after BMT (P < 0.001). median follow-up was 12.3 months (range 5.4–30.3) and 58.7 months (range 4–122.3), for patients receiving pbt and bmt, respectively. seventeen out of 37 (46%) pbt recipients, vs nine out of 37 (24%) BM recipients developed cGVHD. Actuarial probability of cGVHD at 1 year was 59% (95% CI, 39–79) in the PBT group vs 27% (95% CI, 12–42) in the BM group (P = 0.01). Cumulative incidence estimate of cGVHD was 51% and 25%, for patients receiving PBT and BMT respectively (P = 0.03). Clinical characteristics of cGVHD and response to therapy were similar in both groups, except for a higher incidence of de novo cGVHD in the PBT group. Our results suggest that as compared with BMT, PBT may result in an increased incidence of cGVHD.

Donor age-related differences in PBPC mobilization with rHuG–CSF

BACKGROUND: Data on the administration of rHuG–CSF to normal donors <18 years old are very limited.

Administration of recombinant human granulocyte colony-stimulating factor to normal donors: results of the Spanish National Donor Registry. Spanish Group of Allo-PBT.

A Spanish National PBPC Donor Registry has recently been established for short- and long-term safety data collection in normal donors receiving rhG-CSF. To date, 466 donors have been included in the Registry. Median (range) dose and duration of rhG-CSF administration was 10 μg/kg/day (4–20) and 5 days (4–8), respectively. Donors underwent a median of two aphereses (range, 1–5). Adverse effects consisted mainly of bone pain (90.2%), headache (16.9%) and fever (6.1%), but no donor discontinued rhG-CSF prematurely due to toxicity. Side-effects were more frequent in donors receiving >10 μg/kg/day than in those with lower doses (82.8% vs 61.8%; P = 0.004). A significant decrease between baseline and post-apheresis platelet counts was the most important analytical finding (229 × 109/l vs 140 × 109/l; P < 0.0001), with a progressive reduction in platelet count with each apheresis procedure. one donor developed pneumothorax that required hospitalization due to central venous line placement. the mean cd34+ cell dose collected was 6.9 × 106/kg (range, 1.3–36), with only 14 donors (2.9%) not achieving a minimum target of CD34+ cells of 2 × 106/kg. No definitive information about potential long-term side effects is yet available. However, we hope this National Registry will serve as a useful basis for better monitoring of the efficiency and side-effects of cytokine administration in healthy people.