Michele Cottler-Fox

Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3.

Total therapy 3 incorporated bortezomib into a melphalan‐based tandem transplant regimen for 303 newly diagnosed patients with myeloma. Induction chemotherapy prior to and consolidation chemotherapy after transplants each consisted of two cycles of VTD‐PACE (bortezomib, thalidomide, dexamethasone and 4‐d continuous infusions of cis‐platin, doxorubicin, cyclophosphamide, etoposide); 3‐year maintenance comprised monthly cycles of VTD in the first and TD in the remaining years. The median age was 59 years (age >64 years, 28%). A minimum of 20 × 106 CD34 cells/kg was collected in 87% of patients; 83% completed both transplants, and only 5% suffered a treatment‐related death. At 24 months, 83% had achieved near‐complete remission, which was sustained in 88% at 2 years from its onset. With a median follow‐up of 20 months, 2‐year estimates of event‐free and overall survival were 84% and 86% respectively. The 44 patients who experienced an event more often had a high‐risk gene array profile, cytogenetic abnormalities and indicators of high lactate dehydrogenase, beta‐2‐microglobulin, creatinine and International Staging System stage. Toxicities of grade > 2 included thrombo‐embolic events in 27% and peripheral neuropathy in 12%. Results of this phase‐2 study demonstrated that bortezomib could be safely combined with multi‐agent chemotherapy, effecting near‐complete remission status and 2‐year survival rates in more than 80% of patients.

Cancer and the microenvironment: myeloma-osteoclast interactions as a model.

We have investigated the interaction between tumor cells and specific cells in their microenvironment using myeloma as a model. The role of myeloma-induced osteoclastogenesis in the disease was studied ex vivo. Myeloma plasma cells freshly purified from patients’ bone marrow attracted committed osteoclast (OC) precursors (n = 9; P < 0.01) and in 22 experiments directly induced their differentiation to multinucleated, bone-resorbing OCs (P < 0.00002) in a receptor activator of nuclear factor-κB ligand-mediated mechanism that was inhibited by the receptor activator of nuclear factor-κB (RANK-Fc) in 13 experiments by 71 ± 12% (P < 0.008). In contrast, myeloma cells did not induce differentiation of peripheral blood mononuclear cells. Myeloma plasma cells cocultured with OCs retained their viability and proliferative activity for >13 weeks. After 14 days in coculture, the plasma cells from 29 patients had higher viability (P < 2 × 10−6), fewer apoptotic cells (P < 4 × 10−15), and a higher bromodeoxyuridine labeling index (P < 0.0006) than controls. Physical contact between OCs and myeloma cells was required for these effects to take place. No differences were observed between OCs from healthy donors and those from myeloma patients. Blocking interleukin 6 activity, while reducing survival of myeloma cells, had no effect on their proliferative activity. These results support data obtained from animal models and clinical observations on the essential role of the microenvironment in tumor sustenance and progression.

Improved Outcome of Allogeneic Transplantation in High-Risk Multiple Myeloma Patients After Nonmyeloablative Conditioning

PURPOSE We present our experience with relapsed and recently diagnosed patients with high-risk multiple myeloma (MM) receiving immunosuppressive, nonmyeloablative melphalan (MEL)-based conditioning regimens (mini-allograft). PATIENTS AND METHODS Thirty-one MM patients received allografts from HLA-matched siblings (n = 25) or unrelated donors (n = 6) using a mini-allograft. Seventeen had progressive disease (PD) and 14 had responsive disease (RD) (six with primary RD and eight with responsive relapse). Thirty patients had received one (n = 13) or two or more (n = 17) prior autologous transplantations (ATs). Median age was 56 years (range, 38 to 69 years). Twenty-one patients had chromosome 13 abnormality. Two patients were hemodialysis dependent. Blood and bone marrow grafts were administered to 28 and three patients, respectively. Donor lymphocyte infusions were given to 18 patients either to attain full donor chimerism (n = 6) or to eradicate residual disease (n = 12). RESULTS By day 100, 25 (89%) of 28 patients were full donor chimeras, one was a mixed chimera, and two had autologous reconstitution. Acute graft-versus-host disease (GVHD) developed in 18 patients (58%), and 10 progressed to chronic GVHD (limited in six and extensive in four). At a median follow-up of 6 months, 19 (61%) of 31 patients achieved complete/near complete remission. Twelve patients (39%) have died: three of PD, three of early treatment-related mortality (TRM) (before day 100), and six of late TRM. Median overall survival (OS) was 15 months. At 1 year, there was a significantly longer event-free survival (86% v 31%, P =.01) and OS (86% v 48%, P =.04) when a mini-allograft was performed after one versus two or more prior ATs, respectively. When compared with historical MM controls (n = 93) receiving conventional allografts, early TRM was significantly lower (10% v 29%, P =.03), and OS at 1 year was better (71% v 45%; P =.08) in the mini-allograft MM patients. CONCLUSION Mini-allograft induced excellent disease control in MM patients with high-risk disease, but is still associated with a significant GVHD.

T cell-depleted bone marrow transplantation and delayed T cell add- back to control acute GVHD and conserve a graft-versus-leukemia effect

Thirty-eight patients with hematological malignancies, received T cell-depleted marrow transplants (BMT) and cyclosporine to prevent acute graft-versus-host disease (aGVHD), followed by delayed add-back of donor lymphocytes to prevent leukemia relapse. In 26 patients scheduled for donor T cell add-back of 2 × 106 cells/kg on day 30 and 5 × 107 cells/kg on day 45 (schedule 1), the overall probability of grade ⩾II aGVHD developing was 31.5%, with a 15.5% probability of aGVHD occurring after T cell add-back. In 12 patients receiving 107 donor T cells/kg on day 30 (schedule 2), the probability of grade ⩾II aGVHD was 100%. The incidence of grade III–IV aGVHD was higher in schedule 2 than in schedule 1 (P = 0.02). Of 24 evaluable patients, 10 (46%) developed chronic GVHD which was limited in eight and extensive in two. Current disease-free survival for 18 patients at standard risk for relapse (chronic myeloid leukemia (CML) in chronic or accelerated phase, acute myeloid leukemia in remission) vs 20 patients with more advanced leukemia or multiple myeloma were respectively 72% vs 12% (P < 0.01) with a 29% vs 69% probability of relapse (P = 0.08). In 12 CML patients surviving more than 3 months, PCR analysis of the BCR/ABL transcript showed that minimal residual disease after T cell add-back was transient except in two patients who developed hematological relapse. Results indicate that the risk of acute GVHD is low following substantial T cell doses, transfused 45 days after transplant, using cyclosporine prophylaxis. Furthermore a graft-versus-leukemia effect was conserved.

Mobilization of CD34+ cells in elderly patients (≥ 70 years) with multiple myeloma: influence of age, prior therapy, platelet count and mobilization regimen

Summary. The mobilization of peripheral blood stem cells was studied in 984 multiple myeloma patients, including 106 patients aged ≥ 70 years. Increasing age correlated inversely with CD34+ yield (P < 0·0001), but also with ≥ 12 months of prior standard chemotherapy (P = 0·0001), < 200 × 109/l platelets (P = 0·0006) premobilization and mobilization with growth factors only (P = 0·0001). After controlling for these age covariates, multivariate analysis identified ≤ 12 months standard therapy and platelet count ≥ 200 × 109/l premobilization as favourable variables (both P < 0·0001), while increasing patient age remained an unfavourable factor (P = 0·0009). With both favourable variables, 85% of elderly patients collected ≥ 4 × 106/kg CD34+ cells in a median of one collection. The effect of age was incremental with no age threshold showing acceleration in the decline of CD34+ yield. Chemotherapy significantly increased CD34+ yield compared with growth factors only. However, the subgroup of patients with > 12 months prior therapy and premobilization platelet count < 200 × 109/l mobilized as many CD34+ cells with granulocyte colony‐stimulating factor (G‐CSF) alone as with chemotherapy and haematopoietic growth factors. Increasing patient age had no effect on post‐transplant neutrophil recovery, but significantly delayed platelet recovery (≥ 50 × 109/l) if < 2 × 106/kg CD34+ cells were infused, but this effect was eliminated completely with infusion of ≥ 4 × 106/kg CD34+ cells. Increasing age adversely affected CD34+ yield even with limited premobilization therapy, indicating that early collection is important in elderly patients.

DTPACE: An Effective, Novel Combination Chemotherapy With Thalidomide for Previously Treated Patients With Myeloma

PURPOSE To improve outcome in previously treated patients (at least two cycles of standard therapy) with multiple myeloma, thalidomide was combined with cytotoxic chemotherapy as induction therapy. PATIENTS AND METHODS The regimen consisted of 4-days of oral dexamethasone, daily thalidomide, and 4 days of continuous-infusion cisplatin, doxorubicin, cyclophosphamide, and etoposide (DTPACE). Response to two cycles of DTPACE for induction was evaluated in 236 patients. Before being treated with DTPACE, 148 patients (63%) had shown progressive disease while receiving standard chemotherapy, and 55 patients (23%) had chromosome 13 abnormalities. RESULTS The partial remission rate (PR) after two cycles of DTPACE was 32%, with 16% attaining a complete remission (CR) or near-CR (nCR; defined as only immunofixation electrophoresis-positive). Patients with high lactate dehydrogenase (LDH; n = 98) showed a better response than those with normal LDH (n = 138): PR or better, 43% v 27% (P =.01); CR + nCR, 25% v 11% (P =.01). Patients with chromosome 13 abnormalities (n = 55) responded equally well as the other patients (n = 181): PR or better, 35% v 33% (P =.84); CR + nCR, 17% v 15% (P =.73). Patients who received 100% dose of DTPACE for two cycles (n = 115) achieved higher response rates than those with less than 100% dose (n = 121): PR or better, 49% v 17% (P <.0001); CR + nCR, 27% v 6% (P <.0001). CONCLUSION Combination therapy of oral dexamethasone and thalidomide with infusional chemotherapy is effective as induction therapy before autotransplantation, especially in patients with high-risk features.

Infusion of haplo-identical killer immunoglobulin-like receptor ligand mismatched NK cells for relapsed myeloma in the setting of autologous stem cell transplantation

Killer immunoglobulin‐like receptor (KIR)‐ligand mismatched natural killer (NK) cells play a key role in achieving durable remission after haplo‐identical transplantation for acute myeloid leukaemia. We investigated the feasibility of transfusing haplo‐identical, T‐cell depleted, KIR‐ligand mismatched NK cells, after conditioning therapy with melphalan and fludarabine, to patients with advanced multiple myeloma (MM) followed by delayed rescue with autologous stem cells. No graft‐versus‐host disease or failure of autologous stem cells to engraft was observed. There was significant variation in the number of allo‐reactive NK cells transfused. However, all NK products containing allo‐reactive NK cells killed the NK cell target K562, the MM cell line U266, and recipient MM cells when available. Post NK cell infusion there was a rise in endogenous interleukin‐15 accompanied by increasing donor chimaerism. Donor chimaerism was eventually lost, which correlated with the emergence of potent host anti‐donor responses indicating that the immunosuppressive properties of the conditioning regimen require further optimization. Further, blocking of inhibitory KIR‐ligands with anti‐human leucocyte antigen antibody substantially enhanced killing of MM cells thus highlighting the potential for modulating NK/MM cell interaction. Encouragingly, 50% of patients achieved (near) complete remission. These data set the stage for future studies of KIR‐ligand mismatched NK cell therapy in the autologous setting.

Prognostic factors in allogeneic transplantation for patients with high-risk multiple myeloma after reduced intensity conditioning

OBJECTIVES The aim of this study was to identify prognostic factors for outcome of high-risk patients with multiple myeloma after allogeneic transplantation prepared by reduced intensity conditioning (RIC). MATERIALS AND METHODS Data from 45 consecutive patients (median age 52 years, range 38-68), who received grafts from a sibling (n = 34) or unrelated donor (n = 11) were analyzed. Fourteen patients received an RIC allotransplant while chemosensitive (>/=partial remission [PR]), whereas 31 chemoresistant patients (<PR) had either relapsed (n = 28) or were refractory (n = 3) after one or more autografts; of these 28 patients, 4 had secondary myelodysplasia concurrent with relapse. Of the 14 chemosensitive patients, 12 received an RIC allotransplant as consolidation after an autotransplant (AT). RESULTS Twenty-nine (64%) were in a complete remission (CR) or near CR, 5 were in PR, and 5 had progressive disease. Twenty-five patients died, 17 of transplant-related complications, 7 of progressive disease, and 1 of a nontransplant-related cause. With a median follow-up of 15 months, the following factors were significantly associated with a better event-free survival (EFS) probability at 3 years: chemosensitive disease (64% vs 12%), pretransplant performance score (PS, Zubrod) </=2 (36% vs 0%), CR + near CR post transplant (36% vs 0%), and presence of chronic graft-vs-host disease (GVHD; 29% vs 0%). The same factors and absence of grade III to IV acute GVHD (52% vs 0%) were significant for a better overall survival (OS). On multivariate analysis including only pretransplant factors, both chemosensitive response and PS </=2 were significant for overall survival and event-free survival (p < 0.01). When response to RIC allotransplant and GVHD were added to the model, chronic GVHD was significant for better event-free survival, with an odds ratio of 1.5 (p < 0.01). CONCLUSIONS Our data suggest that although RIC allotransplant induces high rates of CR and near CR, even in refractory disease, it appears to result in a durable response only if it is applied early in the disease in high-risk patients, when they still are chemosensitive and have an adequate PS.

Phase I and II study of high-dose ifosfamide, carboplatin, and etoposide with autologous bone marrow rescue in lymphomas and solid tumors.

PURPOSE High-dose chemotherapy produces durable disease-free remissions in a minority of patients with resistant lymphomas and solid tumors. In an attempt to improve on the available regimens, ifosfamide, carboplatin, and etoposide (ICE) were selected for a new high-dose regimen because of their favorable spectrum of nonhematopoietic toxicity and evidence of synergy in in vitro systems. PATIENTS AND METHODS Forty-one patients with drug-resistant Hodgkins and non-Hodgkins lymphomas, and breast and testicular cancers were entered onto a phase I and II trial of a single course of ICE with autologous bone marrow rescue. Before transplantation, all patients received combination chemotherapy until maximal tumor response was achieved. RESULTS Patients received total doses of ifosfamide from 10 to 18 g/m2, carboplatin from 0.9 to 1.98 g/m2, and etoposide from 0.6 to 1.5 g/m2 administered during a 4-day period, with a maximum-tolerated dose (MTD) of ifosfamide 16 g/m2, carboplatin 1.8 g/m2, and etoposide 1.5 g/m2. The dose-limiting toxicities included irreversible renal, cardiac, and CNS dysfunction. There were three toxic deaths (7%), and all occurred above the MTD. Thirteen patients who were treated at the MTD tolerated the regimen well; reversible renal dysfunction and grade 2 mucositis commonly were observed. Of 23 heavily pretreated patients with persistent disease at the time of transplant, 10 (43%) achieved complete remissions (CRs) and 11 (48%) achieved partial remissions (PRs). Hodgkins and non-Hodgkins lymphoma patients who were treated at or below the MTD had a median potential follow-up of 11.9 months, and 12-month progression-free survivals of 62% and 48%, respectively. CONCLUSION High-dose ICE with bone marrow rescue was well tolerated with a high response rate, and should be considered for further testing.

Optimizing dendritic cell-based immunotherapy in multiple myeloma: intranodal injections of idiotype-pulsed CD40 ligand-matured vaccines led to induction of type-1 and cytotoxic T-cell immune responses in patients

Vaccination with idiotype (Id) protein‐pulsed dendritic cells (DCs) has been explored in multiple myeloma and the results have been disappointing. To improve the efficacy of DC vaccination in myeloma, we investigated the use of Id‐ and keyhole limpet haemocyanin (KLH)‐pulsed, CD40 ligand‐matured DCs administered intranodally. Nine patients with smouldering or stable myeloma without treatment were enrolled and DC vaccines were administered at weekly intervals for a total of four doses. Following vaccination, all patients mounted Id‐specific γ‐interferon T‐cell response. Interleukin‐4 response was elicited in two, and skin delayed‐type hypersensitivity reaction occurred in seven patients. More importantly, Id‐specific cytotoxic T‐cell responses were also detected in five patients. Most if not all patients mounted a positive T‐cell response to KLH following vaccination. At 1‐year follow‐up, six of the nine patients had stable disease, while three patients had slowly progressive disease even during the vaccination period. At 5‐year follow‐up, four of the six patients continued with stable disease. No major side effects were noted. In summary, intranodal administration of Id‐pulsed CD40 ligand‐matured DCs was able to induce Id‐specific T and B‐cell responses in patients. Current efforts are geared towards breaking tumour‐mediated immune suppression and improving clinical efficacy of this immunotherapy.