Neurologic Outcomes After Radiation Therapy for Severe Spinal Cord Compression in Multiple Myeloma: A Study of 162 Patients.

BACKGROUND: Bone destruction is the most frequent disease-defining clinical feature of multiple myeloma (MM), resulting in skeletal-related events such as back pain, pathological fractures, or neurologic compromise including epidural spinal cord compression (ESCC). Up to 24% of patients with MM will be affected by ESCC. Radiation therapy has been proven to be highly effective in pain relief in patients with MM. However, a critical knowledge gap remains with regard to neurologic outcomes in patients with high-grade ESCC treated with radiation. METHODS: We retrospectively included 162 patients with MM and high-grade ESCC (grade 2 or 3) who underwent radiation therapy of the spine between January 2010 and July 2021. The primary outcome was the American Spinal Injury Association (ASIA) score after 12 to 24 months, or the last known ASIA score if the patient had had a repeat treatment or died. Multivariable logistic regression was used to assess factors associated with poor neurologic outcomes after radiation, defined as neurologic deterioration or lack of improvement. RESULTS: After radiation therapy, 34 patients (21%) had no improvement in their impaired neurologic function and 27 (17%) deteriorated neurologically. Thirty-six patients (22%) underwent either surgery or repeat irradiation after the initial radiation therapy. There were 100 patients who were neurologically intact at baseline (ASIA score of E), of whom 16 (16%) had neurologic deterioration. Four variables were independently associated with poor neurologic outcomes: baseline ASIA (odds ratio [OR] = 6.50; 95% confidence interval [CI] = 2.70 to 17.38; p < 0.001), Eastern Cooperative Oncology Group (ECOG) performance status (OR = 6.19; 95% CI = 1.49 to 29.49; p = 0.015), number of levels affected by ESCC (OR = 4.02; 95% CI = 1.19 to 14.18; p = 0.026), and receiving steroids prior to radiation (OR = 4.42; 95% CI = 1.41 to 16.10; p = 0.015). CONCLUSIONS: Our study showed that 38% of patients deteriorated or did not improve neurologically after radiation therapy for high-grade ESCC. The results highlight the need for multidisciplinary input and efforts in the treatment of high-grade ESCC in patients with MM. Future studies will help to improve patient selection for specific and standardized treatments and to clearly delineate which patients are likely to benefit from radiation therapy. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Genetic predisposition for medication-related osteonecrosis of the jaws: a systematic review.

The purpose of this study was to assess whether genetic variation is a predictor for the development of medication-related osteonecrosis of the jaws (MRONJ) in patients receiving bisphosphonate therapy for various conditions. A systematic review based on the PRISMA guidelines was performed. A search strategy was developed. Comprehensive searches of major databases were conducted for studies published January 2003 through July 2018. The PICOS strategy was used to develop the inclusion criteria. The analysis in each study was performed primarily using single nucleotide polymorphism (SNP) frequency mean values and odds ratios between cases and controls. A total of 3301 patients were enrolled in the 15 included studies (two genome-wide association studies, n = 1877; 10 candidate gene studies, n = 1195; three whole genome/whole exome studies, n = 229). Multiple myeloma was the most prevalent primary disease (54.8%). Zoledronate was prescribed in 68.8% of patients. No one SNP was definitively identified as a risk factor for the development of MRONJ. To date, studies have failed to show a single gene as a risk factor for MRONJ. Heterogeneity of case and control populations may be contributory. Next generation sequencing studies may help elucidate the role and interplay of genetic events in the development of MRONJ.

A novel Bcl-2/Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma.

Bcl-2 or Bcl-X(L) confers resistance to chemotherapy in multiple myeloma (MM). Here we characterized the effects of ABT-737, a potent small-molecule inhibitor of antiapoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w with markedly higher affinity than previously reported compounds, on human MM cells. ABT-737 induces apoptosis in MM cells, including those resistant to conventional therapy. Examination of purified patient MM cells demonstrated similar results, without significant toxicity against normal peripheral blood mononuclear cells and MM bone marrow stromal cells. Importantly, ABT-737 decreases the viability of bortezomib-, dexamethasone-(Dex) and thalidomide-refractory patient MM cells. Additionally, ABT-737 abrogates MM cell growth triggered by interleukin-6 or insulin-like growth factor-1. Mechanistic studies show that ABT-737-induced apoptosis is associated with activation of caspase-8, caspase-9 and caspase-3, followed by poly(ADP-ribose) polymerase cleavage. Combining ABT-737 with proteasome inhibitor bortezomib, melphalan or dexamethasone induces additive anti-MM activity. Taken together, our study provides the rationale for clinical protocols evaluating ABT-737, alone and together with botezomib, mephalan or dexamethasone, to enhance MM cell killing, overcome drug resistance conferred by Bcl-2 and improve patient outcome in MM.

Novel etodolac analog SDX-308 (CEP-18082) induces cytotoxicity in multiple myeloma cells associated with inhibition of beta-catenin/TCF pathway.

We have reported previously that R-enantiomer of etodolac (R-etodolac), which is under investigation in phase 2 clinical trials in chronic lymphocytic leukemia, induces potent cytotoxicity at clinically relevant concentrations in multiple myeloma (MM) cells. In this study, we demonstrated that SDX-308 (CEP-18082), a novel analog of etodolac, has more potent cytotoxicity than R-etodolac against both MM cell lines and patient MM cells, including tumor cells resistant to conventional (dexamethasone, doxorubicine, melphalan) and novel (bortezomib) therapies. SDX-308-induced cytotoxicity is triggered by caspase-8/9/3 activation and poly (ADP-ribose) polymerase cleavage, followed by apoptosis. SDX-308 significantly inhibits beta-catenin/T-cell factor pathway by inhibiting nuclear translocation of beta-catenin, thereby downregulating transcription and expression of downstream target proteins including myc and survivin. Neither interleukin-6 nor insulin-like growth factor-1 protect against growth inhibition triggered by SDX-308. Importantly, growth of MM cells adherent to bone marrow (BM) stromal cells is also significantly inhibited by SDX-308. Our data therefore indicate that the novel etodolac analog SDX-308 can target MM cells in the BM milieu.

Correction: Pomalidomide, bortezomib, and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma.

Following the publication of this article, the authors noted that the pomalidomide dose for the additional SC cohort in Fig. 1 was incorrectly listed. The correct dose for pomalidomide in the additional SC cohort should be the maximum tolerated dose of 4 mg/day, not 2 mg/day as listed in the original Fig. 1. The authors apologize for any inconvenience caused.

Desorption of water from hydrophilic MCM-41 mesopores: positron annihilation, FTIR and MD simulation studies.

The desorption mechanism of water from the hydrophilic mesopores of MCM-41 was studied using positron annihilation lifetime spectroscopy (PALS) and attenuated total reflection Fourier transform infrared spectroscopy supplemented with molecular dynamics (MD) simulation. PALS results indicated that water molecules do not undergo sequential evaporation in a simple layer-by-layer manner during desorption from MCM-41 mesopores. The results suggested that the water column inside the uniform cylindrical mesopore become stretched during desorption and induces cavitation (as seen in the case of ink-bottle type pores) inside it, keeping a dense water layer at the hydrophilic pore wall, as well as a water plug at both the open ends of the cylindrical pore, until the water was reduced to a certain volume fraction where the pore catastrophically empties. Before being emptied, the water molecules formed clusters inside the mesopores. The formation of molecular clusters below a certain level of hydration was corroborated by the MD simulation study. The results are discussed.

Preclinical activity of CPI-0610, a novel small-molecule bromodomain and extra-terminal protein inhibitor in the therapy of multiple myeloma.

Inhibition of the bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for various hematologic cancers. Previous studies suggest that BET inhibitors constrain tumor cell proliferation and survival mainly through the suppression of MYC transcription and activity. However, suppression of the transcription of additional genes also contributes to the antitumor activity of BET inhibitors but is less well understood. Here we examined the therapeutic potential of CPI-0610, a potent BET inhibitor currently undergoing phase I clinical testing, in multiple myeloma (MM). CPI-0610 displays potent cytotoxicity against MM cell lines and patient-derived MM cells through G1 cell cycle arrest and caspase-dependent apoptosis. CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse model. Our study found IKZF1 and IRF4 to be among the primary targets of CPI-0610, along with MYC. Given that immunomodulatory drugs (IMiDs) stabilize cereblon and facilitate Ikaros degradation in MM cells, we combined it with CPI-0610. Combination studies of CPI-0610 with IMiDs show in vitro synergism, in part due to concomitant suppression of IKZF1, IRF4 and MYC, providing a rationale for clinical testing of this drug combination in MM patients.

Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma.

This phase 1 dose-escalation study evaluated pomalidomide, bortezomib (subcutaneous (SC) or intravenous (IV)) and low-dose dexamethasone (LoDEX) in lenalidomide-refractory and proteasome inhibitor-exposed relapsed or relapsed and refractory multiple myeloma (RRMM). In 21-day cycles, patients received pomalidomide (1-4 mg days 1-14), bortezomib (1-1.3 mg/m2 days 1, 4, 8 and 11 for cycles 1-8; days 1 and 8 for cycle ⩾9) and LoDEX. Primary endpoint was to determine the maximum tolerated dose (MTD). Thirty-four patients enrolled: 12 during escalation, 10 in the MTD IV bortezomib cohort and 12 in the MTD SC bortezomib cohort. Patients received a median of 2 prior lines of therapy; 97% bortezomib exposed. With no dose-limiting toxicities, MTD was defined as the maximum planned dose: pomalidomide 4 mg, bortezomib 1.3 mg/m2 and LoDEX. All patients discontinued treatment by data cutoff (2 April 2015). The most common grade 3/4 treatment-emergent adverse events were neutropenia (44%) and thrombocytopenia (26%), which occurred more frequently with IV than SC bortezomib. No grade 3/4 peripheral neuropathy or deep vein thrombosis was reported. Overall response rate was 65%. Median duration of response was 7.4 months. Pomalidomide, bortezomib and LoDEX was well tolerated and effective in lenalidomide-refractory and bortezomib-exposed patients with RRMM.

Antimyeloma activity of two novel N-substituted and tetraflourinated thalidomide analogs.

Thalidomide alone or in combination with steroids has significant activity in multiple myeloma (MM). However, given its teratogenic potential, analogs have been synthesized, retaining the anti-MM activity without these side effects. We examined the anti-MM activity of two thalidomide analogs, CPS11 and CPS49. Direct cytotoxicity of the drugs on myeloma cell lines and patient myeloma cells was examined using thymidine uptake. Tumor cell apoptosis was evaluated by flow cytometry as well as Western blotting for caspase and PARP cleavage. Cellular signaling events were examined by immunoblotting for phosphorylated proteins. Both drugs inhibit proliferation of several MM cell lines sensitive and resistant to conventional therapies. They decrease secretion of IL-6, IGF, and VEGF by marrow stromal cells. Importantly, they inhibit proliferation of MM cells adherent to stromal cells. These drugs induce caspase-mediated apoptosis in MM cell lines, as well as patient MM cells. They inhibit the PI3K/Akt and JAK/STAT (signal transducers and activators of transcription) pathways in MM cells and are antiangiogenic in matrigel-based assays. CPS11 and CPS49 have potent antimyeloma activity and can overcome protective effects of the tumor microenvironment. They have potent antiangiogenic activity and direct effect on bone marrow stroma. These encouraging preclinical data provide the basis for further evaluation in the clinic.

Functional interaction between retinoblastoma protein and stress-activated protein kinase in multiple myeloma cells.

Previous studies have demonstrated that gamma-irradiation (IR)-induced apoptosis in multiple myeloma (MM) is associated with activation of stress-activated protein kinase (SAPK). In the present study, we examined the molecules downstream of SAPK/C-Jun N-terminal kinase (JNK), focusing on the role of retinoblastoma protein (Rb) during IR-induced MM cell apoptosis. The results demonstrate that IR activates SAPK/JNK, which associates with Rb both in vivo and in vitro. Far Western blot analysis confirms that SAPK/JNK binds directly to Rb. IR-activated SAPK/JNK phosphorylates Rb, and deletion of the phosphorylation site in the COOH terminus domain of Rb abrogates phosphorylation of Rb by SAPK/JNK. Taken together, our results suggest that Rb is a target protein of SAPK/JNK and that the association of SAPK/JNK and Rb mediates IR-induced apoptosis in MM cells.

Pim2 is important for regulating DNA damage response in multiple myeloma cells.

Pan proviral integrations of Moloney virus (PIM) inhibition in multiple myeloma (MM) results in reduced cell viability in tested human-derived MM cell lines and reduces tumor burden in xenograft mouse models, making PIMs important therapeutic targets for the disease. PIM kinase inhibitors are currently being tested clinically in MM. We sought to elucidate the role of the various PIMs in MM. Our data demonstrate that Pim2 has a significant role in MM cell cytotoxicity. Our data provide evidence for a novel role for Pim2 in the regulation of the DNA damage response (DDR). Knockdown of Pim2 upregulates several downstream DDR markers, mimicking the effects of doxorubicin (Dox) treatment of MM cells, and suggesting a role for the kinase as a negative regulator of this pathway. Dox-induced DNA damage results in a decrease in Pim2 levels, placing the kinase directly downstream of the site of Dox-DNA binding. Overexpression of Pim2 confers a slight survival advantage against Dox through antiapoptotic activity, further underscoring its relevance in the DDR pathway. These data provide insights into a novel mechanism of PIM kinase activity and provide the framework for designing therapeutic approaches in MM.

Evaluating results from the multiple myeloma patient subset treated with denosumab or zoledronic acid in a randomized phase 3 trial.

In a phase 3 trial of denosumab vs zoledronic acid in patients (n=1776) with bone metastases and solid tumors or multiple myeloma, denosumab was superior to zoledronic acid for the primary end point of prevention of skeletal-related events. There was no difference in overall survival between the two groups; however, an ad hoc overall survival analysis in the multiple myeloma subset of patients (n=180) favored zoledronic acid (hazard ratio (HR) 2.26; 95% confidence interval (CI) 1.13-4.50; P=0.014). In the present analysis, we found imbalances between the groups with respect to baseline risk characteristics. HRs with two-sided 95% CIs were estimated using the Cox model. After adjustment in a covariate analysis, the CI crossed unity (HR 1.86; 95% CI 0.90-3.84; P=0.0954). Furthermore, we found a higher rate of early withdrawals for the reasons of lost to follow-up and withdrawal of consent in the zoledronic acid group; after accounting for these, the HR was 1.31 (95% CI 0.80-2.15; P=0.278). In conclusion, the survival results in multiple myeloma patients in this trial were confounded and will eventually be resolved by an ongoing phase 3 trial.

Targeting IL-17A in multiple myeloma: a potential novel therapeutic approach in myeloma.

We have previously demonstrated that interleukin-17A (IL-17) producing T helper 17 cells are significantly elevated in blood and bone marrow (BM) in multiple myeloma (MM) and IL-17A promotes MM cell growth via the expression of IL-17 receptor. In this study, we evaluated anti-human IL-17A human monoclonal antibody (mAb), AIN457 in MM. We observe significant inhibition of MM cell growth by AIN457 both in the presence and the absence of BM stromal cells (BMSCs). Although IL-17A induces IL-6 production, AIN457 significantly downregulated IL-6 production and MM cell adhesion in MM-BMSC co-culture. AIN457 also significantly inhibited osteoclast cell differentiation. More importantly, in the SCIDhu model of human myeloma administration of AIN457 weekly for 4 weeks after the first detection of tumor in mice led to a significant inhibition of tumor growth and reduced bone damage compared with isotype control mice. To understand the mechanism of action of anti-IL-17A mAb, we report, here, that MM cells express IL-17A. We also observed that IL-17A knockdown inhibited MM cell growth and their ability to induce IL-6 production in co-cultures with BMSC. These pre-clinical observations suggest efficacy of AIN457 in myeloma and provide the rationale for its clinical evaluation for anti-myeloma effects and for improvement of bone disease.

RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells.

Related Adhesion Focal Tyrosine Kinase (RAFTK; also known as Pyk2), is a member of the Focal Adhesion Kinase (FAK) subfamily and is activated by TNF alpha, UV light and increases in intracellular calcium levels. However, the function of RAFTK remains largely unknown. Our previous studies demonstrated that treatment with dexamethasone (Dex), ionizing radiation (IR), and anti-Fas mAb induces apoptosis in multiple myeloma (MM) cells. In the present study, we examined the potential role of RAFTK during induction of apoptosis in human MM cells triggered by these three stimuli. Dex-induced apoptosis, in contrast to apoptosis triggered by anti-Fas mAb or IR, is associated with activation of RAFTK. Transient overexpression of RAFTK wild type (RAFTK WT) induces apoptosis, whereas transient overexpression of Kinase inactive RAFTK (RAFTK K-M) blocks Dex-induced apoptosis. In contrast, transient overexpression of RAFTK K-M has no effect on apoptosis triggered by IR or Fas. In Dex-resistant cells, Dex does not trigger either RAFTK activation or apoptosis. Finally, interleukin-6 (IL-6), a known survival factor for MM cells, inhibits both activation of RAFTK and apoptosis of MM.1S cells triggered by Dex. Our studies therefore demonstrate Dex-induced RAFTK-dependent, and IR or Fas induced RAFTK-independent apoptotic signaling cascades in MM cells.

Characterization of signaling cascades triggered by human interleukin-6 versus Kaposi's sarcoma-associated herpes virus-encoded viral interleukin 6.

Kaposi's sarcoma-associated herpes virus (KSHV) is associated with Kaposi's sarcoma, multicentric Castleman's disease, and body cavity-based lymphomas, settings in which human interleukin-6 (hIL-6) acts as a growth factor. The KSHV open reading frame K2 encodes for viral IL-6 (vIL-6), a protein with 25% amino acid identity to hIL-6, which can promote the growth of hIL-6-dependent cell lines. In the present study, we characterized biological sequelae and signaling cascades triggered by hIL-6 versus vIL-6 in the hIL-6-dependent MH60 and B9 cell lines. Both hIL-6 and vIL-6 induced significant increases (P < 0.01) in DNA synthesis in these cell lines in a dose-dependent fashion. Neutralizing anti-hIL-6 antibody (Ab) inhibited DNA synthesis triggered by hIL-6, without similarly affecting proliferation in response to vIL-6. On the other hand, antimouse IL-6 receptor (mIL-6R) Ab blocked response to vIL-6, but not that to hIL-6. Both hIL-6 and vIL-6 activated gp130, Janus kinase 1, signal transducers and activators of transcription-3, and mitogen-activated protein kinase in both MH60 and B9 cells. Proliferation of these cell lines in response to both hIL-6 and vIL-6 was blocked by PD98059, an inhibitor of MEK1 activation. These data suggest that MEK1 activation mediates the proliferative response to both cytokines. Finally, both hIL-6 and vIL-6 also maintained viability of serum-starved MH60 and B9 cells and blocked dexamethasone-induced apoptosis of MM.1S human myeloma cells. Further characterization of the signaling cascades mediating the growth and antiapoptotic effects of vIL-6 versus hIL-6 may help identify their unique roles in disease pathogenesis in Kaposi's sarcoma and other KSHV-associated neoplasms.

Immunotherapeutic strategies for the treatment of plasma cell malignancies.

The use of immunotherapy to treat patients with plasma cell dyscrasias (PCD) such as multiple myeloma (MM) and Waldenström's macroglobulinemia (WM) has gained enormous interest in recent years, with considerable efforts being mounted by many investigators. These efforts have included the use of serotherapy (antibody-mediated immunotherapy), vaccination strategies aimed at inducing allogeneic as well as autologous anti-MM immunity, and the use of donor lymphocyte infusions (DLIs). A number of cell surface antigens on malignant plasma cells and/or B cells in MM and/or WM patients have been proposed for use in tumor cell-targeted serotherapy, including immunoglobulin idiotype, CD19, CD20, CD38, CD54, CD138, HM1.24, and MUC1 core protein. Ongoing clinical trials are examining serotherapy targeting CD20 (in MM and WM) and CD38 (in MM), with early reports of responses to the anti-CD20 monoclonal antibody (mAb) Rituximab (Genentech, South San Francisco, CA) in patients with WM and certain patients with MM. The use of agents to induce MM- and WM-selective antigens for targeting in serotherapy has been proposed based on studies demonstrating the upregulation of CD20 by interferon-gamma (IFN-gamma), and of MUC1 core protein by dexamethasone (DEX) on malignant plasma cells. Strategies to induce allogeneic anti-MM immunity have included immunization of the marrow donor to idiotypic protein, as well as DLI. In addition, proposed immunization strategies aimed at inducing autologous immunity include vaccination with dendritic cells pulsed with MM antigens, MM cell-dendritic cell fusions, carrier-linked idiotype protein, catalytic subunit of telomerase, or DNA encoding for single-chain variable fragments (scFv) linked to a carrier protein gene. Whole tumor vaccination strategies are also being examined and include the use of MM cells transfected and/or stimulated with cytokines, costimulatory molecules, or CD40 ligand. Finally, potential obstacles to the use of immunotherapy, including the presence of resistance antigens on MM and WM tumor cells, are discussed.

Isolation and characterization of human multiple myeloma cell enriched populations.

We developed a simple and rapid method to enrich tumor cells within bone marrow (BM) aspirates from patients with multiple myeloma (MM). Thirty patients with a median of 50% (8-85%) MM cells by morphology and 55% (6--85%) MM cells identified by CD38+CD45-cell surface phenotype were studied. BM mononuclear cells (BMMCs) were isolated by Ficoll Hypaque sedimentation and incubated with a cocktail of mouse monoclonal antibodies (mAbs) directed against CD3 (T cells); CD11b and CD14 (monocytes); CD33 (myeloid cells), CD45 and CD45RA (leucocyte common antigen); CD32 as well as glycophorin A. After the addition of anti-mouse Fc Ig-coated immunomagnetic beads, mAb-bound cells were removed in a magnetic field. The residual cell populations were enriched for MM cells, evidenced by >95% plasma cell morphology and >95% CD38+CD45RA-cell surface phenotype. Since this method requires only two short incubations, cell losses were minimal and the yield of MM cells was therefore high (>95%). Viability of the MM-cell enriched fractions was 99%, and these cells were functional in assays of proliferation, cell cycle analysis and immunoglobulin secretion. This immunomagnetic bead depletion method therefore permits the ready isolation of homogeneous populations of patient MM cells for use in both cellular and molecular studies.

An economic evaluation of peripheral blood stem cell transplantation as an alternative to autologous bone marrow transplantation in multiple myeloma.

Autologous peripheral blood stem cell transplantation (PBSCT) is increasingly being utilised as an alternative to autologous bone marrow transplantation (ABMT) in the treatment of malignant diseases. We have performed a pharmacoeconomic study using cost-minimisation analysis to evaluate the two techniques in a population of multiple myeloma patients undergoing PBSCT (n = 37) or ABMT (n = 14). In the PBSCT group, the time to > 0.5 x 10(9)/l neutrophils was significantly shorter (16 vs 22 days; P = 0.0019) as was the time to > 50 x 10(9)/l platelets (19 vs 27 days; P = 0.0019). The faster haematopoietic recovery resulted in a reduced period of intravenous antibiotic therapy (12 vs 19 days; P < 0.0001), reduced requirements for platelet transfusions (12 vs 31.5 units; P = 0.0005), and ultimately, a significant reduction in duration of hospitalisation (19 vs 27.5 days; P < 0.0001). These clinical benefits translated into economic benefits such that the total cost in the PBSCT group was 27.5% less than in the ABMT group (< Pounds 7995 vs < Pounds 11026; P = 0.0001). We conclude that the use of PBSCT as an alternative to ABMT in patients with multiple myeloma is associated with demonstrable economic advantages in addition to clinical benefits.

Kinetics of paraprotein clearance after autografting for multiple myeloma.

The kinetics of paraprotein clearance after autografting for multiple myeloma have not been described. We studied 33 myeloma patients in plateau phase with detectable paraprotein (3-34 milligrams, median 10 milligrams) at the time of ABMT who received melphalan (200 mg/m2) and methylprednisolone (1.5 g x 5) for conditioning. Fifteen patients received interferon-alpha post-transplant as part of a randomized study. Twenty-four of 33 (72.7%) patients eventually cleared the paraprotein at a median of 47 days (range 5-783) post-transplant. The probability of clearance was lower (46.7 vs 94.4%, P = 0.004) and the time taken to clear paraprotein longer (142 vs 29 days, P = 0.003) in patients with a higher level (> 10 milligrams) at the time of the transplant. However, clearance occurred within 6 months in 23 of 24 (95.8%) patients who ultimately cleared the paraprotein. Interferon-alpha did not influence the clearance of paraprotein. We conclude that after autografting for myeloma, the time taken to clear paraprotein is longer and the probability of clearance lower with higher levels at the time of ABMT, and most patients who eventually clear the paraprotein do so within 6 months. Because the probability of clearing paraprotein (and thus attaining remission) in patients with detectable paraprotein 6 months post-transplant is low, a decision about further treatment may be made at this point.

Acute lymphoblastic leukaemia-type intensive chemotherapy to eliminate minimal residual disease after high-dose melphalan and autologous transplantation in multiple myeloma - a phase I/II feasibility and tolerance study of 17 patients.

Aiming to target the minimal residual disease in patients with multiple myeloma, a phase I/II single centre study was undertaken for feasibility and tolerance of intensive acute lymphoblastic leukaemia consolidation chemotherapy (ALL-IC) as part of a strategy for post-transplant consolidation targeted at pre-B cells. Seventeen newly diagnosed patients with myeloma (median age 55 years; 30-65) were initially treated with courses of infused cyclophosphamide, vincristine, adriamycin and methylprednisolone (C-VAMP) followed by melphalan 200 mg/m2(HDM) and peripheral blood stem cell rescue (PBSC). Forty-seven percent were in CR and the rest in PR after HDM. ALL-IC consisted of vincristine, daunorubicin, etoposide, cytarabine, 6-thioguanine and prednisolone given over 5 days. All patients became neutropenic (<0.5 x 109/l) at a median of 10 days (4-18) and one of the 17 patients (5.8%) died 15 days post ALL-IC of sepsis. A further four have died of relapse with an overall survival (OS) of 67% at 4 years. Two of nine patients in PR at the time of ALL-IC achieved CR. Matched-pair analysis of 34 control patients shows no difference for OS and event-free survival between ALL-IC and controls. We conclude that ALL-IC given to myeloma patients after HDM/PBSC is as safe as when used in ALL and warrants further assessment in randomised trials for myeloma.