Greipp, Philip R.

Abstract -Background: An increase in the Vitamin B12 (cobalamin) serum transport protein, transcobalamin II (TCII), has been noted in myeloma (MM) patients (Carmel, Blood. 1978.51(6):1057). Uptake of B12 bound to TCII is regulated by transcobalamin II receptors (TCII-R). Labeled thymidine studies have shown, in vitro, that TCII-R are up-regulated in proliferating malignant cells and correlate with increased incorporation of 3H-thymidine and DNA synthesis (Amagasaki, Blood, 76:1380; 1990). Via cobalt-57 labeled B12 studies, the up-regulation of TCII-R has been demonstrated in solid tumors, in vivo, by Flodh (Int J Cancer, 1968.4(5):694). Indium-111diethylenetriaminepentaacetate adenosylcobalamin (In-111DAC) is a novel radionuclide labeled B12 conjugate that has shown preferential uptake in malignant tissue compared to normal tissue via clinical gamma camera imaging of nude mice with sarcoma xenografts and human patients with various solid tumors (Collins, J Nuc Med, 1997.38(5):717 and Mayo Clin Proc, 2000.75(6):568). Nearly all the human tumors were visualized with In-111DAC and a correlation between increased In-111 uptake and higher invasiveness of the tumor at biopsy was observed. We questioned whether In-111DAC could be utilized to image MM, in vivo in murine models. Methods: In accordance with the Institutional Animal Care and Use Committee, we assessed In-111DAC as an imaging agent for MM in mice with subcutaneous (SQ) MM tumors and mice with systemic MM. 7 week old CB17/scid mice received total body irradiation 150cGy before 1x107 myeloma cells (KAS-6/1-gift of Dr. D.F. Jelinek) were injected SQ between the scapulae. Once tumors reached at least 5mm, both tumor bearing mice and saline control mice without tumor were injected intraperitoneally (IP) with 400 μCi In-111DAC. Mice with SQ tumors were injected with 400 μCi of free In-111 for comparison. Gamma camera images at 15h were followed by CT/SPECT (Single photon emission tomography) images at 18h after IP injection. To evaluate In-111DAC imaging in mice with systemic MM, 7 week old bg-nu-xid mice were injected via tail vein with 1x107 myeloma cells (5TGM1-gift of B.O. Oyajobi). Animals with late stage myeloma (day 23–28) and saline control animals were injected with In-111DAC 400 μCi, and were compared to control animals with late MM, injected with 400 μCi of free In-111. Animals underwent gamma camera and CT/SPECT imaging as in the time-frame above. All animals were sacrificed. Organs and tumors were harvested and weighed. Radioactivity was measured in a NaI scintillation well counter and recorded as cpm/mg. Results: Images and radioactivity measurements in the SQ MM model (KAS-6/1) demonstrated excellent uptake of In-111DAC within the tumor compared to normal tissue and controls. In the 5TGM1 systemic MM model, the spleen is a known sanctuary of MM and displayed especially strong uptake of In-111DAC compared to normal tissue. Conclusion: We report the first murine MM models to be imaged with In-111DAC. Our study affirms that In-111DAC is an excellent imaging agent for MM. In-111DAC imaging could be utilized clinically to complement standard staging studies to assess MM tumor burden in patients at time of diagnosis, relapse, or to assess treatment response; especially in patients with non-secretory disease. Moreover, our study strongly suggests the rationale to exploit TCII-R as a target for MM therapy.

Abstract Background: MM is an incurable disease with an anticipated overall survival ranging from months to decades. Novel therapies like bortezomib have activity in both the relapsed/refractory and up front settings. There are sparse data on whether novel therapies may overcome high risk features. Methods: Patients with newly diagnosed high-risk myeloma (beta-2 microglobulin [B2M] >= 5.5., plasma cell labeling index [PCLI] >= 1, or deletion 13q) were eligible. Patients were treated with bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 days for 8 cycles as induction. After induction, patients received bortezomib 1.3 mg/m2 every other week indefinitely. Patients relapsing on maintenance schedule resumed full induction schedule. Responses were defined by the EBMT criteria. The primary end-point was the response rate (90% power to detect a response rate of >=50% ). Results: Between March 15, 2004 and March 10, 2005, 44 patients enrolled. Among the 43 eligible patients, median age was 63; 51% were male. All had high risk disease: deletion 13q (6/41); PCLI >=1% (17/33); t(4:14) (4/27) and B2M >= 5.5 (34/43). Response data are available for 37 of the 43 eligible patients. The overall response rate was 49% (95% CI: 0.32, 0.66) (0 patients with CR, 1 VGPR, 15 PR, 2 MR, and 11 inevaluable). The response rate allowing for use of serum monoclonal protein levels when a measurable urine monoclonal protein was unavailable at follow-up was 59.5% (1 patient with CR, 1 VGPR, 18 PR, 2 MR, and 6 inevaluable). The median progression free survival is 9.4 months. Thirty-three percent of patients completed the 8 cycles of planned induction therapy and moved to maintenance. Reasons for discontinuing therapy have included progression or death (n=18), adverse events (n=6), and other (n=14). Only 12% of patients remain on active therapy: 0% of deletion 13q patients; 25% of t(4:14) and 12% each of high B2M and high PCLI patients. Of the 14 patients who entered the maintenance phase of treatment, 3 have progressed. Of these 3, 2 took re-induction, and neither responded. Median time to progression for those entering maintenance was12.4 months from the time of starting maintenance. The most common adverse events of grade 3 or higher included neutropenia (33%), diarrhea (31%), hyponatremia (21%), anemia (19%), thrombocytopenia (16%), fatigue (14%). Grade 1–2 sensory peripheral neuropathy occurred in 53% of patients, with only 2% having grade 3 sensory neuropathy. One patient had grade 3 peripheral neuropathy. One patient died after receiving 2 doses of protocol treatment due to heart block and asystole. Updated results on the full study population will be presented at the meeting. Conclusions: In high risk patients, upfront bortezomib appears to result in comparable response rates to those reported for unselected cohorts of newly diagnosed myeloma patients. Continued follow-up of these patients will provide information about whether this will translate into better overall outcomes. Figure Figure

Abstract Background: High dose therapy (HDT) and stem cell transplant has been shown to improve survival in patients with myeloma and remains the standard of care. However, the reported results of initial HDT in these patients reflect the combined effect of the initial therapy and the HDT. The contribution of HDT on its own is often difficult to analyze in this group of patients with varying degree of response to initial therapy. In this single institution retrospective study, we have analyzed the results of HDT in a group of patients with measurable disease at the time of HDT. Methods: We identified patients from our transplant database, who had measurable disease at the time of initiation of transplant as defined by a serum M protein of ≥ 1.0 g/dL, 24 hour urine M-protein ≥ 200 mg or a bone marrow plasma cell % of ≥ 30. Details regarding the clinical outcome were obtained from the database and from patient clinical records. Chi square test was used for comparison of nominal variables and t-test for continuous variables. Kaplan Meier analysis was used for comparing survival and Cox proportional hazards was employed to identify predictors of progression free and overall survival. Responses were defined by the EBMTR criteria, using the measurements at the time HDT and the lowest measurement obtained. VGPR required a 90% reduction in the serum M component with urine protein < 100 mg/24 hours. Results: A total of 440 patients were studied; 271 (61.5%) of whom had a transplant within one year of their diagnosis. Among the 271 patients, 140 (52%) were in the initial plateau, 99 (36%) failed to achieve a PR to initial therapy and 32 (12%) were in their first relapse. Given the known differences in the outcome between these groups of patients, those receiving an early transplant were analyzed separately. The response rates included CR (24%), VGPR (7%), PR (52%), MR or less (17%) and among the late transplants CR (23%), VGPR (8%), PR (61%) and MR or less (8%). The median progression free survival was 23.6 mos and the overall survival from HDT was 62 mos. In a multivariate analysis, presence of cytogenetic abnormalities (RR: 2.5) and high plasma cell labeling index (≥ 1%) (RR: 2.4) at HDT and failure to achieve a CR or VGPR (RR: 1.7) were prognostic for decreased progression free survival post HDT. In a similar model, only high PCLI (RR: 2.8) and abnormal cytogenetics (RR: 2.5) at HDT predicted for poor overall survival after transplant. Conclusion: This study provides a sense of the contribution of HDT, independent of the initial therapy, by determining responses based on the immediate pre-transplant disease measurements and the best values observed post transplant. In this group of patients with residual measurable disease after the initial therapy, HDT therapy leads to complete responses in nearly a quarter of the patients and a VGPR in another 7%, an outcome associated with better progressin free survival. While measurements at transplant do not correlate strictly with response to initial therapy, the aim of this study was to understand the individual contribution of HDT in these patients. Thus some of the patients who would have been classified as having a partial response to induction and HDT may be classified as non-responders in this analysis. These numbers will provide a historical comparison for trials evaluating novel consolidation therapies for myeloma.

Abstract Background: Autologous stem cell transplantation (SCT) improves survival in patients (pts) with multiple myeloma (MM). We have previously demonstrated that the degree of response at transplant does not impact on the outcome of transplant. However, newer induction regimens such as thalidomide and dexamethasone (Thal-Dex) result in higher response rates compared to previously used regimens such as single agent dexamethasone or vincristine, doxorubicin, and dexamethasone (VAD). We examined the outcome of SCT following three different induction therapies for newly diagnosed MM, namely VAD, single agent Dex, and Thal-Dex. Patients and Methods: 340 patients with MM who received their SCT within 12 mos of diagnosis (median 5.8, range 3–12) were studied. Patients receiving more than one induction therapy as well as those in whom thalidomide was added to dexamethasone for lack of response were excluded from the analysis. There were 105 pts in the VAD group, 140 in the Dex group and 95 in the Thal-Dex group. Responses were defined using standard criteria. Results: The study cohort consisted of 209 males (59%), with a median age of 57 years (range 30–76) at transplant. Baseline characteristics were similar in the 3 groups, except for lower age in the VAD group (median 55.8) compared to Dex (59.6) and Thal Dex (57.4) and shorter time to transplant in the Dex group (5.4 m) compared to VAD (6.4) and Thal Dex (5.9). Markers of disease activity pre-transplant, including B2M and marrow plasma cell percentage were higher in the Dex group compared to either VAD or Thal Dex. The proportion of patients with any response to induction therapy was lower in the Dex group compared to the other two. All pts in the Dex and the Thal-Dex groups received melphalan only conditioning compared to 70% in the VAD group, the rest receiving Melphalan/TBI. An objective response was achieved after SCT in 96%, 97%, and 98% of pts in the VAD, Dex and Thal-Dex groups respectively (P=0.8). A complete response to SCT was seen in 49% of patients in VAD group, 45% among those in the Dex group and 38% among those in the Thal Dex group (P=0.38). There was no difference in the median progression free survival after transplant (P=0.21) or overall survival from diagnosis (P=.34) between the three groups. The proportion free from progression at 2 years post transplant was 54%, 55% and 46% for Dex, VAD and Thal-Dex respectively. The proportion surviving at 4 years from diagnosis was 64%, 65.4% and 72% respectively for the three groups. Conclusion: We did not observe any difference in the response rates including complete responses to SCT in the three groups with nearly all pts in each group achieving a response. The progression free survival and overall survival appear to be comparable between the three groups. The results from initial therapy cannot be compared between the three regimens since the study population is restricted to patients reaching stem cell transplant. Within the limits of the study, there does not appear to be any long term impact of the initial therapy for the patients going onto an early stem cell transplant. Figure Figure

Translocations involving immunoglobulin (Ig) loci and chromosome 13 monosomy (Δ13) are frequent cytogenetic findings in multiple myeloma (MM). Similar chromosomal aberrations have been identified in the monoclonal gammopathy of undetermined significance (MGUS), but their prevalence and significance remain uncertain. Bone marrow from 72 patients with MGUS (n = 62) and smoldering MM (n = 10) was evaluated for translocations between the Ig heavy chain (IgH) and chromosomes 4, 11, and 16, translocations involving Ig light chain–lambda (IgL-λ, and Δ13. Fluorescence in situ hybridization (FISH) analysis was done on clonal plasma cells (PCs) detected by immunofluorescence (cIg-FISH) of the cytoplasmic light chain. We also studied cells for cyclin D1 and FGFR3 up-regulation by immunohistochemistry and immunofluorescence, respectively. Twenty-seven (46%) of 59 patients had IgH translocations, and 4 (11%) of 37 had an IgL-λ translocation. A t(11;14)(q13;q32) was found in 15 (25%) of 59 patients, a t(4;14)(p16.3;q32) in 9% of patients, and a t(14;16)(q32;q23) in 5% of patients. All patients with t(4;14)(p16.3;q32) tested (n = 3) had intense cytoplasmic fluorescence with an anti-FGFR3 antibody. PC nuclear staining of cyclin D1 was only observed in patients with t(11;14)(q13;q32); Δ13 was detected in the clonal PCs in 50% of patients. The percentage of abnormal PCs varied with any given abnormality. No obvious clinical or biologic correlations were associated with these chromosome abnormalities. Similar translocations are found in both MGUS and MM, including t(4;14)(p16.3;q32) and t(14;16)(q32;q23). Moreover, Δ13 is common in MGUS and unlikely to play a predominant role in the evolution of MGUS to MM.

Abstract In an attempt to identify novel genetic abnormalities in multiple myeloma (MM) we analyzed 68 MM patient samples and 42 human myeloma cell lines (HMCL) with high-resolution (60kb) array-based comparative genomic hybridization (aCGH). We concentrated on bi-allelic genomic deletions with the expectation that these regions might contain novel tumor suppressor genes and identified a common abnormality at 14q32. Fine mapping of the 14q32 microdeletion by PCR demonstrated a 45 kb minimal deletion encompassing two genes; TRAF3, a negative regulator of the non-canonical NF-kB pathway, and AMN. To determine the frequency of copy number abnormalities of this region a cohort of 161 patients were screened with a FISH probe mapping to the minimally deleted region. This identified 7 (4.4%) patients with bi-allelic deletion and 19 (11.8%) patients with a single copy of the target region. Sequencing of all TRAF3 coding exons in 62 patients and 42 HMCL identified inactivating mutations in 9 patient samples and 4 HMCL. Overall, the incidence of TRAF3 inactivation, bi-allelic deletion or mutation, is 7/42 (16.7%) in HMCL and 12/62 (19.4%) in patients, making it one of the most common genetic abnormalities identified in MM. Importantly, dysregulation of NF-kB pathways is a common event in MM, but the mechanism for this dysregulation is largely unknown. Although TRAF3 is a negative regulator of the non-canonical NF-kB pathway it has not previously been implicated in cancer. Therefore, we tested the tumor suppressor function of TRAF3 by reintroducing TRAF3 into HMCL harboring TRAF3 abnormalities using an adenovirus gene transfer system. Expression of TRAF3 in HMCL with TRAF3 abnormalities rapidly reversed cellular processing of NFKB2 from p100 (an inactive isoform) to p52 (active) and additionally led to a 60% reduction in cellular proliferation (range, 10–89%) associated with Go/G1 cell cycle arrest and induction of cell death by apoptosis. At 48 hrs post infection the proportion of cells entering S-phase or G2/M declined by 31% (range, 8.1–56.1) and the proportion undergoing apoptosis increased by 28% (range 11.7–47.4%). In contrast, over-expression of TRAF3 in control HMCL without TRAF3 abnormalities had no effect. Overall, TRAF3 is identified as a novel tumor suppressor that regulates the non-canonical NF-kB pathway and is inactivated in ~ 20% of MM patients. Given the involvement of the NF-kB pathway in multiple human malignancies and the near constitutive expression of TRAF3 we propose that inactivation of TRAF3, a novel tumor suppressor identified for the first time in this study, may occur in other cancers. In this regard, we have recently identified a Burkitt lymphoma cell line that does not express TRAF3 and thus has constitutive processing of p100 to p52. The clinical and therapeutic consequences of this finding and its frequency in other tumor types are currently the focus of further investigation. In conclusion, the abnormalities identified in this study represent the first mutations identified that cause constitutive NF-kB activation in MM.

Abstract Plasma cell leukemia (PCL) is an aggressive and rare hematological malignancy that can originate either as primary disease (pPCL) or as a leukemic transformation of multiple myeloma (MMLT). We report here on the clinical characteristics, survival and genetic studies of 80 patients with PCL treated at a single institution (including 41 with pPCL and 39 with MMLT) and make comparisons with 439 newly diagnosed cases of multiple myeloma (MM). From our results pPCL presents a decade earlier than MMLT (54.7 vs 65.3 years) and despite substantially poorer clinical and laboratory parameters at presentation (hepatomegaly 32% vs 11%, leukocytes 31.6 vs 20.9, β2M 8.5 vs 4.3) pPCL appears more responsive to conventional combination chemotherapy (VAD, VBMVP or VBAP) than MMLT and is associated with significantly longer survival (median 18.4 vs 3 months). Comparison of pPCL groups treated with combination chemotherapy (n=21) or with other regimens (40% MP, 10% Thal/Dex, 20% other, 30% none)(n=20) identifies no substantial pre-treatment differences between the groups although a higher proportion of patients who received combination chemotherapy subsequently proceeded to stem cell transplantation (30 vs 10%). Importantly, survival of pPCL patients treated initially with combination chemotherapy (median 13.9, mean 27.3 months) was significantly longer compared with patients who did not receive combination chemotherapy (median 5.2, mean 9.9 months)(p=0.035) with 2 long term survivors (> 7 years) in the chemotherapy group. By comparison, patients with MMLT received less active therapy for their leukemic disease than did patients with pPCL (21% VAD, VBMVP or VBAP; 18% MP). Treated MMLT patients showed selection bias for younger age (60.9 vs 66.4 years) and lack of bone disease (0 vs 65%)(p<0.01); however despite this, median survival was disappointingly short for MMLT patients in the treatment group and was not significantly improved compared with non-treated patients (2.3 vs 0.8 months)(p=0.34). Assessment of novel therapies in PCL is therefore urgently required. Karyotype analysis and targeted genetic studies demonstrate that IgH translocations are present with high frequency in both pPCL and MMLT (71 vs 86%) compared with MM (~50%). Notably, IgH translocation in pPCL is almost exclusively targeted at chromosome 11 (cyclin D1) belying its importance in establishing the phenotype. IgH translocation in MMLT is primarily to chromosome 11 [71%], but also targets chromosomes 4 (FGFR3/MMSET) [13%] and 16 (cMaf) [20%], recapitulating MM. Abnormalities of chromosomes 3,5,7,9,11,13,15 and 19 are present equally in all 3 disorders. Deletion of 17p13 (p53) shows strong selection pressure in the leukemias (pPCL 53.8%, MMLT 48.8%, MM 10.7%) and is complemented by p53 mutation (23%). Notably, pPCL tumors show lower rates of Ras mutation (12 vs 40%) and p14 (0 vs 31%) or p16 (25 vs 40%) promoter methylation than MMLT. Together these results therefore indicate that pPCL and MMLT are fundamentally different plasma cell disorders with distinctive biology, genetic abnormalities and treatment responses.

The median survival in primary systemic (AL) amyloidosis is less than 18 months. No published series of patients with AL amyloidosis have reported survival of more than 10 years. The records of all Mayo Clinic patients with a diagnosis of AL amyloidosis between January 1, 1966 and March 1, 1987 were reviewed. Patients with secondary amyloidosis, familial amyloidosis, senile systemic amyloidosis, and localized amyloidosis were excluded. During the 21 years of the study, 841 patients with AL amyloidosis were seen. Of these, 29 were excluded because the diagnosis was made at autopsy, and 2 others were excluded because no follow-up data were available. Actuarial survival for the 810 patients was 51% at 1 year, 16% at 5 years, and 4.7% at 10 years. Thirty patients survived for 10 years or more after the histologic diagnosis of AL amyloidosis; all received alkylating-agent therapy. In 14 patients, the monoclonal protein disappeared from the serum or urine. Of 10 patients with nephrotic syndrome, 4 had an objective response. Congestive heart failure, older age, creatinine value of 2 mg/dL or more, bone marrow plasma cell value of 20% or more, platelet count of 500 × 109/L or less, and the presence of peripheral neuropathy were underrepresented in the 10-year survivors and are unfavorable prognostic features. Five percent of patients with AL amyloidosis survived for 10 years or more.

Abstract Background: Multiple myeloma remains incurable with current approaches and newer therapies are needed to improve the outcome of these patients. While monoclonal antibody based therapies have been successful in some of the hematological malignancies, such approaches have had limited efficacy in the setting of myeloma. Thymoglobulin (polyclonal rabbit antithymocyte globulin, Genzyme) (Thymo) has been extensively evaluated in the setting of allogeneic blood and marrow transplantation and solid organ transplants. Given the polyclonal nature of this product, with antibodies against different B cell antigens, we evaluated the in vitro and in vivo activity of Thymo in myeloma. Methods: MM cell lines were cultured in RPMI 1640 containing 10% fetal bovine serum supplemented with L-Glutamine, penicillin, and streptomycin. The KAS-6/1 cell line was also supplemented with 1 ng/ml IL-6. Cytotoxicity following drug treatment was measured using the MTT viability assay. Apoptosis was measured by flow cytometry using Annexin V/PI in cell lines and Apo 2.7 in primary patient plasma cells. Shifts in expression of a variety of different B cell and plasma cell antigens were examined on several different myeloma cell lines following Thymo treatment in order to identify the potential antigenic targets. In vivo activity of thymo was evaluated in a SCID plasmacytoma model injected with RPMI myeloma cell lines. Results: rATG was cytotoxic in vitro to several MM cell lines (RPMI 8226, U266, OPM1, OPM2) including the IL-6 dependent cell line Kas6/1 with LC50 of around 1 mg/mL. Additionally, thymo was cytotoxic MM cell lines resistant to conventional agents such as doxorubicin (Dox40), melphalan (LR5) and dexamethasone (MM1R). Thymo induced apoptosis in MM cell lines and in patient derived primary myeloma cells. When tested in combination with other anti-myeloma agents an additive effect was seen with doxorubicin, PS341 and melphalan. Using competitive flow cytometry, we identified CD138, CD38, Cd45, CD126, CD49d (VLA4), as well as CD20 as antigens likely to be targeted by Thymo. Tumor bearing mice injected with Thymo at two different doses (5 mg/kg and 10 mg/kg for five days) had significantly delayed tumor growth compared to non-injected mice, and this translated into a better survival for these mice. Mice receiving 10 mg/kg dose had a slower tumor growth compared to 5 mg/kg dose (Figure). Conclusions: Thymoglobulin has promising in vitro and in vivo activity in the setting of myeloma. These studies will provide the rational for future clinical development of this agent in myeloma alone or in combination with other agents. Based on these results, we are in the process of initiating a clinical trial combining Thymo with Melphalan. Figure Figure

Abstract Background: Renal insufficiency of varying severity including end stage renal disease requiring dialysis is often a presenting manifestation of multiple myeloma (MM). While many patients (pts) improve following initiation of therapy for MM, a considerable number of pts proceed to stem cell transplant with less than optimal renal function. It is not clear whether the outcome of their transplants differs from pts with normal renal function. Methods: The MM transplant database was searched to identify pts with a Creatinine clearance (Crcl) of less than 50 ml/min/m2 (study cohort). These pts were then matched to two pts each with a clearance of ≥ 50 ml/min/m2 (control cohort), based on cytogenetic abnormalities (normal vs. abnormal), circulating plasma cells (yes vs. no), age at transplant, % of plasma cells at transplant, plasma cell labeling index, time to transplant from diagnosis and the disease status at transplant, the factors used in that order of importance. Results: Eighty pts with a Crcl < 50 ml/min were identified and matched to 160 pts with Crcl ≥ 50 ml/min. The pts were matched for the above factors and the two groups were similar in terms of their other baseline features except CRP and B2M, both of which were lower in the control group. Pts with reduced renal function were more likely to receive dose reduced melphalan for conditioning (32.5%) compared to the control group (2%; P < 0.0001). The outcomes from the stem cell transplant were similar in both the groups. 96% of pts obtained an objective response to stem cell transplant in each of the groups with no difference in the time to response; and a complete response was seen in 38.5% and 36.6% of the study and control cohorts respectively (P=NS). The median post transplant progression free survival was 18.2 months and 18.4 mos respectively for the study cohort and the control group (P=0.4). However, the median overall survival from transplant was shorter for the study cohort (30.7 mos vs. 60 mos for the controls; P = 0.007; Figure). The time to platelet and neutrophil engraftment was not different between the groups. In terms of transplant related toxicity, the median days hospitalized was higher in the study group (5 days vs. 9.5 days; P=0.003) as was the incidence of grade 3 and 4 mucositis (8% vs. 23%; P= 0.0008). Six pts (7.5%) had treatment related deaths in the study group compared to 3 pts (2%) among the controls (P=0.03), the majority of the deaths being infection related. Conclusion: Here we demonstrate that pts with MM and reduced renal function derive disease free survival comparable to those with normal renal function, despite the increased use of reduced dose Melphalan for conditioning. The toxicity is clearly increased in the presence of abnormal renal function. Interestingly, the overall survival was inferior among the pts with reduced renal function. One possible explanation for this observation is the decreased availability of novel therapies for salvage among pts with reduced renal function as many of them would not be eligible for clinical trials due to reduced renal function. Figure Figure