Serum BCMA levels predict outcomes in MGUS and smoldering myeloma patients.

Soluble BCMA (sBCMA) levels are elevated in monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). However, the association between sBCMA levels and prognosis in MGUS and SMM has not been studied. We retrospectively analyzed sBCMA levels in stored samples from 99 MGUS and 184 SMM patients. Baseline sBCMA levels were significantly higher in MGUS and SMM patients progressing to MM during clinical follow up. When stratified according to the median baseline sBCMA level for each cohort, higher levels were associated with a shorter PFS for MGUS (HR 3.44 comparing sBCMA ≥77 vs <77 ng/mL [95% CI 2.07-5.73, p < 0.001] and SMM (HR 2.0 comparing sBCMA ≥128 vs <128 ng/mL, 95% 1.45-2.76, p < 0.001) patients. The effect of sBCMA on PFS was similar even after adjusting for the baseline MGUS or SMM risk stratification. We evaluated paired serum samples and found that sBCMA increased significantly in MGUS and SMM patients who eventually progressed to MM, whereas among MGUS non-progressors the sBCMA level remained stable. While our results require independent validation, they suggest that sBCMA may be a useful biomarker to identify MGUS and SMM patients at increased risk of progression to MM independent of the established risk models.

Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy.

In this open-label, intra-patient phase I/II trial, bortezomib was replaced with carfilzomib (escalated from 20 to 45 mg/m(2) on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle) for multiple myeloma (MM) patients who progressed while on or within 12 weeks of receiving a bortezomib-containing combination regimen. Study objectives included determination of the maximum tolerated dose (MTD), overall response rate (ORR), clinical benefit rate (CBR), time to progression, time to response, duration of response, progression-free survival and overall survival (OS). Of 38 registered patients, 37 were treated and evaluable for efficacy and safety. Thirty-one carfilzomib-based regimens using 14 different drug combinations were tested. One regimen (carfilzomib (45 mg/m(2)), ascorbic acid (1000 mg) and cyclophosphamide (2.2 mg/kg)) reached MTD. ORR and CBR were 43.2 and 62.2%, respectively. Median progression-free survival, time to progression and OS were 8.3, 9.9 and 15.8 months, respectively. Hematologic adverse events (AEs; ⩾grade 3) included lymphopenia (35.1%), thrombocytopenia (24.3%), anemia (10.8%) and neutropenia (10.8%). Nonhematologic AEs (⩾grade 3) included fever (5.4%) and hypokalemia (5.4%). These results demonstrate that replacing bortezomib with carfilzomib is safe and can be effective for MM patients failing bortezomib-containing combination regimens. This trial was registered at http://www.clinicaltrials.gov (#NCT01365559).

A phase 2 study of pegylated liposomal doxorubicin, bortezomib, dexamethasone and lenalidomide for patients with relapsed/refractory multiple myeloma.

Our previous studies have shown that lowering the dose of pegylated liposomal doxorubicin (PLD) and bortezomib in combination with intravenous dexamethasone on a longer 4-week cycle maintained efficacy and improved tolerability in both previously untreated and relapsed/refractory (R/R) multiple myeloma (MM) patients. Lenalidomide has shown efficacy in combination with bortezomib and dexamethasone but this combination has been poorly tolerated. We conducted this phase 2 study (clinicaltrials.gov identifier: NCT01160484) to evaluate whether a longer 4-week schedule using modified doses and schedules of IV dexamethasone (40 mg), bortezomib (1.0 mg/m(2)) and PLD (4.0 mg/m(2)) administered on days 1, 4, 8, and 11 with lenalidomide 10 mg daily on days 1-14 (DVD-R) would be effective and tolerated for patients with R/R MM. A total of 40 heavily pretreated patients were enrolled and 84.6% showed clinical benefit (complete response, 20.5%; very good partial response, 10.3%; partial response, 17.9%; minimal response, 35.9%) to the combination regimen. An additional 10.3% showed stable disease and 5.1% progressed while on study. The regimen was well tolerated, with a low incidence of adverse events such as fatigue (40%), thrombocytopenia (35%), neutropenia (35%), anemia (30%), peripheral neuropathy (25%) and pneumonia (15%). Thus, the DVD-R regimen is well tolerated and produces high response rates for patients with R/R MM.

Hematopoietic cell transplantation for primary plasma cell leukemia: results from the Center for International Blood and Marrow Transplant Research.

There are limited data on hematopoietic cell transplantation (HCT) in primary plasma cell leukemia (pPCL), an aggressive plasma cell disorder. We report outcomes of 147 patients with pPCL receiving autologous (n=97) or allogeneic (n=50) HCT within 18 months after diagnosis between 1995 and 2006. Median age was 56 years and 48 years for autologous HCT and allogeneic HCT, respectively. Progression-free survival (PFS) at 3 years was 34% (95% confidence interval (CI), 23-46%) in the autologous group and 20% (95% CI, 10-34%) in the allogeneic group. Cumulative incidence of relapse at 3 years was 61% (95% CI, 48-72%) in the autologous group and 38% (95% CI, 25-53%) in the allogeneic group. Overall survival (OS) at 3 years was 64% (95% CI, 52-75%) in the autologous group and 39% (95% CI, 26-54%) in the allogeneic group. Non-relapse mortality (NRM) at 3 years was 5% (95% CI, 1-11%) in the autologous group and 41% (95% CI, 28-56%) in the allogeneic group. The encouraging OS after autologous HCT, establishes the safety and feasibility of this consolidative treatment option after initial induction therapy for pPCL. Allogeneic HCT, although associated with a significantly lower relapse rate, carries a much higher risk of NRM and no OS benefit.

Interference with nuclear factor kappa B and c-Jun NH2-terminal kinase signaling by TRAF6C small interfering RNA inhibits myeloma cell proliferation and enhances apoptosis.

The tumor necrosis factor receptor (TNFR)-associated factor (TRAF) family of six adaptor proteins (TRAF1-6) links the TNFR superfamily to the nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1) transcriptional activators. Unlike other TRAFs, TRAF6 is also involved in Toll-like/interleukin (IL)-1 receptor (TIR) signal transduction. Thus, inhibition of TRAF6 function could interrupt both CD40 (TNFR family) and IL-1 growth signals, pathways critical to myeloma proliferation. To block TRAF6-mediated IL-1 signaling, we constructed small interfering RNA (siRNA) against TRAF6. We found that siRNA targeting the TRAF6 C-terminal (siTRAF6C) receptor interaction domain specifically reduced only TRAF6 protein expression, without affecting TRAF2 or 5 levels, and substantially interfered with IL-1-induced NF-kappaB and c-Jun/AP-1 activation. Inhibition by siTRAF6C was concentration-dependent. SiTRAF6C also significantly reduced myeloma proliferation and enhanced apoptosis in a similar dose-dependent fashion in vitro. More importantly, marked siTRAF6C growth inhibition was detected in vivo when these cells were implanted into the bone marrow of irradiated normal mice. In contrast, introduction of siRNA derived from the TRAF6 Zn-finger domain or an irrelevant siRNA construct failed to alter cell growth or cell death. These studies suggest that TRAF6 may be a new molecular target to block cell signal transduction important for the survival and proliferation of multiple myeloma cells.

The role of nuclear factor-kappaB in the biology and treatment of multiple myeloma.

Increased nuclear factor (NF)-kappaB activity is associated with enhanced tumor cell survival in multiple myeloma (MM). The function of NF-kappaB is inhibited through binding to its inhibitor, IkappaB. Release of activated NF-kappaB follows proteasome-mediated degradation of IkappaBalpha resulting from phosphorylation of the inhibitor and finally conjugation with ubiquitin. We report that myeloma tumor cells show enhanced NF-kappaB activity. In addition, these patients possess polymorphisms of IkappaBalpha at sites important in the degradation of the inhibitor protein. Exposure of myeloma cells to chemotherapy leads to an increase in IkappaBalpha phosphorylation and reduces the levels of this inhibitor of NF-kappaB function. Chemoresistant myeloma cell-lines have increased NF-kappaB activity compared to sensitive lines. An inhibitor of NF-kappaB activity, the proteasome inhibitor PS-341 (Millenium Inc, Boston, MA), showed consistent antitumor activity against chemoresistant and sensitive myeloma cells. The sensitivity of chemoresistant myeloma cells to chemotherapeutic agents was markedly increased (100,000- to 1,000,000-fold) when combined with a noncytotoxic dose of PS-341. In contrast, this combination had little growth inhibitory effect on normal hematopoietic cells. Similar effects were observed using a dominant negative super-repressor for IkappaBalpha. These results suggest that inhibition of NF-kappaB with PS-341 may overcome chemoresistance and allow doses of chemotherapeutic agents to be markedly reduced with antitumor effects without significant toxicity.

Frequent demonstration of human herpesvirus 8 (HHV-8) in bone marrow biopsy samples from Turkish patients with multiple myeloma (MM).

In order to investigate the frequency of HHV-8 in MM patients from another geographic location, we obtained fresh bone marrow (BM) biopsies from Turkish patients with MM (n = 21), monoclonal gammopathy of undetermined significance (MGUS) (n = 2), plasmacytoma (n = 1) with BM plasma cell infiltration, various hematological disorders (n = 6), and five healthy Turkish controls. The frequency of HHV-8 was analyzed by polymerase chain reaction (PCR) in two independent laboratories in the USA and in Turkey. Using fresh BM biopsies, 17/21 MM patients were positive for HHV-8 whereas all five healthy controls, and six patients with other hematological disorders were negative. Two patients with MGUS, and one patient with a solitary plasmacytoma were also negative. The data from the two laboratories were completely concordant. Also using primer pairs for v IRF and v IL-8R confirmed the results observed with the KS330233 primers. Furthermore, sequence analysis demonstrated a C3 strain pattern in the ORF26 region which was also found in MM patients from the US. Thus, HHV-8 is present in the majority of Turkish MM patients, and the absence of the virus in healthy controls further supports its role in the pathogenesis of MM.

Zoledronic acid in cancer patients with bone metastases: results of Phase I and II trials.

Zoledronic acid (Zometa, Novartis Pharmaceuticals Corp, East Hanover, NJ) is a new, highly potent bisphosphonate that may provide improved management of skeletal complications in cancer patients with bone metastases. A total of 383 cancer patients with osteolytic bone lesions was evaluated in two phase I studies and one phase II study of zoledronic acid. The phase I studies used two dosing regimens, either a 5-minute monthly intravenous infusion of 0.1 to 8 mg administered for 3 or more months or a single 30 to 60 second intravenous bolus of 1 to 16 mg. Zoledronic acid was well tolerated in the two phase I studies and a maximum tolerated dose was not reached in either study. A dose-dependent decrease in urinary markers of bone resorption was observed with the monthly 5-minute infusion. A single intravenous bolus of doses ranging from 2 to 16 mg zoledronic acid suppressed biochemical markers of bone resorption for up to 8 weeks. The phase II study evaluated a 5-minute infusion of 0.4, 2, or 4 mg zoledronic acid and a 2-hour infusion of 90 mg pamidronate in 280 patients with bone metastases and multiple myeloma or breast cancer. Significantly fewer patients receiving the 2 and 4 mg doses of zoledronic acid or 90 mg pamidronate required radiation therapy to bone than those patients receiving a 0.4 mg dose of zoledronic acid. Only 30% to 35% of patients in the 2 and 4 mg zoledronic acid groups or in the pamidronate group experienced any skeletal related event compared with 46% in the 0.4 mg zoledronic acid group. Adverse events consistent with an acute phase reaction were observed with both bisphosphonates. No new, unexpected adverse events were observed with this novel bisphosphonate. These studies support the further evaluation of zoledronic acid in cancer patients with osteolytic metastases. Doses of 0.4 mg or less are ineffective, while rapid infusion of more than 8 mg may increase the risk of renal dysfunction. A 4 mg dose given as a brief infusion appears to offer an excellent benefit/risk ratio for further evaluation in phase III trials.

New advances in the biology and treatment of myeloma bone disease.

The bisphosphonates provide effective therapy for the skeletal complications of multiple myeloma (MM). Although the earliest bisphosphonates had poor bioavailability and relatively low potency, newer compounds such as pamidronate and zoledronic acid have greater potency. Bisphosphonates block the development of monocytes into osteoclasts and are thought to promote apoptosis of osteoclasts. These agents prevent osteoclasts from moving to the bone surface and seem to inhibit the production of bone-resorbing cytokines such as interleukin-6 (IL-6) by bone marrow stromal cells. In addition, bisphosphonates seem to have a direct antimyeloma effect by inducing apoptosis of malignant plasma cells. The beneficial effects of pamidronate have been demonstrated in a clinical trial setting. Patients who failed to respond to chemotherapy had a slight prolongation of survival and better performance status and quality of life. Ongoing clinical trials with ibandronate and zoledronic acid indicate the latter is 100 to 1,000 times more potent than pamidronate. Biochemical effects of zoledronic acid continue for as long as 8 weeks after a single administration. In a new trial comparing pamidronate and zoledronic acid, 90% of the patients who received zoledronic acid were normocalcemic, compared with 69% of those who received pamidronate at 10 days. In addition, the time to relapse or development of hypercalcemia was shorter for patients receiving pamidronate compared with zoledronic acid.

Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases.

BACKGROUND: This study evaluated the dose-response relation for zoledronic acid, a new generation high potency bisphosphonate, given as a 5-minute infusion in patients with malignant osteolytic disease. METHODS: Two-hundred eighty patients with osteolytic lesions due to metastatic breast carcinoma or multiple myeloma were randomized to double-blind treatment with either 0.4, 2.0, or 4.0 mg of zoledronic acid or 90 mg pamidronate. The primary efficacy endpoint was the proportion of patients receiving radiation to bone. Other skeletal-related events, bone mineral density (BMD), bone markers, Eastern Cooperative Oncology Group performance status, pain and analgesic scores, and safety also were evaluated. RESULTS: Zoledronic acid at doses of 2.0 and 4.0 mg and pamidronate at a dose of 90 mg each significantly reduced the need for radiation therapy to bone (P < 0.05) in contrast with 0.4 mg zoledronic acid, which did not. Skeletal-related events of any kind, pathologic fractures, and hypercalcemia also occurred less frequently in patients treated with 2.0 or 4.0 mg zoledronic acid or pamidronate than with 0.4 mg zoledronic acid. Increases in lumbar spine BMD (6.2-9.6%) and decreases in the bone resorption marker N-telopeptide (range, -37.1 to -60.8%) were observed for all treatment groups. Skeletal pain, fatigue, nausea, vomiting, and headache were the most commonly reported adverse events. Adverse events were similar in nature and frequency with zoledronic acid and pamidronate. CONCLUSIONS: A 5-minute infusion of 2.0-4.0 mg zoledronic acid was at least as effective as a 2-hour 90-mg pamidronate infusion in treatment of osteolytic metastases. A 0.4-mg dose of zoledronic acid was significantly less effective. Both zoledronic acid and pamidronate were well tolerated.

A phase I dose-ranging trial of monthly infusions of zoledronic acid for the treatment of osteolytic bone metastases.

Bisphosphonates are potent inhibitors of bone resorption and provide a therapeutic benefit for patients with bone metastases. Zoledronic acid is a highly potent, nitrogen-containing bisphosphonate. In the present trial, we assessed the safety and tolerability of increasing doses of zoledronic acid and its effects on urinary markers of bone resorption in cancer patients with bone metastases. Fifty-nine cancer patients with bone metastases were enrolled sequentially into one of 8 treatment groups in the core protocol. Each patient received a 5-min i.v. infusion of 0.1, 0.2, 0.4, 0.8, 1.5, 2, 4, or 8 mg zoledronic acid monthly for 3 months. Patients were monitored for clinical findings, adverse events, electrocardiograms, markers of bone resorption, as well as routine hematology, blood chemistries, and urinalysis. Thirty patients who demonstrated a radiographic response to treatment or stable disease in the core protocol were enrolled in a humanitarian extension protocol and continued to receive monthly infusions. Zoledronic acid was well tolerated at all dose levels. Adverse events reported by >10% of patients included skeletal pain, nausea, fatigue, upper respiratory tract infection, constipation, headache, diarrhea, and fever. Three patients in the core protocol and one patient in the extension protocol experienced grade 3 skeletal pain, "flu-like" symptoms, or hypophosphatemia, which were possibly related to treatment; all recovered completely. Adverse events were reported with similar frequency across all of the dosage groups. Zoledronic acid resulted in sustained, dose-dependent decreases in urinary markers of bone resorption. Zoledronic acid was safe and well tolerated and demonstrated potent inhibition of bone resorption.

A Phase I, open label, dose ranging trial of intravenous bolus zoledronic acid, a novel bisphosphonate, in cancer patients with metastatic bone disease.

BACKGROUND: Bone metastases typically are associated with osteolytic bone destruction, resulting in bone pain, pathologic fractures, spinal cord compression, and hypercalcemia. Bisphosphonates are potent inhibitors of normal and pathologic bone resorption and represent a significant therapeutic improvement in the management of patients with lytic bone metastases. Zoledronic acid is a new-generation, highly potent, nitrogen-containing bisphosphonate that to the authors knowledge is the most potent inhibitor of bone resorption currently in clinical trials. The objectives of the current study were to assess the safety and tolerability of increasing doses of zoledronic acid and to determine its activity with respect to reducing biochemical markers of bone resorption in cancer patients with bone metastases. METHODS: Forty-four cancer patients with bone metastases or primary bone lesions were enrolled sequentially into 1 of 5 fixed ascending-dose treatment groups. Each patient received a single intravenous bolus injection of 1, 2, 4, 8, or 16 mg of zoledronic acid over 30-60 seconds. Patients were monitored for 8 weeks for the evaluation of clinical findings, adverse events, vital signs, electrocardiograms, markers of bone resorption, and urinary N-acetyl-beta-D-glucosaminidase. RESULTS: Zoledronic acid was safe and well tolerated at all dose levels tested. Commonly reported adverse events included bone pain, fever, anorexia, constipation, and nausea, which were experienced by a similar proportion of patients in each treatment group. Seven patients reported serious adverse events, none of which appeared to be related to the study drug. Zoledronic acid effectively suppressed biochemical markers of bone resorption, including the highly specific markers N-telopeptide and deoxypyridinoline, for up to 8 weeks in the 2-16-mg dose groups and for a shorter duration in the 1-mg group. CONCLUSIONS: In the current study, zoledronic acid was safe and well tolerated and demonstrated potent inhibition of bone resorption. The authors believe it may improve the treatment of metastatic bone disease.

Bone disease in myeloma.

The major clinical manifestation of multiple myeloma results from osteolytic bone destruction. The only currently Food and Drug Administration-approved drug for the treatment of the bony complications of multiple myeloma is monthly intravenous pamidronate at a dose of 90 mg infused over 4 hours. Recent studies have shown the safety of 2-hour infusions. A randomized trial comparing pamidronate to placebo continued to show benefits throughout the 21-month trial. Although the duration of therapy has not been firmly determined, it is likely that discontinuation of this drug will be met by enhanced bone loss and an increased risk of bony complications for these patients. Thus, it is recommended that the drug be continued indefinitely. Support for this recommendation also comes from the reduced bone density observed in women with postmenopausal osteoporosis following the withdrawal of bisphosphonate treatment. Recent attempts to give higher doses, more frequent infusions (every 2 weeks or less), or more rapid infusions (1 hour or less) of pamidronate have occasionally been associated with albuminuria and azotemia. These modifications should therefore be avoided. Importantly, the drug can be safely administered at 90 mg monthly to patients with poor renal function. The use of pamidronate for myeloma patients without lytic bone involvement or with Durie-Salmon stages I or II disease has not been evaluated. However, it is recognized that most patients with earlier stages of disease or without lytic bone involvement also develop bony complications. There is no reason to believe that these patients would not benefit from monthly intravenous infusions of pamidronate. The potential antimyeloma effect of this agent is another reason to administer this drug in these types of patients. Thus, it is our practice to administer monthly pamidronate to myeloma patients regardless of stage or bone involvement. However, trials evaluating oral bisphosphonates have produced inconsistent clinical results, probably as a result of the erratic and scanty poor absorption as well as poor oral tolerability of these drugs. Although these oral agents may be useful in some patients, it is impossible to identify which myeloma patients will benefit from orally administered bisphosphonates. The more potent nitrogen-containing bisphosphonate zoledronic acid more effectively reverses hypercalcemia of malignancy than pamidronate, and it appears promising in reducing bone loss in cancer patients. However, its efficacy in preventing skeletal complications is still being evaluated. Many other types of new agents are in early clinical trials, but their efficacy remains unproven at the present time.

Advances in the biology and treatment of myeloma bone disease.

Potential antitumor effects of bisphosphonates are discussed, and trial results of zoledronic acid, a bisphosphonate that recently received FDA approval for the treatment of hypercalcemia of malignancy (HCM), are described. Substitution at two sites on the central carbon in the phosphate-carbon-phosphate backbone has resulted in bisphosphonates increasingly more potent than the first such drug, etidronate disodium. Besides having an antihypercalcemic effect, the nitrogen-containing bisphosphonates pamidronate disodium and zoledronic acid have been shown to have an antitumor effect. Possible mechanisms include inducing apoptosis in tumor cells, inhibiting angiogenesis, and reducing adherence of cancer cells to the bone matrix. Zoledronic acid 4 mg is superior to pamidronate disodium 90 mg in achieving a normal serum calcium concentration, without increased toxicity. Zoledronic acid has a higher response rate, faster onset, and longer duration of action, and is more convenient to administer. Doses of > or = 1.5 mg given every four weeks for three months resulted in sustained reductions in urinary markers of bone resorption. Clinical trial results suggest that zoledronic acid 4 mg is at least as effective as pamidronate disodium 90 mg in preventing skeletal complications of osteolytic disease. Zoledronic acid is superior to pamidronate disodium in treating HCM and more convenient to administer. More research to evaluate its safety and effectiveness at higher doses is needed before its full antitumor potential is realized.

Human herpesvirus 8 open reading frame 26 and open reading frame 65 sequences from multiple myeloma patients: a shared pattern not found in Kaposi's sarcoma or primary effusion lymphoma.

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus, has been implicated in the pathogenesis of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman's disease, and recently multiple myeloma (MM). DNA sequence analyses of HHV-8 suggest that multiple HHV-8 strains exist. We extracted DNA from 24 patients with MM and 3 patients with monoclonal gammopathy of undetermined significance and compared HHV-8 open reading frames (ORFs) 26 and 65 sequences with those derived from patients with KS, PEL, and two HHV-8-positive PEL cell lines KS-1 and BC-1. ORF26 sequence data suggest that MM patients are consistently carriers of HHV-8 strain subtype C3. All MM patients also consistently revealed either a single bp deletion or substitution at position 112197 in ORF65. This unique alteration is not present in patients with KS or PEL or in PEL cell lines. It occurs in the portion of ORF65 that is known to be responsible for a serological response to HHV-8.

The role of human and viral cytokines in the pathogenesis of multiple myeloma.

Multiple myeloma (MM) is characterized by the accumulation of monoclonal plasma cells, a terminally differentiated form of B lymphocyte, in the bone marrow. This disease is most often associated with bone destruction, anemia and renal failure. Besides the malignant plasma cells, it has become clear that nonmalignant cells in the bone marrow also contribute to the development of this malignancy by the release of cytokines. Further support for the importance of the supporting cells comes from our recent finding of the human herpesvirus 8 (HHV-8) in the nonmalignant bone marrow stromal cells from these patients.

Myeloma--the therapeutic challenge.

BACKGROUND: Bone loss--the major clinical manifestation of multiple myeloma--often leads to pathologic fractures, spinal cord compression, hypercalcemia and bone pain. THERAPY AND RESULTS: Analgesics, surgery and radiotherapy may effectively palliate patients with complications from myeloma bone disease, but cannot slow the progressive bone loss. Chemotherapy may reduce tumor burden but has little impact on the underlying bone disease. A dramatic change was the demonstration that intravenous pamidronate could reduce skeletal complications. Importantly, because bisphosphonates lack significant bone marrow suppressive effects they can be administered to other cytotoxic therapy. Laboratory studies show the improved potency of the 3rd-generation bisphosphonate zoledronic acid in its anti-bone resorptive as well as anti-myeloma effects. Phase-I and -II studies evaluating zoledronic acid in myeloma patients show marked and sustained inhibition of bone resorption markers. CONCLUSION: The randomized studies evaluating zoledronic acid have demonstrated its superiority to pamidronate in overcoming tumor-induced hypercalcemia. Results of ongoing phase-III studies will determine its relative safety and efficacy compared to pamidronate.

Lack of serologic association of human herpesvirus-8 (KSHV) in patients with monoclonal gammopathy of undetermined significance with and without progression to multiple myeloma.

Because human herpesvirus-8 (HHV-8) DNA has been found in multiple myeloma (MM) patients by polymerase chain reaction, it was suggested that HHV-8 may play a role in the transformation of monoclonal gammopathy of undetermined significance (MGUS) to MM. Therefore, 362 MGUS sera with and without progression to MM were tested for IgG antibody to HHV-8. Only 7.8% of the MGUS sera contained HHV-8 antibody to lytic proteins, and IgG antibody to HHV-8 latent antigen was even lower than lytic antibody (2.9%). No differences were observed in the distribution of antibody to HHV-8 in sera from MGUS patients who progressed to MM. The seroprevalences of HHV-8 in MGUS (7.8%), MM (5.4%), and healthy donors (5.9%) were similar, thus arguing for the lack of epidemiologic evidence of HHV-8 participation in the pathogenesis of MM. MGUS patients were immune competent in response to Epstein-Barr virus (EBV) infection because 97% contained antibody to EBV virus capsid antigen.

Recent advances in multiple myeloma.

Multiple myeloma is the second most common hematologic malignancy, with approximately 15,000 new cases each year in the United States. Our understanding of the pathophysiology underlying myeloma continues to expand, but the cause of this plasma cell dyscrasia remains unclear. Though controversy remains regarding a possible viral cause of myeloma, evidence suggesting a role for the human herpesvirus-8 is mounting. The roles of cytogenetic abnormalities as well as aberrant angiogenesis and cytokine expression in the etiology of myeloma continue to be explored and may lead to future therapeutic strategies. Transplantation in myeloma is rarely curative but offers clinical benefit not only for young but possibly for older myeloma patients as well. Newer bisphosphonates may offer greater ease of administration, improved efficacy, and possibly even enhanced antitumor effect. Finally, thalidomide offers significant clinical benefit to patients with myeloma previously refractory to multiple agents, and its role in early stages of the disease is under investigation.