Survival rates with tandem transplants

Superior 12-year survival after at least 4-year continuous remission with tandem transplantations for multiple myeloma.

Barlogie B, Zangari M, Bolejack V, Hollmig K, Anaissie E, van Rhee F, Pineda-Roman M, Mohiuddin A, Crowley J, Tricot G.

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, 72205, USA. barlogiebart@uams.edu

BACKGROUND: Complete response has been considered a surrogate for favorable long-term outcome in multiple myeloma. Data on the impact of the duration of response on prognosis are lacking.

PATIENTS AND METHODS: Of the 899 patients enrolled in Total Therapy trials (Total Therapy 1, N = 231; Total Therapy 2, N = 668), 254 survived for > 5 years. The prognostic impact of continuous (Rc) versus discontinuous (Rd) 4-year remission after 5-year survival was examined along with laboratory features present at baseline and at 5 years.

RESULTS: Most baseline prognostic features were evenly distributed among Rc and Rd groups; however, a greater proportion of Rc patients were enrolled in Total Therapy 2 (60%) compared with Rd (19%; P < 0.001). Twelve-year survival (7 years after the 5-year landmark) was 66% with Rc and only 30% with Rd. Hypodiploidy and deletion 13, present in 24 patients at baseline, were associated with a 12-year survival of only 20%. Among the 200 patients lacking these cytogenetic abnormalities, Rc (n = 141) defined a superior 12-year survival rate of 70% versus 35% among those with Rd (n = 59). Initial quality of response (complete response) or having received the scheduled tandem transplantations did not affect post-5-year survival.

CONCLUSION: Five-year Rc appears to be an important prerequisite for prolonged subsequent overall survival.

MMRC Scientific Agenda Priority Research Areas

The MMRF and MMRC identified three priority research areas that are critical in bringing new therapies to patients and in advancing our understanding of the disease.

• Genomics, with research efforts focused on the identification and validation of new druggable targets for myeloma
• Compound and Target Validation and Prioritization, with research efforts focused on the validation of existing compounds and moving these onward into early-stage clinical trials
• Clinical Trials and Correlative Sciences, with research efforts focused on the design and implementation of early-stage clinical trials to advance promising treatments into the clinic where patients can benefit

All of these research programs are now underway.

Warfarin decreases incidence of VTE in Multiple Myeloma

Low-Dose Warfarin Decreases Incidence of Thalidomide-Associated Venous Thromboembolism in Patients With Multiple Myeloma: Presented at EHA

Low dose warfarin (Coumadin) provides protection against thalidomide-associated venous thromboembolism (VTE) in patients with multiple myeloma, according to results of a study presented at the European Hematology Association (EHA) in June.

For multiple myeloma, VTE remains a potential side-effect of thalidomide use, particularly when combined with other agents, such as dexamethasone and doxorubicin.

The prophylaxis treatment used against thalidomide-associated VTE was 1 mg warfarin for body weights <70 kg, and 2 mg warfarin for greater than or equal to 70 kg.

With the use of warfarin in these patients, 5 cases (6.6%) of VTE have been seen so far in this cohort. This represents a significant decrease in incidence when compared to historic controls, which have shown substantial increases in VTE occurrence (up to 26%) with the combination of thalidomide and other therapeutic agents.

Weight-adjusted, low-dose warfarin appears to be a convenient, patient-friendly, and cost-effective method for VTE prophylax, but requires confirmation through a randomised study.

[Presentation title: Low-Dose Warfarin Decreases the Incidence of Thalidomide (T)-Associated Venous Thromboembolism (VTE) in Patients (Pts) With Multiple Myeloma (MM). Abstract 0901]

Update: PXD101

CuraGen Corporation (Nasdaq: CRGN) and TopoTarget A/S (Copenhagen Stock Exchange: TOPO) announced today the initiation of patient dosing in a Phase II clinical trial evaluating the activity of PXD101, a small molecule histone deacetylase (HDAC) inhibitor, for the treatment of mesothelioma. This trial is being sponsored by the National Cancer Institute (NCI) under a Clinical Trials Agreement with CuraGen for the clinical development of PXD101.

PXD101 is a promising small molecule HDAC inhibitor being investigated for its role in the treatment of a wide range of solid and hematologic malignancies either as a single-agent, or in combination with other active anti-cancer agents, including 5-fluorouracil (5-FU), carboplatin, paclitaxel and Velcade(R) (bortezomib) for Injection. HDAC inhibitors represent a new mechanistic class of anti-cancer therapeutics that target HDAC enzymes and have been shown to: arrest growth of cancer cells (including drug resistant subtypes); induce apoptosis, or programmed cell death; promote differentiation; inhibit angiogenesis; and sensitize cancer cells to overcome drug resistance when used in combination with other anti-cancer agents.

PXD101 is currently being evaluated in multiple clinical trials as a potential treatment for multiple myeloma, T-cell lymphoma, and colorectal and ovarian cancers. In August 2004, CuraGen signed a Clinical Trials Agreement with the NCI under which the NCI will sponsor several clinical trials to investigate PXD101 for the treatment of various cancers, both as a single-agent and in combination chemotherapy regimens.

ThaDD

The addition of pegylated liposomal doxorubicin to the combination of thalidomide and dexamethasone appears to improve outcomes in patients with advanced multiple myeloma.

Laura Corvatta, MD, co-investigator and physician, hematology clinic, United Hospitals of the Polytechnic University of Ancona, Ancona, Italy, presented the results of a retrospective, case-matched study on June 16 at the 2006 Congress of the European Hematology Association.

The overall response rate (including minimal response) for ThaDD was significantly greater than for Thal-Dex (87% vs 64%; P < .01). In particular, there were significantly better qualities of response for ThaDD over Thal-Dex, respectively, for partial response or better (76.6% vs 59.6%, P = .077); very good partial response or better (36.2% vs 14.9%, P = .018), and complete plus near complete response (29.8% vs 10.6%, P = .021).

Median progression-free survival was significantly longer for ThaDD, at 22 months versus 11.5 months (36% vs 13%; P = .0008), as was the median event-free survival of 21 months versus 11.5 months (28% vs 13%; P = .0077). Overall survival was not reached in the ThaDD group, showing a trend in favor of this treatment (not reached vs 23.5 months; 52% vs 26% at 3 years; P = .0511).

The toxicity profiles for the ThaDD and Thal-Dex combinations showed significantly greater grade 3/4 neutropenia (25% vs 0%, respectively; P < .0001) and grade 3/4 infections (23% vs 0%; P < .0001). The researchers also observed a trend towards lower grades of peripheral neuropathy with the ThaDD regimen (grade 1, 19% vs 6.5%; grade 2, 6.5% vs 21%; grade 3, 2% vs 0%; P = .0510).

However, Dr. Corvatta noted that the addition of ciprofloxacin prophylaxis to the ThaDD regimen reduced infections to <10%.

"The main message is that ThaDD in combination with chemotherapy is superior to thalidomide alone or in combination with dexamethasone," she said, and noted that the increased infections seen with ThaDD were manageable and largely preventable with adequate prophylaxis.

ASCO: Revlimid boosts survival in multiple myeloma

Revlimid improves survival in previously treated patients with multiple myeloma by at least a year compared with those taking standard treatment, according to data released at ASCO.

Data from a late-stage or Phase III clinical trial presented at the annual meeting of the American Society of Clinical Oncology (ASCO) showed that patients who took Revlimid plus chemotherapy lived at least a year longer than those who took chemotherapy plus a placebo.

Results from the trial, conducted in North America, showed that in the placebo group about half the patients had died within two years, the median point for that study.

By contrast, more than half the patients in the Revlimid group are still alive after three years, which means the median point in that group has not yet been reached.

Results from a similarly sized trial in Europe, which started six months later, appear to track those in the North American trial, according to Celgene.

Revlimid, which is currently approved to treat a group of blood disorders known as myelodysplastic syndromes, is expected shortly to also be approved as a treatment for multiple myeloma.

Data presented at the ASCO meeting last year showed that patients with advanced multiple myeloma who were given Revlimid in combination with chemotherapy took an average of 15 months to relapse compared with five months for patients taking chemotherapy plus a placebo.

Revlimid is expected to be approved as a treatment for patients who have failed other therapies, including Celgene's drug Thalomid, which is currently the standard of care for multiple myeloma

ASCO: Clarithromycin, lenalidomide and dexamethasone as primary treatment of myeloma

Abstract No: 7545

Citation: Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 7545

Authors: R. Niesvizky, D. S. Jayabalan, J. R. Furst, H. J. Cho, R. N. Pearse, F. Zafar, R. W. Lent, J. Tepler, M. W. Schuster, J. P. Leonard, M. Coleman

Abstract:

Background: Lenalidomide (Revlamid [R]) is the leading clinical compound in a new group of drugs called IMiDs. Our group demonstrated that clarithromycin (Biaxin [Bi]) augments tumor mass reduction and improves responses in patients (pts) receiving low-dose thalidomide and/or dexamethasone (D). We report the results of the combination of Bi plus R plus D (BiRD) in newly diagnosed MM.

Methods: A phase II trial designed to accrue 50 pts. A 2-stage design rejects a CR rate of <>30%). Between Nov. 2004 and Jan. 2006, 46 pts have been accrued of which 40 pts are eligible for evaluation. R is given po at 25 mg daily on days 1-21 of a 28-day cycle. D is given po at 40 mg once weekly. Bi is given po at 500 mg bid. Pts receive low dose aspirin (ASA)(81mg) qd as thrombosis (TE) prophylaxis. Responses are defined according to modified EBMTR criteria. Analysis is by intent-to-treat. Patient Selection: Median age: 62.5 years (36-80), Male/Female 25/15, Hgb: 10.6 g/dL (7.2-15.1), Plt 234 k/uL (51-526), β2m: 3 mg/L (0.8-12.8), CRP: 0.6 mg/dL (0.12-14.2), creat: 1.1 mg/dL (0.6-3.1), albumin 3.5 g/dL (2.3-4.9). SD stage IIIa: 48%, stage IIIb: 10% and IIa: 42%. ISS stage I: 50%, stage II: 25% and stage III: 25%. Cytogenetics and FISH: trisomy 11 (10 pts), tetrasomy 11 (3 pts), del13q14 (14 pts), t (4,14) (1pt), t (11,14) (3 pts).

Results: Of the 40 evaluable pts, 38 (95%) have achieved an objective response (>PR) within 3-4 months of Rx with the remaining pts continuing to respond. Seventeen pts (43%) had a >90% reduction of the initial paraprotein. Nearly one third of pts have achieved either a CR (10/40) or a nCR (2/40-continuing on Rx). CR has been confirmed in all pts by normalization of free light chain levels and ratio. The remaining 26 pts (65%) achieved a PR. Of those pts who achieved a PR, 5/26 pts (19%) had >90% reduction in the initial paraprotein. Nineteen pts have experienced grade >3 adverse events. Heme toxicities: anemia (11%), neutropenia (9%) and thrombocytopenia (9%). Non-heme toxicities (NHT) include TE in 7 patients (15%) 2 of them fatal. Four of the TE events were while off ASA. Other NHT include myopathy (6%), GI (4%), and mood (4%).

Conclusions: BiRD therapy is a safe and highly effective primary therapy for symptomatic, treatment-naïve MM.

ASCO: Velcade in untreated patients

Abstract No: 7504

Citation: Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 7504

Author(s): K. Anderson, P. Richardson, A. Chanan-Khan, R. Schlossman, N. Munshi, A. Oaklander, L. Heffner, H. Hassoun, D. Avigan, A. Amato

Abstract:

Background: Bortezomib is effective in relapsed and/or refractory MM. This trial evaluated its efficacy and safety as monotherapy in previously untreated MM.

Methods: Pts with untreated, symptomatic MM were eligible, with pts receiving concomitant steroids, platelet count <>9/L, or grade > 2 peripheral neuropathy [PN] excluded. Endpoints included response rate (RR), time to progression, safety, incidence/severity of PN, and effect of dose modifications on PN. Pts received bortezomib 1.3 mg/m² (d1, 4, 8, 11 every 21d) for 8 cycles. Comprehensive neurologic evaluation including electrophysiologic testing [NCS] and skin biopsy was performed in a subset of pts (n = 34).

Results: Sixty-six pts (47% with stage III MM) were treated and 60 pts are evaluable for response, with an overall RR of 38% (CR 10%, PR 28%). PN was reported in 55% (36/65) pts (23 grade 1, 12 grade 2). One pt with grade 3 PN was discontinued. Other common treatment-associated adverse events reported to date include grade 1-2 fatigue in 21% (6/29), and rash in 17% (5/29) pts. Preliminary analysis shows PN improved or resolved in 75% (6/8 pts, with available follow-up data) with dose reduction. At baseline, small-fiber neuropathy (SFN) was seen in 52% (17/33) and large fiber axonal neuropathy (LFN) occurred in 9% (3/34) pts by NCS. SFN worsened in 41% (7/17) pts with baseline SFN. After completion of treatment, new SFN was seen in 33% (8/24) pts and LFN in 17% (4/24) pts by NCS.

Conclusion: Single agent bortezomib is active in newly diagnosed MM pts (CR 10%), has manageable toxicity and offers a steroid-sparing approach. Underlying SFN appears more common in MM than previously appreciated and can also develop during bortezomib therapy, with symptomatic PN improving with dose modification.

Myeloma and bone disease: "the dangerous tango"

Epstein J, Walker R.

University of Arkansas Medical Sciences College of Medicine, Little Rock, AR 72205, USA.

Osteolytic bone disease is the most debilitating manifestation of myeloma. However, myeloma-induced effects on the bone-active cells in the bone marrow are more than just a manifestation of disease-the myeloma derives essential support from the changed balance between bone-forming and -resorbing cells. This observation has lead to the notion that effective control of myeloma bone disease by reducing osteoclast activity and restoring osteoblast activity will contribute to long-term control of myeloma progression. Unlike osteolysis associated with other tumors that metastasize to bone, myeloma-associated lytic lesions are unique in that they do not repair even after many years in complete remission, reflecting a total loss of osteoblastic activity in areas of myeloma foci, apparently induced by the myeloma. Advances in imaging technology including positron emission tomography-computed tomography scanning allows accurate detection of lytic lesions and the monitoring of treatment effects. Effective antimyeloma therapy combined with anti-osteoclast drugs can halt the progression of osteolysis; in severe cases with vertebral compression fractures, effective physical support in the form of vertebroplasty or kyphoplasty is required for control of function, pain, and stature. Fractures of the long bones are usually treated by intramedullary rod placement. New approaches to enhance osteoblast activity while controlling osteoclast activity currently under investigation may prove effective in controlling lytic bone disease and myeloma progression.

PMID: 16728940 [PubMed - in process]