Background. Newer systemic therapies have significantly advanced the treatment of multiple myeloma, but additional agents are needed. Bortezomib is a proteasome inhibitor with efficacy in relapsed/refractory multiple myeloma that inhibits tumor angiogenesis, a process that has been implicated in multiple myeloma pathogenesis. Methods. In AMBER("A Randomized, Blinded, Placebo-Controlled, Multicenter, Phase II Study of Bevacizumab in Combination With Bortezomib in Patients With Relapsed or Refractory Multiple Myeloma"), patients with relapsed or refractory multiple myeloma were randomized to receive bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11 of each 21-day cycle) and either placebo or bevacizumab (15 mg/kg on day 1 of each cycle) for up to 8 cycles. At completion, patients in the bortezomib-plus-bevacizumab arm could continue bevacizumab until they developed progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results. The stratified hazard ratio of PFS for the bevacizumab-containing arm (n = 49) relative to the bortezomib monotherapy arm (n = 53) was 0.743 (95% confidence interval [CI], 0.43-1.28; P =.2804); the median PFS was 6.2 months (95% CI, 4.4-8.5 months) and 5.1 months (95% CI, 4.2-7.2 months), respectively; the overall response rates were 51% and 43.4% (P =.4029), respectively; and the median response duration was 6.9 months (95% CI, 4.73-11.83 months) and 6.0 months (95% CI, 4.86-8.31 months), respectively. Frequent adverse events occurred at similar rates across treatment arms, but hypertension, fatigue, and neuralgia occurred more frequently in the bevacizumab-containing arm. Conclusions. The addition of bevacizumab to bortezomib in unselected patients with pretreated multiple myeloma did not result in significant improvements in efficacy outcomes. The combination was well tolerated, and no new safety concerns for either agent were identified. © 2012 American Cancer Society.

Maintenance therapy has become a hot field in myeloma, and it may be particularly relevant in elderly patients because the major benefit results from the initial therapy. We report the results of a randomized comparison of maintenance with bortezomib plus thalidomide (VT) or prednisone (VP) in 178 elderly untreated myeloma patients who had received 6 induction cycles with bortezomib plus either melphalan and prednisone or thalidomide and prednisone. The complete response (CR) rate increased from 24% after induction up to 42%, higher for VT versus VP (46% vs 39%). Median progression-free survival (PFS) was superior for VT (39 months) compared with VP (32 months) and overall survival (OS) was also longer in VT patients compared with VP (5-year OS of 69% and 50%, respectively) but the differences did not reach statistical significance. CR achievement was associated with a significantly longer PFS (P < .001) and 5-year OS (P < .001). The incidence of G3-4 peripheral neuropathy was 9% for VT and 3% for VP. Unfortunately, this approach was not able to overcome the adverse prognosis of cytogenetic abnormalities. In summary, these maintenance regimens result in a significant increase in CR rate, remarkably long PFS, and acceptable toxicity profile. The trial is registered at www.clinicaltrials.gov as NCT00443235.

We assessed efficacy, safety, and reversal of renal impairment (RI) in untreated patients with multiple myeloma given bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide (VMPT-VT) maintenance or bortezomib-melphalan-prednisone (VMP). Exclusion criteria included serum creatinine ≥ 2.5 mg/dL. In the VMPT-VT/VMP arms, severe RI (estimated glomerular filtration rate [eGFR] ≤ 30 mL/min), moderate RI (eGFR 31-50 mL/min), and normal renal function (eGFR > 50 mL/min), were 6%/7.9%, 24.1%/24.9%, and 69.8%/67.2%, respectively. Statistically significant improvements in overall response rates and progression-free survival were observed in VMPT-VT versus VMP arms across renal cohorts, except in severe RI patients. In the VMPT group, severe RI reduced overall survival (OS). RI was reversed in 16/63 (25.4%) patients receiving VMPT-VT versus 31/77 (40.3%) receiving VMP. Multivariate analysis showed male sex (P = .022) and moderate RI (P = .003) significantly predicted RI recovery. VMP patients achieving renal response showed longer OS. In both arms, greater rates of severe hematologic adverse events were associated with RI (eGFR < 50 mL/min), however, therapy discontinuation rates were unaffected. VMPT-VT was superior to VMP for cases with normal renal function and moderate RI, whereas VMPT-VT failed to outperform VMP in patients with severe RI, although the relatively low number of cases analyzed preclude drawing definitive conclusions. VMPT-VT had no advantage in terms of RI reversal over VMP.

Background: Bortezomib is a proteasome inhibitor which has demonstrated activity against recurrent or newly diagnosed multiple myeloma (MM) and mantle cell lymphoma. Peripheral neuropathy has been described with this agent, although the overall incidence and relative risk remain unclear. We performed a meta-analysis to calculate the incidence of peripheral neuropathy associated with the use of intravenous bortezomib in MM and lymphoma and to compare the relative risk compared with placebo.

BACKGROUND:

Patients (pts) with multiple myeloma (MM) refractory to bortezomib (BTZ) and an immunomodulatory drug have limited treatment options and a poor prognosis. In a phase I study of pts with relapsed or relapsed/refractory MM treated with panobinostat (PAN) + BTZ, clinical responses were observed overall and in pts with BTZ-refractory disease. We report results in PANORAMA 2, a trial in relapsed and BTZ-refractory pts.

METHODS:

PANORAMA 2 is a single-arm, phase II study of PAN + BTZ + dexamethasone (Dex) in pts with relapsed and BTZ-refractory MM. Treatment phase 1 (TP1) consists of eight 3-week cycles of oral PAN + intravenous BTZ + oral Dex. Pts demonstrating clinical benefit enter treatment phase 2 (TP2) which consists of four 6-week cycles of PAN + BTZ + Dex. The primary endpoint is overall response (≥ partial response [PR]) in TP1.

RESULTS:

Fifty-five pts with BTZ-refractory MM were enrolled with 10 pts ongoing and 28 in follow-up. The median age was 61 years (range 41-88 years). Pts were heavily pretreated: the median number of prior regimens was 4 (range 2-11), and most pts (64%) received prior autologous stem cell transplant. Twenty-seven (49%) and 36 (65%) pts had BTZ and Dex in their most recent prior line of therapy, respectively. Eighteen pts achieved ≥ PR for an overall response rate of 33% (1 near complete response and 17 PR), and 13 pts achieved MR for a clinical benefit rate of 56%. Three pts achieved a VGPR. Eighteen pts completed TP1 and entered TP2, and 2 have completed ≥ 12 cycles. Common adverse events (AEs) of any grade included thrombocytopenia (66%), fatigue (64%), diarrhea (62%), nausea (58%), dyspnea (40%), anemia (38%), decreased appetite (36%), and dizziness (36%). Common grade 3/4 AEs included thrombocytopenia (58%), fatigue (17%), anemia (15%), pneumonia (15%), neutropenia (13%), and diarrhea (13%). Only 1 pt (2%) experienced grade 3/4 peripheral neuropathy.

CONCLUSIONS:

PAN synergizes with BTZ in recapturing responses in heavily pretreated, BTZ-refractory MM pts. The combination of PAN and BTZ is a promising treatment for pts with BTZ-refractory MM that is generally well tolerated, with several pts receiving therapy long term.

RECORD STATUS:

None

CITATION:

Andersson PO, Blimark C, Veskovski L, Strandell A, Samuelsson O, Svanberg T, Liljegren A. Lakemedelsbehandling vid relaps av myelom; bortezomib, lenalidomid, talidomid. [Treatment in relapsed multiple myeloma; bortezomib, lenalidomide, thalidomide] Gothenburg: The Regional Health Technology Assessment Centre (HTA-centrum). HTA-rapport 2011:32. 2011

Three-drug induction regimens have become the standard of care in newly diagnosed transplant-eligible multiple myeloma patients. Two frequently used protocols are bortezomib, cyclophosphamide and dexamethasone (VCD) and bortezomib, thalidomide and dexamethasone (VTD). Comparisons between the two are lacking. The present study aimed to identify the differences in response rate and toxicity between the two regimens. Databases were searched using the terms 'VTD' or 'VCD' and 'induction regimens for newly diagnosed multiple myeloma'. Prospective trials evaluating initial response in transplant eligible patients were included. The main outcome measures were response rates and adverse events. Eight clinical trials were eligible for analysis. Overall 672 patients were treated with either VCD (n = 157) or VTD (n = 515) as induction therapy. Patients treated with VTD presented with a significantly higher complete/near complete response (34% vs. 6%, P = 0·002) as well as a higher very good partial response rate or better, following induction therapy (62% vs. 27%, P < 0·0001). Although grade 3-4 neurotoxicity was more frequent during VTD therapy (11% vs. 6%, P = 0·057), a higher incidence of overall grade 3-4 adverse events was found in the VCD-treated patients (74% vs. 51%, P < 0·001). VTD induction therapy may be superior in achieving deeper response rate following induction therapy, and is better tolerated.

BACKGROUND:

Bortezomib has shown significant activity in myeloma. In this multicenter trial, we assessed for the first time the combination of bortezomib, doxorubicin and low-dose dexamethasone (PAd) in the treatment of relapsed/refractory myeloma.

PATIENTS AND METHODS:

Sixty-four patients were treated for a median of four 28-day cycles (1-6). Bortezomib was given at 1.3 mg/m(2) (days 1, 4, 8, 11) and dexamethasone at 40 mg (days 1-4); 34 patients receive doxorubicin at 20 mg/m(2) (days 1, 4) while 30 patients pegylated liposomal doxorubicin at 30 mg/m(2) (day 1).

RESULTS:

Fifty-eight percent of patients had undergone prior autologous transplantation, 70% prior anthracycline and 27% prior bortezomib-based regimens. Forty-three patients (67%) achieved at least a partial response including 16 (25%) with at least a very good partial response. One-year event-free survival was 34% after PAd and 31% after the previous line of therapy (hazard ratio 1.20, 95% confidence interval 0.76-1.90, P = 0.43). One-year overall survival from the start of PAd was 66%. Grade 3-4 toxic effects included thrombocytopenia (48%), neutropenia (36%), infections (15%), anemia (13%), gastrointestinal disturbances (11%) and peripheral neuropathy (10%). Two patients had grade 3-4 cardiac heart failure.

CONCLUSIONS:

PAd is an active salvage therapy with manageable toxicity in patients with relapsed/refractory myeloma.

Community practice experience allows a nonselective care of patient using information derived from a more controlled clinical trial environment. We present our community experience with multiple myeloma patients with advanced age, long disease duration since diagnosis, advanced stage, multiple prior therapies including stem cell transplantation, co-morbidities, and other poor prognostic features, such as low albumin, high B-2 microglobulin, renal failure, and the presence of poor risk chromosomal abnormalities. Our response rates are comparable to those from clinical trials. Bortezomib is well tolerated in this population of multiple myeloma patients with the exception of infection adverse events that are generally mild grade 1-2.

The proteasome is an intracellular enzyme complex that degrades ubiquitin-tagged proteins and thereby regulates protein levels within the cell. Given this important role in maintaining cellular homeostasis, it is perhaps somewhat surprising that proteasome inhibitors have a therapeutic window. Proteasome inhibitors have demonstrated clinical efficacy in the treatment of multiple myeloma and mantle cell lymphoma and are under evaluation for the treatment of other malignancies. Bortezomib is the first and only Food and Drug Administration-approved proteasome inhibitor that inhibits this enzyme complex in a reversible fashion. Although bortezomib improves clinical outcomes when used as a single agent, most patients do not respond to this drug and those who do respond almost uniformly relapse. As such, efforts are underway to develop proteasome inhibitors that act through mechanisms distinct from that of bortezomib. Specifically, inhibitors that bind the active site of the proteasome and inhibit the complex irreversibly have been developed and are in advanced clinical trials. Inhibitors that act on sites of the proteasome outside of the catalytic center have also been identified and are in preclinical development. In this review, we discuss the structure and function of the proteasome. We then focus on the molecular biology, chemistry, and the preclinical and clinical efficacy of novel proteasome inhibitors as strategies to inhibit this target and overcome some forms of bortezomib resistance.