ALBERT

Description: Introduction: Histone deacetylases (HDACs) affect cell growth at the transcriptional level by regulating the acetylation status of nucleosomal histones, and HDAC inhibition induces differentiation and/or apoptosis in transformed cells. We have recently shown that HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), induce apoptosis of human multiple myeloma (MM) cells via a constellation of antiproliferative and/or proapoptotic molecular events, including decreased expression of multiple signaling molecules and oncogenes implicated in MM pathophysiology. Based on these promising pre-clinical data, we embarked on a phase I clinical trial of oral SAHA in patients with advanced MM. Methods: An open-label phase I dose-escalation of oral SAHA (200, 250 and 300 mg po bid for 5 consecutive days followed by 2 days of rest) was administered in 4-week cycles in pts with relapsed/refractory MM. The primary objective was to determine the maximum tolerated dose (MTD), and secondary objectives included evaluation of tumor response, as well as assessment of markers of biologic activity in peripheral blood mononuclear cells and bone marrow plasma cells. Dose limiting toxicity (DLT) was defined as grade 4 or greater hematologic toxicity and/or grade 3 or greater non-hematologic toxicity within the first 28 days of treatment. Results: To date, 8 pts with advanced MM (5 relapsed and 3 with relapsed, refractory MM) have been enrolled at the first 2 dose levels, receiving a median of 3 cycles (range 2–9) of therapy. In 7 evaluable pts, one pt at the 2nd dose level (250 mg po bid) developed DLT with grade 3 fatigue, prompting dose reduction with the next cycle. Other side effects have included grade 2 fatigue (3 pts), grade 2 diarrhea (2 pts), grade 2 indigestion (2 pts) and grade 2 dehydration (2 pts), which have been manageable with appropriate supportive care. In one patient, during cycle 4 at dose level 2, grade 3 dehydration occurred with associated metabolic abnormalities that readily resolved with electrolyte supplementation and rehydration. The patient has continued on therapy at reduced dose (250 mg po bid, 4 days on, 3 days off) without recurrence of this toxicity. Importantly, no significant myelosuppression, neuropathy or sedation, which are associated with other anti-MM agents, has been seen. In 7 evaluable pts: minor responses (MR) were documented in 2 patients (25–50% reduction in serum paraprotein levels); stable disease (SD: less than 25% reduction in paraprotein levels) was observed in 2 pts; and progressive disease (PD) was documented in 3 pts. Conclusion: SAHA is an orally administered HDAC inhibitor with manageable toxicity and preliminary evidence of antitumor activity in advanced MM. Clinical evaluation of this agent continues, with enrolment at 250 mg b.i.d. ongoing, to further define the safety and tolerability at this dose level and provide insight into the future uses of SAHA, either alone or in combination with other agents, to treat pts with advanced MM.

Description: This multicenter, open-label, randomized phase 2 study evaluated 2 dose regimens of lenalidomide for relapsed, refractory myeloma. Seventy patients were randomized to receive either 30 mg once-daily or 15 mg twice-daily oral lenalidomide for 21 days of every 28-day cycle. Patients with progressive or stable disease after 2 cycles received dexamethasone. Analysis of the first 70 patients showed increased grade 3/4 myelo-suppression in patients receiving 15 mg twice daily (41% versus 13%, P = .03). An additional 32 patients received 30 mg once daily. Responses were evaluated according to European Group for Blood and Marrow Transplantation (EBMT) criteria. Overall response rate (complete, partial, or minor) to lenalidomide alone was 25% (24% for once-daily and 29% for twice-daily lenalidomide). Median overall survival in 30-mg once-daily and twice-daily groups was 28 and 27 months, respectively. Median progression-free survival was 7.7 months on once-daily versus 3.9 months on twice-daily lenalidomide (P = .2). Dexamethasone was added in 68 patients and 29% responded. Time to first occurrence of clinically significant grade 3/4 myelosuppression was shorter in the twice-daily group (1.8 vs 5.5 months, P = .05). Significant peripheral neuropathy and deep vein thrombosis each occurred in only 3%. Lenalidomide is active and well tolerated in relapsed, refractory myeloma, with the 30-mg once-daily regimen providing the basis for future studies as monotherapy and with dexamethasone.

Description: Introduction: Bortezomib, a first in class proteasome inhibitor, has become a standard of care in the treatment of relapsed and refractory MM. A recent randomized Phase 3 trial showed an improvement in time to progression (TTP) and overall survival relative to dexamethasone (dex) in patients with relapsed MM and 1–3 prior lines of therapy. In relapsed MM, the rate of treatment -emergent significant peripheral neuropathy (PN) with bortezomib was higher in patients with baseline neuropathy. The incidence and severity of PN in front-line treatment will be important to define. This multi-center, Phase 2 study was planned to evaluate the activity and toxicity (in particular PN) of single agent bortezomib in previously untreated pts. Methods: Response rate, TTP, tolerability, incidence and severity of PN, and the effect of dose modification, symptomatic treatment and nutritional supplements on PN were evaluated in previously untreated, symptomatic MM pts. Pts received bortezomib 1.3 mg/m2 on D 1, 4, 8, and 11 of a 21-d cycle and response to treatment was assessed every 2 cycles. Dex was not permitted. Neurologic evaluation was required before and after treatment, and if significant PN developed during therapy. Results: 28 pts with symptomatic MM have been treated with a median age of 60 yrs, IgG isotype in 68% and Stage III disease in 52%. Analysis of best paraprotein response after ≥ 2 cycles revealed CR in 1 (5%) pt and PR in 8 (36%), for an ORR of 41% in 22 evaluable pts. An additional 5 pts (23%) achieved MR, with stable disease in 6 pts (27%); 2 pts progressed (9%). The most commonly reported adverse events included PN, fatigue, GI symptoms and rash. Neurological evaluation has been performed in all pts, including nerve conduction studies (NCS), assessment of autonomic function and skin biopsy for EM imaging of small fibers in a subset (n=19). Six of 28 pts (21%) so far have developed PN with most being G2: 1 pt experienced G3 PN and drug was discontinued. Dose modification was required in 4 pts and supplements have been used in all pts with PN. Preliminary results of neurological testing and NCS have indicated subclinical PN at baseline prior to therapy in 6/19 (30%) of pts evaluated by NCS, with small fiber, axonal PN documented in 1 pt with treatment-emergent PN. Bortezomib-related toxicity has otherwise been manageable. Conclusion: Single agent bortezomib is a promising approach for newly diagnosed pts and is without the complications of high-dose dex. The incidence of subclinical PN by NCS at baseline prior to therapy is currently 30%; G2 or greater treatment-emergent PN has occurred in 21% of pts and was G3 in only 1 pt (4%) to date. Further assessment of PN including analysis of skin biopsies is ongoing.