Rakesh Popat

Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial

BACKGROUNDnPanobinostat (a pan histone deacetylase inhibitor) is approved in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma who have received two or more previous lines of therapy. We aimed to improve the safety of this combination and investigate efficacy by incorporating low-dose thalidomide, using sub-cutaneous weekly bortezomib, and determining the maximum tolerated dose of panobinostat in this regimen.nnnMETHODSnWe did a phase 1/2, multicentre, open-label trial (MUK six) at four hospitals in the UK, enrolling patients with relapsed, or relapsed and refractory, multiple myeloma aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 2 or less who had previously received 1-4 lines of therapy. Exclusion criteria included any antimyeloma treatment within 28 days of study drugs (except dexamethasone 160 mg >48 h before treatment). We used a rolling six escalation design to determine the maximum tolerated dose of panobinostat, and allocated patients to receive subcutaneous bortezomib 1·3 mg/m2, and oral thalidomide 100 mg, dexamethasone 20 mg, and panobinostat 10, 15, or 20 mg (escalated to 20 mg according to the escalation schedule). Treatment was given during a 21-day cycle (bortezomib on days 1 and 8; thalidomide every day; dexamethasone on days 1, 2, 8, and 9; and panobinostat on days 1, 3, 5, 8, 10, and 12) for 16 cycles in the absence of disease progression or unacceptable toxicity. Patients were permitted to come off study for autologous stem cell transplantation. The primary objective was to determine the maximum tolerated dose and recommended dose of panobinostat, and to estimate the proportion of patients with an overall response that was equal to a partial response or greater within 16 cycles of treatment at the recommended panobinostat dose in the modified intention-to-treat population. We assessed safety in all patients who received a trial drug (ie, bortezomib, thalidomide, dexamethasone, or panobinostat). This trial is registered at ClinicalTrials.gov, number NCT02145715, and with the ISRCTN registry, number ISRCTN59395590 and is closed to recruitment.nnnFINDINGSnBetween Jan 31, 2013, and Oct 30, 2014, we enrolled 57 eligible patients who received at least one dose of trial medication or any drug. One dose-limiting toxicity was reported (grade 3 hyponatremia at the 20 mg dose), therefore the maximum tolerated dose was not reached, and 20 mg was deemed to be the recommended dose. 46 patients were treated with panobinostat 20 mg (the intention-to-treat population). 42 patients (91%, 80% CI 83·4-96·2) of 46 achieved the primary endpoint of an overall response that was equal to a partial response or greater. Most adverse events were grade 1-2 with few occurrences of grade 3-4 diarrhoea or fatigue. The most common adverse events of grade 3 or worse in the safety population (n=57) were reduced neutrophil count (15 [26%]), hypophosphatemia (11 [19%]), and decreased platelet count (8 [14%]). 46 serious adverse events were reported in 27 patients; of 14 suspected to be related to the trial medication, seven (50%) were gastrointestinal disorders.nnnINTERPRETATIONnPanobinostat 20 mg in combination with bortezomib, thalidomide, and dexamethasone is an efficacious and well tolerated regimen for patients with relapsed multiple myeloma.nnnFUNDINGnNovartis and Myeloma UK.

Real‐world use of pomalidomide and dexamethasone in double refractory multiple myeloma suggests benefit in renal impairment and adverse genetics: a multi‐centre UK experience

Myeloma patients who become refractory to immunomodulatory agents (IMiDs) and bortezomib have poor survival, with limited therapeutic options. Pomalidomide has shown improved survival and good tolerability in this patient cohort in clinical trials, but real world data are scarce. We retrospectively analysed all patients treated with pomalidomide at five UK centres between 2013 and 2016. Of 85 patients identified, 70 had sufficient information for response assessments. Median age was 66 years [40–89], 96·5% were refractory to IMiDs, 72·9% were refractory to both an IMiD and bortezomib and 92·9% were refractory to their last treatment. Of 45 patients with fluorescence in situ hybridization results 64% had adverse risk, 19 patients (22·4%) had an estimated glomerular filtration rate <45 ml/min. Grade ≥3 non‐haematological toxicities occurred in 42·4%, and grade ≥3 neutropenia and thrombocytopenia in 38% and 24% respectively, but only 18·8% had dose reductions. The overall response rate was 52·9%. At a median follow‐up of 13·2 months, median progression‐free survival was 5·2 months [95% confidence interval (CI) 4·150–6·238], and median overall survival was 13·7 months (95% CI 11·775–15·707). No significant difference was seen in response, survival or tolerability by renal function, age or cytogenetic risk. This real‐world data support the results seen in published clinical trials.

Whole body magnetic resonance imaging in newly diagnosed multiple myeloma: early changes in lesional signal fat fraction predict disease response

Cross‐sectional imaging techniques are being increasingly used for disease evaluation in patients with multiple myeloma. Whole body magnetic resonance imaging (WB‐MRI) scanning is superior to plain radiography in baseline assessment of patients but changes following treatment have not been systematically explored. We carried out paired WB‐MRI scans in 21 newly diagnosed patients prior to, and 8‐weeks after, starting chemotherapy, and analysed stringently selected focal lesions (FLs) for parametric changes. A total of 323 FLs were evaluated, median 20 per patient. At 8 weeks, there was a reduction in estimated tumour volume (eTV), and an increase in signal fat fraction (sFF) and apparent diffusion coefficient (ADC) in the group as a whole (P < 0·001). Patients who achieved complete/very good partial response (CR/VGPR) to induction had a significantly greater increase in sFF compared to those achieving ≤ partial response (PR; P = 0·001). When analysed on a per‐patient basis, all patients achieving CR/VGPR had a significant sFF increase in their FLs, in contrast to patients achieving ≤PR. sFF changes in patients reaching maximal response within 100 days (fast responders) were greater compared to slow responders (P = 0·001). Receiver Operator Characteristic analysis indicated that sFF changes at 8 weeks were the best biomarker (area under the Curve 0·95) for an inferior response (≤PR). We conclude that early lesional sFF changes may provide important information on depth of response, and are worthy of further prospective study.

Re‐transplantation after bortezomib‐based therapy

Whilst the use of high dose alkylating agents and autologous stem cell transplantation (ASCT) has a fundamental role in consolidating initial anti-tumour induction therapy, its role in salvage therapy consolidation remains to be determined. Bortezomib has been shown to be an effective agent at first and subsequent relapse, with responses equivalent or better than the response to previously used conventional therapies in first-line therapy (Richardson et al, 2005; Laubach et al, 2009). Combining bortezomib re-induction with a second ASCT after maximal anti-tumour response is, therefore, an attractive concept. Accordingly, we undertook a retrospective review of patients proceeding to a second ASCT after bortezomib-based re-induction therapy. Patients undergoing a second ASCT after progression from an initial ASCT and subsequent bortezomib re-induction therapy in 12 centres were identified (n = 40). Detailed information on the patients was obtained through anonymized clinical data retrieval forms, capturing critical patient and disease-specific factors including response to initial induction therapy, response to first ASCT, time to progression, subsequent therapies, bortezomib-based re-induction therapy and response to second ASCT (including the type of transplant and stem cell source). Response to therapy was categorized according to the International Myeloma Working Group criteria (Durie et al, 2006). Kaplan Meier plots were made using the Statistical Package for the Social Sciences (spss) IBM, Chicago, Illinois, USA. There were insufficient cytogenetic data for analysis. A total of 40 patients were identified in this retrospective study. Two patients had planned reduced intensity allogeneic (RIC-Allo) transplants after their second autologous transplant and weren excluded from further analysis. Patient characteristics including age, sex, type of myeloma, therapy prior to their first and second transplants are shown in Table Ia. One patient who relapsed 10 months after their bortezomib therapy was transplanted in relapse. All other patients were transplanted prior to disease progression. Twenty-six patients were treated with a combination of bortezomib and dexamethasone, eight patients had PAD chemotherapy (bortezomib, adriamycin and dexamethasone (Oakervee et al, 2005). Two patients had bortezomib monotherapy, one patient had bortezomib plus intravenous melphalan and one patient had bortezomib plus cyclophosphamide, dexamethasone and idarubicin. The median number of cycles of bortezomib therapy was 4 (range 2–12). Patients receiving PAD chemotherapy also had a median of four cycles

The histone deacetylase inhibitor UCL67022 has potent activity in multiple myeloma and non-Hodgkin lymphoma pre-clinical models.

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Extended follow-up and the feasibility of Panobinostat maintenance for patients with Relapsed Multiple Myeloma treated with Bortezomib, Thalidomide, Dexamethasone plus Panobinostat (MUK six open label, multi-centre phase I/II Clinical Trial).

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A new prognostic model for myeloma patients relapsing from upfront autologous transplantation based on ISS and PFS1

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RNA-Seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature

Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.

Real world experience of bortezomib re-treatment for patients with multiple myeloma at first relapse.

The routine use of proteasome inhibitors and immunomodulatory agents has improved the outcomes for patients with multiple myeloma (MM). In the United Kingdom (UK), bortezomib (Velcade, Janssen-Cilag Ltd, High Wycombe, UK) based triplet regimens are commonly used as first-line therapy for both transplant eligible and ineligible patients. The efficacy of re-treatment with bortezomib monotherapy or bortezomib plus dexamethasone in subsequent lines of therapy has been previously reported (Petrucci et al, 2013), (Sood et al, 2009). However there are limited data on re-treatment at first relapse, particularly with bortezomib-based triplet regimens, which are more commonly used in current practice. This was a retrospective analysis of MM patients at first relapse treated with bortezomib, who had also received bortezomib as first line therapy. Twenty-three sequential patients from a single UK centre who had achieved at least a partial response (≥PR) and a treatment-free interval of a minimum of 60 days from first line bortezomib treatment [i.e. not refractory (Anderson et al, 2008)] were identified. All patients had completed first relapse therapy at least 2 months prior to the data cut-off for analysis. Response to treatment and disease progression were defined by the International Myeloma Working Group criteria. Patient demographics are shown in Table S1.The median age at initial treatment was 63 3 years (range 38 7–97 7). Eleven patients (48%) were International Staging System (ISS) stage 1, six (26%) were stage 2 and six (26%) were stage 3. Fourteen patients (78%) had cytogenetic data available, of which five (22%) had adverse risk features as defined by the presence of t(4;14), t(14;16) or del(17p). Median follow up was 3 8 years from start of initial treatment. A triplet bortezomib combination was used as first line therapy in 78% of patients (n = 18/23) with a median of five cycles given (range 4–8) (Table I). Ten patients (43%) received consolidation with high dose melphalan and autologous stem cell transplantation (ASCT). All patients responded to first line therapy (PR 13%, very good partial response (VGPR), 61%, complete response (CR) 26%), with five patients improving their response post-ASCT. No patient received maintenance therapy. The median time to best response (TTBR) was 3 5 months (range 0 7–9 0) and the median duration of response (DOR) was 14 9 months (range 4 7–44 5). Treatment regimens at first relapse are listed in Table S1. A similar proportion received triplet combinations at relapse (83%) as compared to at first line (78%). The overall response rate (ORR) to bortezomib re-treatment was 87% (PR 39%, VGPR 35%, CR 13%) with 48% achieving at least a VGPR (Table I). The median TTBR was 4 1 months (range 0 7–15 0) and median DOR was 11 5 months (range 1 0– 18 5). The three patients who achieved CR with bortezomib retreatment had all achieved a CR with first line treatment and were ISS stage 1. The six patients with adverse risk genetics all achieved ≥VGPR with first line bortezomib and three VGPR, two PR and one ≤PR after re-treatment. Patients received a median of five cycles (range 1–8) and 11 patients (48%) proceeded to a salvage ASCT. Outcomes for the two treatment lines are shown in Fig 1. After front line bortezomib, the median time to progression was 18 9 months (range 7 3–49 6) whilst it was 14 4 months (range 1 4–16 6) at first relapse (although only 14 patients had disease progression at the time of analysis). The median treatment-free interval was 20 7 months (range 2 0–62 8) after first-line bortezomib and 10 4 months (range 1 0–14 0) after bortezomib re-treatment. Ten patients received ASCT at first line compared to 11 at first relapse. Treatment-related toxicity was also evaluated. At first line, 11 patients (48%) experienced peripheral neuropathy (PN) (all grade 1). Dose reductions were all due to PN (n = 6, 26%), except for one due to frailty. There were three (13%) grade 3–4 adverse events (AEs), which were all infections. Six patients (26%) were hospitalized; three for infection, one for headache, one for bone pain and one for a new fracture (grade