Analysis of the Efficacy of Thalidomide Plus Dexamethasone-Based Regimens in Patients With Relapsed/Refractory Multiple Myeloma Who Received Prior Chemotherapy,Including Bortezomib and Lenalidomide: KMM-166 Study

BackgroundFor patients with multiple myeloma (MM) that relapsed after treatment with bortezomib- and lenalidomide-based regimens, there were no other treatment options in Korea until 2016. We aimed to determine the efficacy of thalidomide plus dexamethasone-based regimens in patients with relapsed/refractory MM (RRMM).Patients and MethodsWe conducted a multicenter retrospective analysis in Korea for patients with RRMM treated with thalidomide-based regimens who previously received bortezomib and immunomodulatory agents (IMiDs), including thalidomide and lenalidomide.ResultsIn 47 patients with RRMM, the median age was 64 years and the median number of previous treatment lines, including bortezomib and IMiDs, was 3. Primary resistance to bortezomib and lenalidomide was observed in 12 (26%) and 8 (17%) patients, respectively. The most common regimen was a combination of thalidomide, cyclophosphamide, and dexamethasone. The overall response rate was 38%; 2 patients (4%) experienced a complete response, and 2 patients (4%) experienced a very good partial response. The overall response rate of patients previously exposed to thalidomide was 53%. The median progression-free survival was 5.9 months, and overall survival was 9.2 months. Patients with disease that responded to the thalidomide-based regimen had better progression-free survival compared to those who did not (median, 8.8 vs. 2.5 months; P = .008). The most common adverse events were anemia (51%) for hematologic toxicities and peripheral neuropathy (30%) for nonhematologic toxicities.ConclusionThalidomide-based regimens are potential salvage treatment options for patients with RRMM, even those with disease with prior resistance to IMiDs.     

Outcomes of Daratumumab,Pomalidomide, and Dexamethasone,Followed by High-dose Chemotherapy and Autologous Stem Cell Transplantation,in Patients With Relapsed/Refractory Multiple Myeloma

BackgroundThe number of therapeutic options for patients with relapsed/refractory multiple myeloma (RRMM) has increased significantly. Our institute treated a series of patients with RRMM using DPd (daratumumab, pomalidomide, dexamethasone) as salvage therapy, followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT).Patients and MethodsWe treated 18 patients with RRMM from May 2016 to April 2020, with DPd as salvage therapy, followed by HDCT and ASCT. DPd was administered as daratumumab 16 mg/kg weekly for cycles 1 and 2, every 2 weeks for cycles 3 to 6, and then every 4 weeks. Pomalidomide was given at 4 mg orally on days 1 to 21 of a 28-day cycle, and dexamethasone at 20 or 40 mg weekly.ResultsThe patients had received a median of 2 (range, 1-4) previous regimens. Of the 18 patients, 13 (72%) had received ASCT before this treatment. In addition, 78% had disease refractory to proteasome inhibitors, 78% refractory to immunomodulatory agents, and 72% double refractory to immunomodulatory agents and proteasome inhibitors. The overall response rate after salvage treatment with DPd was 100% and at day 100 after ASCT was 100%; 67% had achieved a complete response or better and 78% had achieved a very good partial response or better. No treatment-related mortality had occurred by day 100. The 2-year progression-free and overall survival rates were 83.3% and 94.4%, respectively. The most common grade ≥ 3 adverse events were thrombocytopenia (100%), neutropenia (100%), and neutropenic fever (67%).ConclusionsDPd as salvage therapy, followed by HDCT and ASCT, demonstrated deep, durable, and clinically meaningful responses with a manageable safety profile in patients with RRMM.     

Use of depth of response to predict progression‐free survival in relapsed or refractory multiple myeloma: Evaluation of results from 102 clinical trials

Progression‐free survival (PFS) is the standard endpoint for demonstration of clinical effectiveness of novel therapies in relapsed or refractory multiple myeloma (RRMM). However, the long evaluation times for PFS limits its usefulness in the development of new therapies. Therefore, the objective of this analysis was to determine the relationship between response rates and median PFS in RRMM. A database was systematically developed from 268 identified RRMM trials reported from 1999 to 2016. Evaluated covariates for the relationship between response rates and PFS included age, sex, drug class(es), and number of drug classes. One‐hundred two (102) trials involving 136 cohorts were included in the meta‐analysis, representing 13 322 patients in total. Regression analysis using response rates and median PFS indicated that the correlation between very good partial response (VGPR) or better and median PFS was higher (R² = 0.63) than the separately analyzed correlations between clinical benefit, overall response, or complete response rate and median PFS (R² = 0.47 – 0.52). Subsequent covariate analysis revealed that treatment with an immunomodulatory imide drug (IMiD) further improved the relationship (R² = 0.69), with a longer median PFS at a given VGPR or better rate when at least 1 drug treatment was an IMiD. Number of drug classes was not found to alter this relationship. In conclusion, VGPR or better rate can be used to predict the median PFS, with adjustment for the additional PFS provided by an IMiD.     

Single-agent belantamab mafodotin in patients with relapsed/refractory multiple myeloma: Final analysis of the DREAMM-2 trial

Background

Patients with relapsed/refractory multiple myeloma (RRMM) have a high unmet treatment need. Belantamab mafodotin (belamaf), a first-in-class, B-cell maturation antigen-binding antibody-drug conjugate, eliminates myeloma cells through direct cell killing and an anti-myeloma immune response.

Methods

DREAMM-2 (NCT03525678) was a phase 2, two-arm, open-label trial in patients with heavily pretreated RRMM who had three or more prior therapies, were refractory to an immunomodulatory agent and a proteasome inhibitor, and refractory or intolerant to an anti-CD38 monoclonal antibody. Belamaf was given at 2.5 or 3.4 mg/kg every 3 weeks. The primary end point was overall response rate (ORR); secondary end points included progression-free survival (PFS), overall survival (OS), safety, ocular symptoms, and health-related quality of life (HRQOL).

Results

This final analysis (cutoff date, March 31, 2022), N = 223, with median follow-up of 12.5 and 13.8 months, demonstrated an ORR of 32% and 35%, median PFS of 2.8 and 3.9 months, and median OS of 15.3 and 14.0 months in the 2.5 mg/kg and 3.4 mg/kg cohorts, respectively. Median duration of response was 12.5 and 6.2 months. No new safety signals were observed; the most common Grade 3 and 4 adverse events were keratopathy (29% vs. 25%), thrombocytopenia (22% vs. 29%), and anemia (21% vs. 28%). HRQOL outcomes suggest that overall global health status/quality of life, physical and role functioning, and overall disease symptoms were maintained or improved during treatment.

Conclusions

This final analysis of DREAMM-2 confirms that in patients with triple-class refractory RRMM, single-agent belamaf results in durable and clinically meaningful responses with a manageable safety profile.     

Pomalidomide,Cyclophosphamide, and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma: Real-World Analysis of the Pethema-GEM Experience

IntroductionTreatment of relapsed/refractory multiple myeloma (RRMM) is highly challenging, especially for patients with disease refractory to initial therapy, and in particular for disease developing refractoriness to lenalidomide. Indeed, with currently approved treatments, median progression-free survival (PFS) in the lenalidomide-refractory setting is less than 10 months, reflecting the difficulty in treating this patient population. Pomalidomide is a second-generation immunomodulatory drug that has shown activity in lenalidomide-refractory disease in the setting of different combinations.Patients and MethodsA real-world study was conducted by the Spanish Myeloma group in a cohort of patients with RRMM treated with pomalidomide, cyclophosphamide, and dexamethasone (PomCiDex). One hundred patients were treated with a median of 3 prior lines of therapy.ResultsOverall response rate was 39%, with a clinical benefit rate of 93%. Median PFS was 7.6 months; median overall survival (OS) was 12.6 months. Median PFS and OS survival were consistent across the different subgroups analyzed. Prolonged PFS and OS were found in patients with responsive disease.ConclusionOur results compared favorably with those obtained with different pomalidomide-based combinations in a similar patient population. PomCiDex remains a manageable, cost-effective, and all-oral triplet combination for RRMM patients.     

Early Access Program Results From Turkey and a Literature Review on Daratumumab Monotherapy Among Heavily Pretreated Patients With Relapsed/Refractory Myeloma

BackgroundIn countries where frontline drug approval is limited to first-generation proteasome inhibitors or immunomodulatory drugs, relapses have been both more frequent and less durable. We investigated real world data on the efficacy and safety of daratumumab monotherapy among patients with relapsed refractory multiple myeloma (RRMM) from Turkey using a prospective early access program.Patients and MethodsA total of 42 patients with RRMM after a minimum of 3 previous lines of proteasome inhibitor/immunomodulatory drug-based treatments were included from 25 centers across Turkey. Daratumumab monotherapy was administered intravenously at a dose of 16 mg/kg weekly (cycles 1-2), on alternate weeks (cycles 3-6), and monthly thereafter.ResultsThe median daratumumab monotherapy duration was 5.5 months (range, 0.2-28.7 months). The overall response rate was 45.2%, including 14 (33.3%) partial responses, 4 (9.5%) very good partial responses, and 1 (2.4%) complete response. The median duration of response was 4.9 months. The median progression-free survival (PFS) was 5.5 (95% confidence interval, 2.6-8.4 months) with 12- and 18-month PFS rates of 35.7% and 31.0%, respectively. The median overall survival was not reached; the 12- and 18-month overall survival rates were 64.3% and 59.5%, respectively. The depth of response had a significant effect on PFS (log-rank test, P = .026). Overall, of the 76 adverse events reported, 33 (43.4%) were grade ≥ 3; only 4 (9.52%) were grade 3 infusion-related reactions. No infusion-related reactions or adverse events led to treatment discontinuation.ConclusionThe present findings from our daratumumab early access program have confirmed the efficacy and safety profile of daratumumab monotherapy in heavily pretreated Turkish patients with RRMM.     

Clinical and Sociodemographic Characteristics of Patients With Relapsed and/or Refractory Multiple Myeloma and Their influence on Treatment in the Real-World Setting in Spain: The CharisMMa Study

IntroductionTreatment of relapsed and/or refractory multiple myeloma (RRMM) should be established based on multiple factors, including previous treatment and the sociodemographic/clinical characteristics of the patients. However, patients enrolled in randomized-controlled trials often do not mirror the scenario encountered in real-world practice, thus challenging therapeutic decisions in day-to-day practice.Patients and methodsThis observational, cross-sectional, multicenter study aimed to investigate the sociodemographic and clinical characteristics of patients with RRMM treated in routine practice in Spain and their influence on treatment regimens.ResultsThe study included 276 RRMM patients (median age 69 years; no gender predominance). Seventy-four percent of patients had CRAB features at the time of study inclusion, 65.9% bone lesions, 28.7% high-risk cytogenetics, and 27.0% were at ISS stage III; 65.1% were retired and lived in urban areas (75.7%) with their relatives (85.8%); 28.7% had some dependence degree. Patients had experienced their last relapse in a median of 1.61 months before enrollment and had received a median of 2 treatment lines (range 1-10). Second-and third-line therapies were mostly based on immunomodulatory drugs, followed by proteasome inhibitors (PIs), whereas monoclonal antibodies prevailed in later treatment lines. The presence of extramedullary plasmacytomas, the absence of osteopenia, and being in the second or third treatment line (vs. later lines) significantly increased the odds of receiving PIs.ConclusionsRRMM treatment in the real-world setting is highly heterogeneous and is primarily influenced by the number of previous lines. The consideration of patients’ clinical and sociodemographic characteristics may support clinicians in making therapeutic decisions.     

Weekly carfilzomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma: A phase 1 and PK/PD trial

This open‐label multicenter phase 1 study evaluated the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of weekly carfilzomib and dexamethasone (Cd) in Japanese patients with relapsed or refractory multiple myeloma (RRMM). Carfilzomib was administered by 30‐minute intravenous infusion on Days 1, 8 and 15 in a 28‐day cycle starting at 20 mg/m² on Day 1/Cycle 1 and 70 mg/m² thereafter until progressive disease or unacceptable toxicity. Dexamethasone 40 mg was administered on Days 1, 8, 15 and 22 in Cycles 1‐9 and on Days 1, 8 and 15 thereafter. Six patients were enrolled between March 2015 and June 2015. Patients had received a median of 4.5 (range, 4‐8) prior regimens; all patients had previous therapies with bortezomib and immunomodulatory drugs. Of the 6 patients, 1 had a dose‐limiting toxicity (DLT), and tolerability was confirmed. The DLT was grade 3 thrombotic microangiopathy, which was considered serious and occurred on Day 11/Cycle 1. All 6 patients (100%) experienced at least 1 grade ≥3 adverse event (AE). Two patients (33.3%) experienced AE (also considered adverse drug reactions) leading to study discontinuation: thrombotic microangiopathy (Day 11/Cycle 1) and thrombotic thrombocytopenic purpura (Day 6/Cycle 2). The overall response rate was 83.3% (95% confidence interval, 43.6‐97.0). The weekly Cd regimen at a carfilzomib dose of 20/70 mg/m² was well‐tolerated among Japanese patients with RRMM. Our results could be the basis for the further development of carfilzomib treatment considering safety profiles including microangiopathy‐related events and efficacy.     

A Phase II Study of Venetoclax in Combination With Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma

BackgroundVenetoclax is a selective BCL-2 inhibitor with clinical activity in relapsed/refractory multiple myeloma (RRMM). Combinations of venetoclax with agents that have complementary mechanisms of action may improve venetoclax efficacy in RRMM. This study evaluated venetoclax with pomalidomide and dexamethasone (VenPd) in RRMM.Patients and MethodsThis phase II open label study (NCT03567616) evaluated VenPd in patients with RRMM who had received ≥ 1 prior therapy and were refractory to lenalidomide. Venetoclax was administered orally daily for days 1 to 28, pomalidomide was administered orally daily for days 1 to 21, and dexamethasone was administered weekly for each 28-day cycle. The primary objective was to characterize the safety and tolerability of VenPd. The secondary objectives were to evaluate the efficacy and pharmacokinetics. The study was terminated early due to partial clinical hold and decision to pursue biomarker driven strategy.ResultsEight patients were enrolled. Patients had a median age of 67.5 years. All patients received 400 mg venetoclax; 4 patients experienced dose-limiting toxicities and the dose was not escalated. All patients had a grade ≥ 3 adverse event, and the most common was neutropenia (n = 6); cytopenias were the most prevalent adverse events. Five patients (63%) had a confirmed response, and the median duration of response was 12.9 months. The median progression-free survival was 10.5 months.ConclusionsGiven the limited enrollment, no clear safety or efficacy conclusions about VenPd can be drawn. Preliminary safety data, particularly the occurrence of cytopenias, can be used to guide dosing strategies for future combinations of venetoclax with immunomodulatory agents.     

Daratumumab With Cetrelimab,an Anti–PD-1 Monoclonal Antibody,in Relapsed/Refractory Multiple Myeloma

BackgroundDaratumumab is approved for relapsed or refractory multiple myeloma (RRMM) as monotherapy or in combination regimens. We evaluated daratumumab plus cetrelimab, a programmed death receptor-1 inhibitor, in RRMM.Patients and MethodsThis open-label, multiphase study enrolled adults with RRMM with ≥ 3 prior lines of therapy. Part 1 was a safety run-in phase examining dose-limiting toxicities of daratumumab (16 mg/kg intravenously weekly for cycles 1-2, biweekly for cycles 3-6, and monthly thereafter) plus cetrelimab (240 mg intravenously biweekly, all cycles). In Parts 2 and 3, patients were to be randomized to daratumumab with or without cetrelimab (same schedule as Part 1). Endpoints included safety, overall response rate, pharmacokinetics, and biomarker analyses.ResultsNine patients received daratumumab plus cetrelimab in the safety run-in, and 1 received daratumumab in Part 2 before administrative study termination following a data monitoring committee’s global recommendation to stop any trial including daratumumab combined with inhibitors of programmed death receptor-1 or its ligand (programmed death-ligand 1). The median follow-up times were 6.7 months (safety run-in) and 0.3 months (Part 2). No dose-limiting toxicities occurred. All 10 patients had ≥ 1 treatment-emergent adverse event; 7 patients had grade 3 to 4 treatment-emergent adverse events, and none led to treatment discontinuation or death. In the safety run-in, 7 (77.7%) patients had ≥ 1 infusion-related reaction (most grade 1-2), and 1 had a grade 2 immune-mediated reaction. Among safety run-in patients, the overall response rate was 44.4%.ConclusionsNo new safety concerns were identified for daratumumab plus cetrelimab in RRMM. The short study duration and small population limit complete analysis of this combination.     

Final analysis of a phase 1/2b study of ibrutinib combined with carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma

Patients with multiple myeloma (MM) inevitably relapse on initial treatment regimens, and novel combination therapies are needed. Ibrutinib is a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, an enzyme implicated in growth and survival of MM cells. Preclinical data suggest supra-additivity or synergy between ibrutinib and proteasome inhibitors (PIs) against MM. This phase 1/2b study evaluated the efficacy and safety of ibrutinib plus the PI carfilzomib and dexamethasone in patients with relapsed/refractory MM (RRMM). In this final analysis, we report results in patients who received the recommended phase 2 dose (RP2D; ibrutinib 840 mg and carfilzomib 36 mg/m² with dexamethasone), which was determined in phase 1. The primary efficacy endpoint was overall response rate (ORR). Fifty-nine patients with RRMM received the RP2D (18 in phase 1 and 41 in phase 2b). These patients had received a median of three prior lines of therapy; 69% were refractory to bortezomib, and 90% were refractory to their last treatment. ORR in the RP2D population was 71% (stringent complete response and complete response: 3% each). Median duration of clinical benefit and median duration of response were both 6.5 months. Median progression-free survival (PFS) was 7.4 months, and median overall survival (OS) was 35.9 months. High-risk patients had comparable ORR and median PFS (67% and 7.7 months, respectively) to non–high-risk patients, whose ORR was 73% and median PFS was 6.9 months, whereas median OS in high-risk patients was 13.9 months and not reached in non–high-risk patients. The most common grade ≥3 hematologic treatment-emergent adverse events (TEAEs) were anemia and thrombocytopenia (17% each); the most common grade ≥3 non-hematologic TEAE was hypertension (19%). In patients with RRMM treated with multiple previous lines of therapy, ibrutinib plus carfilzomib demonstrated anticancer activity within the expected efficacy range. No new safety signals were identified and the combination was well-tolerated.     

Carfilzomib,lenalidomide and dexamethasone in patients with heavily pretreated multiple myeloma: A phase 1 study in Japan

This is the first study in which the carfilzomib, lenalidomide and dexamethasone (KRd) regimen was evaluated in heavily pretreated multiple myeloma. This study is a multicenter, open‐label phase 1 study of KRd in Japanese patients with relapsed or refractory multiple myeloma (RRMM) patients. The objectives were to evaluate the safety, tolerability, efficacy and pharmacokinetics of the regimen. Carfilzomib was administrated intravenously over 10 min on days 1, 2, 8, 9, 15 and 16 of a 28‐day cycle. In cycle 1, the dosage for days 1 and 2 was 20 mg/m², followed by 27 mg/m². Lenalidomide and dexamethasone were administered at 25 mg (days 1–21) and 40 mg (days 1, 8, 15 and 22), respectively. Twenty‐six patients were enrolled. Patients had received a median of four prior regimens and 88.5% and 61.5% received previous bortezomib and lenalidomide, respectively. High‐risk cytogenetics were seen in 53.8% of patients. The overall response rate was 88.5%. A higher rate of hyperglycemia was observed than in a previous carfilzomib monotherapy study, but this was attributed to dexamethasone. Carfilzomib pharmacokinetics were not affected by lenalidomide and dexamethasone. The KRd regimen was well tolerated and showed efficacy in Japanese RRMM patients.     

Safe and prolonged survival with long-term exposure to pomalidomide in relapsed/refractory myeloma

BackgroundThe IFM2009-02 trial studied pomalidomide (4 mg daily, 21/28 versus 28/28) and dexamethasone in very advanced relapsed or refractory multiple myeloma (RRMM). We observed that 40% of patients had a prolonged progression-free survival (PFS) and subsequently overall survival (OS). We sought to analyze the characteristics of these patients and study the effect of long exposure to pomalidomide.DesignWe separated the studied population into two groups: 3 months to 1 year (<1 year) and more than 1 year (≥1 year) of treatment with pomalidomide and dexamethasone based on clinical judgment and historical control studies. We then analyzed the characteristics of patients according to duration of treatment.ResultsThe overall response rate (ORR) for the <1-year group was 43%, the median PFS 4.6 months [95% confidence interval (95% CI) 3.8–6.4] with only 6% at 12 months, and the median OS was 15 months (11.7–20.3) and 40% at 18 months. For the ≥1-year group, the response rate and survival were strikingly different, ORR at 83%, median PFS 20.7 months (14.7–35.4), median OS not reached, and 91% at 18 months.ConclusionPomalidomide and dexamethasone favored prolonged and safe exposure to treatment in 40% of heavily treated and end-stage RRMM, a paradigm shift in the natural history of RRMM characterized with a succession of shorter disease-free intervals and ultimately shorter survival. Although an optimization of pomalidomide–dexamethasone regimen is warranted in advanced RRMM, we claim that pomalidomide has proven once more to change the natural history of myeloma in this series, which should be confirmed in a larger study.     

Avelumab,a PD-L1 Inhibitor,in Combination with Hypofractionated Radiotherapy and the Abscopal Effect in Relapsed Refractory Multiple Myeloma

Lessons Learned

• Despite the initial optimism for using immune checkpoint inhibition in the treatment of multiple myeloma, subsequent clinical studies have been disappointing.
• Preclinical studies have suggested that priming the immune system with various modalities in addition to checkpoint inhibition may overcome the relative T‐cell exhaustion or senescence; however, in this small data set, radiotherapy with checkpoint inhibition did not appear to activate the antitumor immune response.

BackgroundExtramedullary disease (EMD) is recognized as an aggressive subentity of multiple myeloma (MM) with a need for novel therapeutic approaches. We therefore designed a proof‐of‐principle pilot study to evaluate the synergy between the combination of the anti–PD‐L1, avelumab, and concomitant hypofractionated radiotherapy.MethodsThis was a single‐arm phase II Simon two‐stage single center study that was prematurely terminated because of the COVID‐19 pandemic after enrolling four patients. Key eligibility included patients with relapsed/refractory multiple myeloma (RRMM) who had exhausted or were not candidates for standard therapy and had at least one lesion amenable to radiotherapy. Patients received avelumab until progression or intolerable toxicity and hypofractionated radiotherapy to a focal lesion in cycle 2. Radiotherapy was delayed until cycle 2 to allow the avelumab to reach a study state, given the important observation from previous studies that concomitant therapy is needed for the abscopal effect.ResultsAt a median potential follow‐up of 10.5 months, there were no objective responses, one minimal response, and two stable disease as best response. The median progression‐free survival (PFS) was 5.3 months (95% confidence interval [CI]: 2.5–7.1 months), and no deaths occurred. There were no grade ≥3 and five grade 1–2 treatment‐related adverse events.ConclusionAvelumab in combination with radiotherapy for patients with RRMM and EMD was associated with very modest systemic clinical benefit; however, patients did benefit as usual from local radiotherapy. Furthermore, the combination was very well tolerated compared with historical RRMM treatment regimens.     

Isatuximab-Pomalidomide-Dexamethasone Versus Pomalidomide-Dexamethasone in East Asian Patients With Relapsed/Refractory Multiple Myeloma: ICARIA-MM Subgroup Analysis

BackgroundIn the pivotal phase III, randomized, multicenter ICARIA-MM study (NCT02990338), isatuximab plus pomalidomide and dexamethasone (Isa-Pd) improved progression-free survival and overall response rate versus pomalidomide and dexamethasone (Pd) in the overall population of patients with relapsed/refractory multiple myeloma.Patients and MethodsIn this predefined subgroup analysis, efficacy, and safety between East Asian patients and the overall population were assessed.ResultsIn total, 36 East Asian patients were included (Japanese, n = 13; Korean, n = 9; Taiwanese, n = 14). At a median follow-up of 11.6 months, median progression-free survival was not reached (95% confidence interval [CI] 5.80–not calculable) in the Isa-Pd arm and was 7.9 months (95% CI 2.90–not calculable) in the Pd arm. The hazard ratio for the between-group difference was 0.52 (95% CI 0.19-1.39), which was similar to the overall population (hazard ratio, 0.60; 95% CI 0.44-0.82). No new safety signals were observed, except that a higher proportion of patients in the East Asian population experienced Grade ≥ 3 neutropenia compared with the overall population.ConclusionThese results confirm the efficacy of Isa-Pd in East Asian patients with relapsed/refractory multiple myeloma, and the related safety data are consistent with those observed in the overall population and are manageable.     

Efficacy and tolerability of the histone deacetylase inhibitor panobinostat in clinical practice

The histone deacetylase inhibitor panobinostat has shown efficacy in phase‐II and phase‐III trials for multiple myeloma and has recently received market approval in combination with bortezomib and dexamethasone. Here, we retrospectively report our single center experience with panobinostat/bortezomib/dexamethasone (FVD) in a heavily pretreated patient population (n = 24) with a high degree of refractoriness to proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Median age was 67 years (range 49‐87) and the median number of prior therapies was 5 (range 2‐17). Fourteen patients (58%) had high‐risk cytogenetic aberrations. Thirteen (54%) and 21 (88%) patients were refractory to PIs and IMiDs, respectively. Twelve patients (50%) were refractory to bortezomib and 7 (29%) to carfilzomib; 6 patients (25%) were refractory to both bortezomib and carfilzomib. In 21 patients evaluable for response, overall response rate (ORR; ≥PR) was 33% (7/21) and 81% (17/21) achieved at least stable disease. Median progression‐free survival (PFS) and overall survival were 3.5 and 9.8 months, respectively. Significant differences between bortezomib‐sensitive and ‐refractory patients were observed. In bortezomib‐sensitive patients, median PFS was 6.3 months compared to 2.3 months in bortezomib‐refractory patients (P < .001). Median overall survival was not reached vs 4.8 months (P = .046) in bortezomib‐sensitive and bortezomib‐refractory patients, respectively. The only patient refractory to carfilzomib but sensitive to bortezomib achieved very good partial remission and PFS of 6.3 months, suggesting discrete mechanisms of resistance to different PIs. As expected, thrombocytopenia and fatigue/asthenia occurred in nearly all patients (96% and 83%, respectively). Diarrhea was observed in only 19% of patients which compares favorably with the high rates of diarrhea reported in the PANORAMA trials. With panobinostat dose reductions in 67% of patients, FVD was tolerated by the majority of patients. In conclusion, FVD showed efficacy in a heavily pretreated, high‐risk multiple myeloma population with a high degree of patients refractory to novel agents including PIs.     

Durable remission with salvage second autotransplants in patients with multiple myeloma

BACKGROUND:

High‐dose chemotherapy with autologous hematopoietic cell transplant (auto‐HCT) has been shown to improve survival in patients with newly diagnosed multiple myeloma. However, the role of salvage auto‐HCT for relapsed patients, particularly in the era of novel therapeutics, is not well defined.

METHODS:

The authors performed a retrospective analysis of all 44 myeloma patients (24 men, 20 women) who received a second auto‐HCT as salvage between January 3, 1992 and November 4, 2008 at The University of Texas MD Anderson Cancer Center.

RESULTS:

Median interval between the first and salvage auto‐HCT was 30 months (range, 2‐78 months). Median age at salvage HCT was 54 years (range, 38‐73 years), and median number of salvage treatment regimens was 2 (range, 0‐5). Eleven (25%) patients had high‐risk chromosomal abnormalities on conventional cytogenetic studies between diagnosis and salvage auto‐HCT. Ten patients (23%) experienced grade 3 or higher nonhematologic toxicity after the salvage auto‐HCT. One patient died within 100 days, for a treatment‐related mortality of 2%. Best responses after salvage chemotherapy + salvage auto‐HCT were as follows: complete response (CR) + near CR, 11%; partial response, 79%; overall response rate, 90%. Eighteen (41%) patients received post auto‐HCT maintenance therapy. Median follow‐up from salvage HCT was 41 months. Kaplan‐Meier estimates of median progression‐free survival (PFS) and overall survival (OS) from time of salvage auto‐HCT were 12.3 and 31.7 months, respectively. Median OS from the time of diagnosis was 75 months. In a fitted Bayesian multivariate model, shorter time to progression after first auto‐HCT, greater number of prior therapies, African American race, and immunoglobulin G subtype were significantly associated with worse OS.

CONCLUSIONS:

In selected myeloma patients, a second auto‐HCT for salvage therapy is well tolerated, with acceptable toxicity. The overall response rate and PFS are comparable to other salvage regimens. Cancer 2012;3549–3555. © 2011 American Cancer Society.     

Infection risk with immunomodulatory and proteasome inhibitor–based therapies across treatment phases for multiple myeloma: A systematic review and meta-analysis

BackgroundThe objective of this review was to determine the impact of immunomodulatory drugs (IMiDs) and proteasome inhibitor (PI)–based therapy on infection risk in patients with myeloma across three treatment periods: induction, maintenance therapy and relapse/refractory disease (RRMM).MethodsA systematic review and meta-analysis of randomised controlled trials (RCT) of IMiD and PI-based therapy versus conventional therapy from 1990 to 2015 using MEDLINE, EMBASE and CENTRAL was conducted. Study methods, characteristics, interventions, outcomes and rate of infection were extracted using a standardised tool.FindingsThirty RCTs of 13,105 patients fulfilled inclusion criteria. The rate of severe infection with the use of IMiD-based therapy was 13.4%, 22.4%, 10.5% and 16.6% for induction therapy for non-transplant- and transplant-eligible patients, maintenance therapy and therapy for RRMM, respectively. Rate of severe infection with PI-based induction in transplant-eligible patients was 19.7%. Compared to conventional therapy, use of IMiD-based induction therapy was associated with reduced risk for transplant patients (RR 0.76, p < 0.01). There was no significant difference with PI-based therapy. For maintenance therapy and RRMM, use of IMiD-based therapy was significantly associated with 74% and 51% increased risk of severe infection, respectively. Compared to thalidomide, bortezomib-based induction therapy and lenalidomide maintenance therapy were associated with increased risk of severe infection (RR 2.03, p < 0.01; RR 1.95, p = 0.03).InterpretationThe differential impact of myeloma therapies on risk for infection and the effect of treatment phases upon risk have now been established. Thalidomide is associated with the lowest risk of severe infection when used for induction and maintenance therapy.FundingFight Cancer Foundation.     

Belantamab in Combination with Dexamethasone in Patients with Triple-class Relapsed/Refractory Multiple Myeloma

BackgroundTriple-class relapsed/refractory multiple myeloma (RRMM) has a poor prognosis. This study analyzed the clinical outcomes of Belantamab mafadotin in combination with dexamethasone (Bd) in triple-class RRMM.MethodsWe identified 35 patients with triple-class RRMM who received Bd at the University of Kansas from October 2019 to November 2021.ResultsThe median age was 66 years (42-85) and the median prior lines of therapy was 5 (3-15). Nineteen (54%) patients had R-ISS stage III disease, 15 (43%) patients had high-risk cytogenetics, and 15 patients (43%) had extramedullary disease (EMD). Eight patients received prior BCMA-targeted therapy. Overall response rate (ORR) was 43%, with 23% achieving very good partial response and better. At a median follow up of 10.7 months, the median progression-free survival and survival were 4.9 and 10.7 months, respectively. The most common adverse event was keratopathy, which occurred in 30 (86%) patients. Twenty-four patients required dose reduction or delay due to keratopathy. Other common toxicities included anemia (83%), thrombocytopenia (80%), neutropenia (34%), and elevated liver function tests (51%).ConclusionOur analysis shows Bd has good activity in triple-class RRMM. Keratopathy remains a challenging AE and the leading cause of dose reduction, delay and treatment cessation.