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.     

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.     

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.     

Real-World Evidence of Daratumumab Monotherapy in Relapsed/Refractory Multiple Myeloma Patients and Efficacy on Soft-Tissue Plasmacytomas

IntroductionDaratumumab is an anti-CD38 agent that was first investigated as single agent in GEN501 and SIRIUS trials in patients with advanced multiple myeloma (MM). Overall response rate (ORR) was 30% with positive impact on progression-free survival (PFS). However, there is a lack of information regarding plasmacytoma response.Materials and MethodsHere, we described a heavily pretreated group of 43 patients who received daratumumab monotherapy after EMA approval and focused on plasmacytoma response.ResultsAfter a median follow-up of 26 months, median time to best response was 2.9 months (range 0.8-13.1), median PFS was 5.2 months (95% CI 2.5 – 8.8) and median OS was 11.2 months (95% CI 6.3 – 17.0). Patients who achieved at least partial response had longer median PFS and OS (12.8 and 20.2 months, respectively) than those who achieved minimal response or stable disease (5.3 and 11.2 months, respectively). Ten patients (23%) had plasmacytomas (70% paraskeletal, 30% extramedullary). The clinical benefit for patients with and without plasmacytomas was 20% versus 42%. A dissociation between serological and plasmacytoma response was observed in 40% of the patients. Thus, 50% of the patients with plasmacytomas achieved at least serological minimal response but only 20% had plasmacytoma response.ConclusionThis is the first real-world study of daratumumab monotherapy that focuses on efficacy data regarding soft-tissue plasmacytomas in patients with relapsed/refractory mieloma, showing a limited benefit in this patient population.     

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.     

Post Salvage Therapy Autologous Transplant for Relapsed Myeloma,Ongoing Relevance within Modern Treatment Paradigms?

BackgroundSalvage transplant has been historically considered effective therapy for myeloma patients relapsing after first transplant, if they achieved adequate remission duration. However, the efficacy of novel agent combinations has called this paradigm into question.Materials and MethodsWe performed a retrospective analysis in a homogeneously treated cohort of 106 patients undergoing ASCT2 at our institution, all of whom received novel agent-based chemotherapy (immunomodulatory agent [IMiD] and/or proteasome inhibitor [PI]) for both induction and relapse. As an exploratory objective we assessed whether predictive thresholds of progression free survival post first transplant (ASCT1) for benefit post ASCT2 vary with use of IMiD maintenance post ASCT1.ResultsThe overall response rate (ORR) was 98% post-ASCT2 and treatment-related mortality (TRM) was low at 1.8%. With a median follow-up of 26 months (range 0.5-85) from ASCT2, median overall survival (OS) is estimated at 80 months (95% CI: ≥ 49-months) and median progression-free survival after ASCT2 (PFS2) at 24 months (95% CI 19-39). PFS post first transplant (PFS1) at >/= 50 months was associated with improved OS. Predictors of PFS2 included PFS1 ≤42 months and progression on IMiD-based maintenance post- ASCT1.ConclusionASCT2 continues to offer acceptable outcomes for most patients treated within modern day treatment paradigms, with longer PFS after ASCT1 and IMiD non-refractory disease being associated with improved outcomes     

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.     

Daratumumab,Bortezomib, and Dexamethasone versus Bortezomib and Dexamethasone in Chinese Patients With Relapsed or Refractory Multiple Myeloma: Updated Analysis of LEPUS

BackgroundIn the phase 3 LEPUS study, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Here, we report updated efficacy and safety results from LEPUS.Patients and MethodsChinese patients with ≥ 1 prior line of therapy were randomized 2:1 to bortezomib (1.3 mg/m²) and dexamethasone (20 mg) for eight cycles ± daratumumab (16 mg/kg) until disease progression. The primary endpoint was progression-free survival (PFS).ResultsIn total, 211 patients were randomized to D-Vd (n = 141) or Vd (n = 70). At a 25.1-month median follow-up, D-Vd prolonged PFS versus Vd (median, 14.8 vs. 6.3 months; hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.24-0.51; P < .00001). PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib (HR, 0.36; 95% CI, 0.25-0.53), patients who were refractory to last prior line of therapy (HR, 0.42; 95% CI, 0.27-0.65), and patients with high-risk cytogenetics (HR, 0.41; 95% CI, 0.23-0.71). Overall response rate (84.7% vs.66.7%; P = .00314) and rates of very good partial response or better (71.5% vs. 34.9%; P < .00001) and complete response or better (40.1% vs 14.3%; P = .00016) were higher with D-Vd versus Vd. No new safety concerns were identified.ConclusionsIn this updated analysis, D-Vd maintained significant efficacy benefits versus Vd alone and demonstrated a consistent safety profile, further supporting the use of D-Vd as a standard of care in Chinese patients with RRMM.     

Outcomes of VD-PACE With Immunomodulatory Agent as a Salvage Therapy for Relapsed/Refractory Multiple Myeloma

BackgroundAggressive relapsed/refractory multiple myeloma (RRMM) often requires salvage cytotoxic chemotherapy. We evaluated the efficacy and toxicity of VD-PACE (bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, etoposide) with an immunomodulatory agent (IMiD) in RRMM.Patients and MethodsWe retrospectively reviewed the effectiveness and tolerability among 30 patients with RRMM receiving ≥ 1 cycle of VD-PACE + IMiD between January 2012 to April 2019.ResultsOf 30 patients, 26 (86%) had myeloma double refractory to protease inhibitors and IMiDs, and had received a median of 3 lines prior of therapy. The overall response rate was 67.7%, 13% patients experienced complete remission or better, and 13% experienced very good partial response. Median progression-free and median overall survival were 11 and 26 months, respectively. The most common grade 3 or higher adverse events were hematologic events, which were manageable.ConclusionVD-PACE + IMiD is an effective and tolerable salvage treatment for RRMM, with an impressive response rate in pretreated RRMM.     

Daratumumab,Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Chinese Patients with Relapsed or Refractory Multiple Myeloma: Phase 3 LEPUS (MMY3009) Study

BackgroundDaratumumab plus bortezomib/dexamethasone (D-Vd) significantly improved outcomes versus Vd in patients with relapsed or refractory multiple myeloma (RRMM) in the phase 3 CASTOR study. We report the results of a prespecified interim analysis of the phase 3 LEPUS study of D-Vd versus Vd in Chinese patients with RRMM.Patients and MethodsChinese patients with ≥ 1 prior line of therapy were randomized 2:1 to receive 8 cycles (21 days/cycle) of bortezomib (1.3 mg/m² subcutaneously) and dexamethasone (20 mg orally/intravenously) ± daratumumab (16 mg/kg intravenously). The primary endpoint was progression-free survival (PFS).ResultsA total of 211 patients were randomized (D-Vd, 141; Vd, 70). After an 8.2-month median follow-up, D-Vd significantly prolonged PFS versus Vd (median, not reached vs. 6.3 months; hazard ratio, 0.28; 95% confidence interval, 0.17-0.47; P < .00001) and significantly improved the rates of overall response (83% vs. 65%; P = .00527), ≥ very good partial response (65% vs. 33%; P = .00002), ≥ complete response (33% vs. 11%; P = .00079), and minimal residual disease negativity (10^–5 sensitivity; 22% vs. 3%; P = .0002). The PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib treatment and with high-risk cytogenetics. Thrombocytopenia (D-Vd, 51%; Vd, 37%), lymphopenia (44%; 29%), and lung infection (30%; 22%) were the 3 most common grade 3/4 treatment-emergent adverse events. Although patients in both treatment groups experienced higher rates of grade 3/4 lymphopenia and infections versus patients in CASTOR, the safety profile was generally consistent with that of CASTOR.ConclusionThese data support the use of D-Vd in Chinese patients with RRMM.     

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.     

Hyperfractionated Cyclophosphamide and Dexamethasone Alone or in Combination with Daratumumab and/or Carfilzomib for the Treatment of Relapsed or Refractory Multiple Myeloma: A Single-Center Retrospective Analysis

BackgroundHyperfractionated cyclophosphamide and dexamethasone (HyperCd) alone, or with carfilzomib(K) and/or daratumumab(D), represents a potential treatment option when rapid disease control is needed for patients with aggressive presentations of relapsed/refractory multiple myeloma (RRMM).Patients and MethodsThis is a single-center, retrospective analysis of adult patients with RRMM who received HyperCd with or without K and/or D between May 1, 2016 and August 1, 2019 at the University of Texas MD Anderson Cancer Center. We here report treatment response and safety outcomes.ResultsData from 97 patients, 12 with plasma cell leukemia (PCL), were reviewed in this analysis. Patients had had a median of 5 prior lines of therapy and received a median of 1 consecutive cycle of hyperCd-based therapy. The overall response rate (ORR) of all patients was 71.8% (HyperCd 75%, HyperCdK 64.3%, D-HyperCd 73.3%, and D-HyperCdK 76.9%). Median progression-free survival and overall survival among all patients was 4.3 months (HyperCd 3.1 months, HyperCdK 4.5 months, D-HyperCd 3.3 months, and D-HyperCdK 6 months) and 9.0 months (HyperCd 7.4 months, HyperCdK 9.0 months, D-HyperCd 7.5 months, and D-HyperCdK 15.2 months), respectively. Grade 3/4 hematologic toxicities were common, thrombocytopenia being the most frequent at 76%. Notably, 29-41% of patients per treatment group had existing grade 3/4 cytopenias at initiation of hyperCd-based therapy.ConclusionHyperCd-based regimens provided rapid disease control among MM patients, even when heavily pre-treated and with few remaining treatment options. Grade 3/4 hematologic toxicities were frequent, but manageable with aggressive supportive care.     

KarMMa-RW: comparison of idecabtagene vicleucel with real-world outcomes in relapsed and refractory multiple myeloma

Patients with relapsed and refractory multiple myeloma (RRMM) who are triple-class exposed (to an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody) have limited treatment options and there is no standard of care. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T-cell therapy, demonstrated efficacy in triple-class exposed RRMM patients in the KarMMa trial ({"type":"clinical-trial","attrs":{"text":"NCT03361748","term_id":"NCT03361748"}}NCT03361748). In this retrospective study (KarMMa-RW), patient-level data from triple-class exposed RRMM patients were merged into a single data model and compared with KarMMa using trimmed stabilized inverse probability of treatment weighting. Endpoints included overall response rate (ORR; primary), rate of very good partial response or better (≥VGPR), progression-free survival (PFS), and overall survival (OS). Of 1949 real-world triple-class exposed RRMM patients, 190 received subsequent (index) line of therapy and met KarMMa eligibility criteria (Eligible RRMM cohort). With a median follow-up of 13.3 months in KarMMa and 10.2 months in Eligible RRMM, ORR, and ≥VGPR were significantly improved in KarMMa versus Eligible RRMM (ORR, 76.4% vs 32.2%; ≥VGPR, 57.9% vs 13.7%; both P < 0.0001) as were PFS (11.6 vs 3.5 months; P = 0.0004) and OS (20.2 vs 14.7 months; P = 0.0006). This study demonstrated that ide-cel significantly improved responses and survival compared with currently available therapies in triple-class exposed RRMM.Subject terms: Cancer, Medical research     

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.     

Generic Lenalidomide Rivelime Versus Brand-name Revlimid® in the Treatment of Relapsed/Refractory Multiple Myeloma: A Retrospective Single-center Experience on Efficacy,Safety and Survival Outcome

BackgroundThis study aimed to compare use of original brand-name lenalidomide (Revlimid®) vs. generic equivalent (Rivelime®) in terms of efficacy, safety and survival outcome in patients with relapsed/refractory multiple myeloma (RRMM)Patients and MethodsA total of 184 patients RRMM (median age: 62 years, 60.9% were males) who received singlet, doublet or triplet lenalidomide-containing regimens including either Revlimid® (n=74) or Rivelime® (n=110) were included in this study. Treatment response was based on evaluation of objective response to treatment (ORR) including the sum of patients who achieved partial response (PR), very good partial responses (VGPR) or complete response (CR) to therapy. Progression-free survival (PFS), overall survival (OS) and safety data were also recorded.ResultsRevlimid® and Rivelime® groups were similar in terms of ORR (54.1 vs. 60.0%), CR (22.5 vs. 28.8%), VGPR (55.0 vs. 50.0%) and PR (22.5 vs. 21.2%) rates. Median (SE) PFS time were similar between Rivelime® vs. Revlimid® treated patients who were in the 2^nd line (30.3(3.8) vs. 22.7(7.0) months, p=0.827) or 3^rd line of therapy (38.1(12.1) vs. 20.1(0.9) months, p=0.147) at lenalidomide initiation. Two groups also had similar OS rate (83.8 vs. 73.6%) and OS time (mean 122.3 vs. 123.5 months). Side effects were manageable in both groups.ConclusionIn conclusion, replacing Revlimid® with its generic version Rivelime® in singlet, doublet or triplet lenalidomide containing RRMM regimens seems not to compromise the efficacy of treatment, and to yield a similarly improved response rates and survival outcome and no additional toxic effects, enabling a long-term therapy.     

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.     

Comparative Efficacy of Teclistamab Versus Physician's Choice of Therapy in the Long-term Follow-up of APOLLO,POLLUX, CASTOR,and EQUULEUS Clinical Trials in Patients With Triple-class Exposed Relapsed or Refractory Multiple Myeloma

BackgroundThe efficacy and safety of teclistamab in patients with RRMM who received ≥3 prior lines of therapy and were triple-class exposed (TCE) are being evaluated in the single-arm, multicohort, phase I/II MajesTEC-1 trial (NCT04557098). We evaluated the comparative effectiveness of teclistamab versus physician's choice (PC) of therapy in TCE RRMM patients.MethodsIndividual patient-level data from MajesTEC-1 patients who received teclistamab (1.5 mg/kg weekly; clinical cutoff March 16, 2022) were included. An external control arm was created from patients in long-term follow-up of 4 clinical trials of daratumumab who were treated with PC therapy after discontinuation of trial treatments. In the primary analysis, inverse probability of treatment weighting was used to adjust for imbalances in 9 baseline covariates. A fully adjusted model included 5 additional prognostic factors. Outcomes included overall response rate (ORR), very good partial response or better (≥VGPR) rate, overall survival (OS), progression-free survival (PFS), and time to next treatment (TTNT).ResultsAfter adjustment, baseline characteristics were balanced between cohorts. In the primary analysis, outcomes were significantly improved with teclistamab versus PC: ORR (OR [95% CI] 4.81 [3.04-7.72]; P < .0001); ≥VGPR rate (OR, 12.07 [6.91-22.11]; P < .0001); OS (HR, 0.54 [0.40-0.73]; P < .0001); PFS (HR, 0.59 [0.46-0.78]; P = .0001); and TTNT (HR, 0.32 [0.24-0.42]; P < .0001). Results of the fully adjusted model were consistent with the primary analysis.ConclusionTeclistamab showed significantly improved effectiveness versus PC on all outcomes, highlighting its clinical benefit in patients with TCE RRMM and limited treatment options.     

A Phase II,Single-arm Trial of Sunitinib and Erlotinib in Advanced Renal Cell Carcinoma

BackgroundOverexpression of the epidermal growth factor receptor (EGFR) and its ligands occur frequently in renal cell carcinoma (RCC). Combined vascular endothelial growth factor receptor (VEGF-R) and EGFR inhibition may overcome resistance to VEGF-R inhibitor monotherapy. We performed a dose-escalation phase II study of sunitinib plus erlotinib in advanced renal cell carcinoma.Patients and MethodsPatients with metastatic clear cell or papillary RCC were eligible. Prior therapy was allowed except sunitinib or erlotinib. Three dose levels of erlotinib (50, 100, 150 mg daily) were evaluated in combination with sunitinib 50 mg. Thirty-seven patients were treated at maximum tolerated dose to determine efficacy. The primary endpoint was 8-month progression-free survival (PFS) rate. The trial was powered to assess for a difference between a median PFS of less than 50% with a targeted 70% PFS for the combination.ResultsThe 8-month PFS rate was 40% (95% CI: 23-56). Median PFS was 5.8 months (95% CI: 4.1-9.7) and median overall survival (OS) was 26.3 months (95% CI: 16.1-34.0). The objective response rate was 22% and an additional 59% of patients had stable disease for at least 6 weeks. The most common adverse events for all grades were diarrhea, rash, fatigue, and dysgeusia. Dose reduction in 1 or both of the drugs was undertaken in 17 (46%) patients, while 5 (14%) discontinued study therapy due to toxicity.ConclusionWhile sunitinib and erlotinib are combinable,the 8-month PFS rate did not suggest efficacy improvement over sunitinib monotherapy (NCT00425386).     

Safety Analysis of Five Randomized Controlled Studies of Daratumumab in Patients With Multiple Myeloma

BackgroundMultiple studies have demonstrated the efficacy and safety of daratumumab for relapsed/refractory multiple myeloma (MM) and primary treatment for transplant-eligible and -ineligible patients.Materials and MethodsWe conducted an integrated safety analysis to characterize the frequency, severity, natural history, and outcomes of adverse events (AEs) with daratumumab versus comparators. Data were pooled from 5 completed phase III randomized controlled studies that had included 1798 daratumumab-treated and 1797 comparator-treated patients with MM as a first line in both transplant-eligible and transplant-ineligible patients and for relapsed/refractory disease. Safety analyses included reporting of AEs using crude and exposure-adjusted incidence rates.ResultsThe median follow-up duration was 16.84 months (range, 7.4-28 months) for both daratumumab-treated and comparator-treated patients. Discontinuation for any reason occurred less often with daratumumab (22% vs. 33.9%), although discontinuation because of AEs occurred at similar rates (25% vs. 26%) as did deaths owing to AEs (2.25% vs. 1.84%). When adjusted for exposure, neutropenia, lymphopenia, diarrhea, fatigue, dyspnea, pneumonia, and hypertension were the only common grade 3/4 AEs reported more often with daratumumab than with the comparators. The prevalence of common grade 3/4 AEs with daratumumab were < 7% apart from neutropenia, lymphopenia, and pneumonia (45.9% vs. 32.3%, 13% vs. 7.5%, and 10.6% vs. 7.2%, respectively). Grade 3/4 daratumumab infusion-related reactions happened in 3.8% of patients. The majority of infusion-related reactions occurred after the first infusion.ConclusionsThese results from an integrated analysis support a favorable benefit/risk profile of daratumumab in patients with MM.     

含脂质体阿霉素方案治疗复发难治性多发性骨髓瘤伴继发髓外病变患者的临床研究

  目的  探讨复发/难治性多发性骨髓瘤（relapsed/refractory multiple myeloma,RRMM）患者伴继发髓外病变（secondary extramedullary disease,sEMD）后应用脂质体阿霉素（liposomal doxorubicin,LPD）治疗的疗效、无进展生存期（progression-free survival,PFS）与安全性,以及RRMM患者出现sEMD的总生存期（overall survival,OS）及预后因素。  方法  回顾性分析2015年1月至2020年1月就诊于首都医科大学附属北京朝阳医院西院的40例RRMM伴sEMD、接受LPD治疗患者的临床资料。记录患者初诊基线特征,继发sEMD的临床表现。观察其应用LPD的疗效、不良反应与PFS;并根据sEMD临床特点对其进行亚组分析,多因素分析得出sEMD-OS预后因素。  结果  多因素分析显示国际分期系统（international stage system,ISS）Ⅲ期为继发EMD的危险因素。所有患者完成中位5（3～9）个疗程的LPD治疗,2个疗程总体反应率（overall response rate,ORR）为60.0%,13例完成6个疗程及以上化疗,ORR为100%;3级以上不良反应率为5%;预计中位PFS（median PFS,mPFS）为8.0个月（95%CI:7.5～8.5）,界标分析示LPD≥6个疗程组相比于<6个疗程组PFS延长（P=0.093）。预计sEMD中位OS（median OS,mOS）为22.0个月（95%CI:18.2～25.8）,1年OS率为73.6%,2年OS率为38.2%。多因素回归分析显示,非骨旁sEMD与乳酸脱氢酶（lactate dehydrogenase,LDH）>250 U/L为sEMD-OS的独立预后因素。  结论  含LPD方案治疗RRMM继发EMD短期疗效好,安全性高。非骨旁sEMD及LDH>250 U/L预后不良,此类患者需寻求其他治疗策略。