The updated results of the POLLUX trial, reported in the Journal of Clinical Oncology by Dimopoulos and colleagues and in this issue of The ASCO Post, showed significantly improved overall survival with daratumumab plus lenalidomide/dexamethasone (DRd) vs Rd in patients with previously treated multiple myeloma.1 The findings, taken along with those of the CASTOR trial and several other phase III trials in the setting of patients with relapsed myeloma with one to three lines of therapy, highlight the dramatic transformation of the treatment landscape in myeloma that has occurred in the past decade. The trial results confirmed the improvement in overall survival, as had been expected, and delivered several important messages.
First and foremost, the trial joins the rank of several other trials that have now demonstrated improved overall survival with a triplet vs a doublet in the setting of relapsed myeloma, highlighting the importance of using a triplet in the treatment of relapsed disease, as is the case in newly diagnosed myeloma.2-4 This important principle of using at least two drug classes with differing mechanisms of action has clearly paid dividends and is likely the singular most important change in our treatment approach that has led to the improved survival in this disease.
Shaji Kumar, MD
This is consistent with the approach in oncology in general, where development of resistance among the heterogeneous tumor clones can be delayed by use of combinations rather than single drugs. This is particularly relevant in a genetically heterogeneous disease like myeloma, where clonal tiding based on the selection pressure from the ongoing treatment has been clearly demonstrated.5
Since patients in the Rd control arm in POLLUX were allowed to receive daratumumab monotherapy at relapse, nearly 28% did get treated with daratumumab monotherapy and had a median overall survival that did not quite reach that of the DRd arm. More important, despite the fact that 58% of patients in the Rd arm received daratumumab alone or in combinations as subsequent therapy, DRd maintained the superior overall survival advantage. This once again highlights the importance of using the effective drugs in combination at each step of myeloma treatment and not saving them for later lines of therapy.
Another important finding, highlighting the progress in the field, is the impressive 78-month overall survival among patients with one prior line of therapy, which added to an average of 36 months seen with the regimens used in this era would suggest an overall survival from diagnosis of nearly 10 years—consistent with some of the recent figures from the Surveillance, Epidemiology, and End Results (SEER) registry and single-institution studies.6 However, the relatively huge dropoff (~2 years) in survival as we go from one prior line of therapy to two and three lines highlights the challenge we face in curing this malignancy, including the likely impact of clonal evolution and acquisition of resistance to therapies.
Benefit of Anti-CD38 Antibodies
From a drug-specific standpoint, results seen with daratumumab in different combinations and in different disease settings highlight the benefit that anti-CD38 antibodies bring to bear in this disease. Even though CD38 expression on plasma cells had been known for a long time, it took another decade or more after rituximab was introduced in lymphoma for an effective monoclonal antibody to be available for treatment of myeloma, heralding the era of immunotherapy in this disease.
In particular, the improved progression-free and overall survival seen in POLLUX and CASTOR underscore the ability of monoclonal antibodies to integrate with all classes of existing myeloma therapies. The long-term results with DRd in relapsed disease is consistent with the survival advantage seen with this regimen in the newly diagnosed setting, as shown in the MAIA trial—albeit in an older patient population.7 Recent updates from the MAIA trial clearly demonstrated an improvement in overall survival in older patients with newly diagnosed myeloma compared with Rd, with survival likely exceeding 7 years, a previously unachievable goal in this older population.
The POLLUX findings...highlight the dramatic transformation of the treatment landscape in myeloma that has occurred in the past decade.— Shaji Kumar, MD
Tweet this quote
Given the increasing adoption of the DRd regimen in the newly diagnosed setting based on the results of the MAIA trial, and the nearly universal acceptance of lenalidomide maintenance in first-line therapy, it is unclear how much this regimen will be used in the future in the relapsed setting. For those patients not exposed to daratumumab, but exposed to or refractory to lenalidomide, other combinations of daratumumab or isatuximab with pomalidomide or carfilzomib will play a major role.8-11 For those who have already received daratumumab, often until disease progression, in the first-line setting, it remains unclear whether the drug will have a major role as a retreatment strategy.
The Toxicity Cost of Care
Looking at the adverse-event profile in POLLUX, it is clear these improvements come at a cost. Although the regimen was well tolerated in the long term, the ever-present signal of infection should be kept in mind. Prolonged use of anti-CD38 antibodies may lead to profound hypogammaglobulinemia, often exacerbating that caused by the disease itself. This is unlikely the sole cause for the increased risk of infections, but intravenous immunoglobulin replacement strategies in select patients consistent with current guidelines should be an important component of supportive care. It is certainly comforting to see there are no concerning signals of increased risk of second malignancies, once the prolonged survival is factored in.12 What is unclear from the current report, as is common in phase III trial reports, is the impact of low-grade chronic toxicities. These side effects should be an integral part of clinical trials when one considers treatment approaches to disease progression.13
Duration of Treatment
Another important aspect of myeloma treatment strategy that was not explored in the current trial is the ideal duration of treatment.14 As with the trials that preceded this one, there have been few (if any) that explored a defined duration of treatment. With the increasing efficacy of the current combinations and the deep responses achieved, the time is ripe for us to explore a defined duration or response-adapted duration of these treatment strategies.
The important principle of using at least two drug classes with differing mechanisms of action has clearly paid dividends...— Shaji Kumar, MD
Tweet this quote
DISCLOSURE: Dr. Kumar reported financial relationships with Oncopeptides, MedImmune/AstraZeneca, Adaptive, Takeda, Janssen, Celgene, and AbbVie.
REFERENCES
1. Dimopoulos MA, Oriol A, Nahi H, et al: Overall survival with daratumumab, lenalidomide, and dexamethasone in previously treated multiple myeloma (POLLUX): A randomized, open-label, phase III trial. J Clin Oncol 41:1590-1599, 2023.
2. Sonneveld P, Chanan-Khan A, Weisel K, et al: Overall survival with daratumumab, bortezomib, and dexamethasone in previously treated multiple myeloma (CASTOR): A randomized, open-label, phase III trial. J Clin Oncol 41:1600-1609, 2023.
3. Siegel DS, Dimopoulos MA, Ludwig H, et al: Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol 36:728-734, 2018.
4. Dimopoulos MA, Lonial S, White D, et al: Elotuzumab, lenalidomide, and dexamethasone in RRMM: Final overall survival results from the phase 3 randomized ELOQUENT-2 study. Blood Cancer J 10:91, 2020.
5. Keats JJ, Chesi M, Egan JB, et al: Clonal competition with alternating dominance in multiple myeloma. Blood 120:1067-1076, 2012.
6. Binder M, Nandakumar B, Rajkumar SV, et al: Mortality trends in multiple myeloma after the introduction of novel therapies in the United States. Leukemia 36:801-808, 2022.
7. Facon T, Kumar SK, Plesner T, et al: Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): Overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol 22:1582-1596, 2021.
8. Attal M, Richardson PG, Rajkumar SV, et al: Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): A randomised, multicentre, open-label, phase 3 study. Lancet 394:2096-2107, 2019.
9. Moreau P, Dimopoulos MA, Mikhael J, et al: Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): A multicentre, open-label, randomised phase 3 trial. Lancet 397:2361-2371, 2021.
10. Dimopoulos MA, Terpos E, Boccadoro M, et al: Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): An open-label, randomised, phase 3 trial. Lancet Oncol 22:801-812, 2021.
11. Dimopoulos M, Quach H, Mateos MV, et al: Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): Results from a randomised, multicentre, open-label, phase 3 study. Lancet 396:186-197, 2020.
12. Raje NS, Anaissie E, Kumar SK, et al: Consensus guidelines and recommendations for infection prevention in multiple myeloma: A report from the International Myeloma Working Group. Lancet Haematol 9:e143-e161, 2022.
13. Thanarajasingam G, Minasian LM, Bhatnagar V, et al: Reaching beyond maximum grade: Progress and future directions for modernising the assessment and reporting of adverse events in haematological malignancies. Lancet Haematol 9:e374-e384, 2022.
14. Moreau P, Hulin C, Perrot A, et al: Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): An open-label, randomised, phase 3 trial. Lancet Oncol 22:1378-1390, 2021.
