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Pomalidomide + Vd for RRMM: Latest updates on the OPTIMISMM trial

Jul 27, 2020

There is an unmet need for therapy options without lenalidomide (len) for patients progressing under len-based treatment. Despite being a member of the same drug-class (immunomodulators or IMiDs®), pomalidomide has previously demonstrated its efficacy in patients relapsed from len-containing regimens, especially when combined with other anti-myeloma agents.

The phase III OPTIMISMM trial ( NCT01734928 )investigated the use of the triplet pomalidomide (P), bortezomib (V), and dexamethasone (d) against Vd in patients with relapsed/refractory multiple myeloma (RRMM) previously exposed to len. The interim resultswere reported on the Multiple Myeloma Hub in May 2019. Since then, the OPTIMISMM trial results have been updated and analyzed according to patient subgroups of special interest. In this article, we review the latest subanalyses published and presented at the 25th European Hematology Association (EHA) Virtual Annual Congress.

Subanalysis according to age, previous stem cell transplant (SCT), and presence of high-risk cytogenetic abnormalities 1

Meletios Dimopoulos, National and Kapodistrian University of Athens, GR, presented a poster at this year’s 25th EHA Virtual Congress regarding assessment of the OPTIMISMM trial efficacy and safety data with respect to important baseline characteristics. 1

The results of this subanalysis showed that PVd significantly improved progression-free survival (PFS) and overall response rate (ORR) compared with Vd regardless of age, prior SCT, and high-risk cytogenetics. The reduction in risk of death or disease progression achieved with PVd was smaller in older patients and in those who did not undergo a prior SCT, as shown in Table 1.

Table 1.The effect of different variables on PFS in patients treated with PVd vsVd 1

CI, confidence interval; d, dexamethasone; HR, Hazard ratio; P, pomalidomide; PFS, progression-free survival; SCT, stem cell transplant; V, bortezomib

Variable

Median PFS, months

HR (95% CI)

p value

PVd

Vd

Age

≤ 65 years

22.0

13.1

0.49 (0.26–0.93)

0.0258

> 65 years

17.6

9.9

0.57(0.34–0.97)

0.0369

Prior SCT

Yes

22.0

13.8

0.48 (0.25–0.92)

0.0241

No

16.5

9.5

0.59 (0.35–0.99)

0.0454

 

PFS was improved for patients with high risk cytogenetics treated with PVd vs. Vd by nearly 5 months; however, the group size was too small to perform statistical comparisons.

The findings of this subanalysis support the continued use of PVd at first relapse in len pretreated patients with multiple myeloma (MM).

 PVd in patients with renal impairment 2

Fredrik Schjesvold, Oslo Myeloma Centre, Oslo, NO, presented a poster at the 25th EHA Virtual Congress on the efficacy and safety of PVd at first relapse according to renal baseline function, as measured by creatinine clearance (CrCl; < 60 vs≥ 60 mL/min). 2

 The ORR was significantly increased with the PVd treatment regardless of renal status compared with Vd, but this efficacy across subgroups did not translate into a clear benefit in survival outcomes. In fact, median PFS improved in both renal groups with the PVd treatment compared with Vd; however, the difference was only significant in the CrCl ≥ 60 mL/min group (p < 0.002). In terms of renal function, the median time to first improvement tended to shorten in the PVd group compared with Vd, in both renal groups.

 The results on the effect of PVd compared with Vd on disease progression and ORR for each renal group are shown in Table 2.

  Table 2.ORR and PFS in patients treated with PVd vsVd 2

CrCl, creatinine clearance; d, dexamethasone; HR, Hazard ratio; P, pomalidomide; PFS, progression-free survival; ORR, overall response rate; V, bortezomib

CrCl (mL/min)

ORR

PVd vsVd (%)

p value

Median PFS, months

HR (95% CI)

p value

PVd

Vd

< 60

91.4 vs53.6

< 0.001

15.1

9.5

0.67 (0.34–1.34)

0.253

≥ 60

89.5 vs55.2

< 0.001

22.0

13.1

0.45 (0.27–0.76)

0.002

 

In terms of safety, there were no new safety issues noted for renally impaired patients, and otherwise the profile was consistent with past reports of P, V, and d.

Overall, this subanalysis showed that PVd is safe and effective for patients with RRMM, including patients with mild to moderate renal insufficiency. Nevertheless, more effective therapy alternatives are needed for patients with MM and heavily compromised renal function at frontline and relapsed settings. Read a recent review published on the Multiple Myeloma Hub about updated outcomes and recommendations for newly diagnosed patients requiring dialysis.

Japanese subset analysis 3

Kazutaka Sunami , National Hospital Organization Okayama Medical Center, Okayama,JP, recently published in Cancer Sciencea subanalysis of 17 Japanese patients who were included in the OPTIMISMM trial. All of them were previously treated with len, and 76% were deemed refractory to len.

After a median follow-up of 14.8 months, the median PFS was 17.6 months for PVd vs4.4 months for Vd. ORR was 100% vs60% for PVd compared with Vd, respectively. Similar to the results reported in the full cohort, the most common Grade 3–4 adverse events (AEs) experienced with PVd by Japanese patients were neutropenia (50%), thrombocytopenia (17%), and infections (42%). None of the patients discontinued the study treatment due to treatment-emergent AEs.

The results of this subanalysis evaluating the triplet PVd combination in Japanese patients are consistent with, or slightly better than, the ones reported in the global OPTIMISMM study population. This confirms the clinical benefit and manageable safety profile of PVd also in Japanese patients with RRMM.

Conclusion

Len is a standard first-line treatment for patients with MM. There is a continued need for efficacious treatment for the growing number of patients who are refractory to len after first relapse. These subanalyses confirm the safety profile and effectiveness of PVd in len pretreated patients with MM, despite presenting baseline characteristics associated with poorer prognosis.

Further resources

The results of the OPTIMISMM trial raise again the question of what is the optimal order of treatment to give the greatest beneficial effect to patients, particularly following first relapse? This has been discussed in our recent article on the Multiple Myeloma Hub about sequencing treatments presented at the 6th World Congress on Controversies in Multiple Myeloma. Go hereto learn more.

  1. Dimopoulos M, Weisel K, Moreau P, et al. OPTIMISMM subanalysis: pomalidomide, bortezomib, dexamethasone after 1 prior line of therapy in relapsed or refractory multiple myeloma by age, prior transplant, and high-risk cytogenetics. Oral Abstract #EP957. 25th EHA Annual Congress; Jun 18, 2020; Virtual.
  2. Schjesvold F, Dimopoulos M, Beksac M, et al. Pomalidomide, bortezomib, dexamethasone after 1 prior line of therapy in patients with relapsed or refractory multiple myeloma and renal impairment: OPTIMISMM subanalysis. Oral Abstract #EP1015. 25th EHA Annual Congress; Jun 18, 2020; Virtual.
  3. Sunami K, Matsue K, Suzuki K, et al. Pomalidomide‐bortezomib‐dexamethasone in relapsed or refractory multiple myeloma: Japanese subset analysis of OPTIMISMM.  Cancer Sci. 2020; 111(6): 2116-2122. DOI: 1111/cas.14415